An ultrasonically responsive compound and its application

Abstract

This application provides an ultrasound-responsive compound and its applications, relating to the field of biomedical technology. The ultrasound-responsive compound provided in this application has the structure of formula (I) or formula (II), its geometric isomers, optical isomers, salts, hydrates, solvates, or polymorphs. Under ultrasound, this ultrasound-responsive compound releases active molecules via hydrolysis of an imine intermediate, achieving spatiotemporally controllable activation and significantly reducing toxicity. The compound has a simple structure, is easy to synthesize, has high safety, and strong universality, and can be extended to the modification of various amine-containing drug molecules. This application provides a robust and controllable drug release pathway for precision medicine, helping to broaden the therapeutic window, increase local drug concentration at lesions, and optimize the balance between efficacy and safety, with broad clinical application prospects. Formula (I); Formula (II).

Description

Technical Field

[0001] This application relates to the field of biomedical technology, and in particular to an ultrasound-responsive compound and its applications. Background Technology

[0002] Ultrasound, as a mechanical wave, possesses excellent tissue penetration, non-invasiveness, and spatiotemporal controllability, and has been widely used in clinical diagnosis, treatment, and controlled drug release, becoming a promising prodrug activation method. Ultrasound can generate cavitation effects by creating and disrupting microbubbles in water, leading to localized high temperatures, high pressures, strong impacts, and microjets. Water molecules can be broken down into highly reactive free radicals, such as hydroxyl and hydrogen radicals, and dissolved oxygen can be converted into superoxide radicals. This unique high-energy environment induced by ultrasonic cavitation provides the possibility for sonochemical reactions, thus laying the foundation for designing ultrasound-responsive prodrugs.

[0003] Currently, common ultrasound response systems mainly rely on the following types of substances: The first type is ultrasound contrast agents, such as gas-filled microbubbles with lipid, protein, or polymer shells. Under ultrasound, these microbubbles undergo periodic oscillations and even cavitation effects, thereby enhancing ultrasound imaging contrast. However, these microbubbles are typically in the micrometer range, making it difficult to penetrate the vascular endothelial spaces of tumor tissue. Furthermore, their short in vivo half-life and poor stability limit their application in treatment. The second type is sonosensitive agents, such as organic molecules like porphyrins and phthalocyanines, and inorganic nanoparticles like titanium dioxide. These can generate reactive oxygen species such as singlet oxygen under ultrasound irradiation, which can be used for sonodynamic therapy. However, traditional organic sonosensitive agents are mostly borrowed from photosensitizers, and generally suffer from residual phototoxicity, poor water solubility, and low ultrasound response efficiency. The biodegradability and long-term safety of inorganic sonosensitive agents still need improvement. The third category consists of polymer and supramolecular assemblies containing unstable chemical bonds (such as disulfide bonds, azo bonds, etc.) or coordination bonds. These assemblies utilize the mechanical force or local thermal effect generated by ultrasound to break the bonds, thereby triggering drug release. However, such systems often require high ultrasound intensity and have limited response sensitivity, easily causing thermal or mechanical damage to normal tissues.

[0004] In summary, existing ultrasound-responsive compounds or materials generally suffer from bottlenecks such as high response thresholds and difficulty in simultaneously achieving in vivo stability and response sensitivity. Therefore, there is an urgent need to develop ultrasound-responsive compounds with novel structures, high efficiency at lower sound intensities, good biocompatibility, and functionalizability to meet the demand for high-performance ultrasound-responsive building blocks in precision medicine and expand their applications in targeted drug delivery, sonodynamic therapy, and ultrasound imaging. Summary of the Invention

[0005] In view of this, this application provides an ultrasound-responsive compound and its application. The ultrasound-responsive prodrug provided in this application has a simple structure, is easy to synthesize, has wide applicability, and can significantly reduce drug toxicity, thus having potential for medical treatment.

[0006] This application provides an ultrasonically responsive compound having a structure of formula (I) or formula (II), its geometric isomers, optical isomers, salts, hydrates, solvates, or polymorphs; Formula (I); Formula (II); In formula (I), R1 is an organic primary amine drug residue after deamination, and R2 is selected from H or a substituent having α-H; In formula (I), R1 and R2 are two residues of an organic secondary amine drug that have been deaminoked; The R3 is selected from substituents having α-H; The To remove hydrogen residues from the ring A of organic secondary amine drugs containing ring A.

[0007] In some specific implementations, the substituent having α-H is selected from substituted or unsubstituted C2~C. 20 Alkyl, substituted or unsubstituted C3~C 20 cycloalkyl, substituted or unsubstituted C2~C 20 Heterocyclic alkyl groups, substituted or unsubstituted C2~C 20 heteroaryl, substituted or unsubstituted C6~C 20 aryl, substituted or unsubstituted C3~C 20 The alkynyl group or substituted or unsubstituted C2~C 20 alkenyl; The substituents are selected from C6~C6. 20 aryl, C1~C 20 The carboxyl group, C1~C 20 ester group, C1~C 20 alkoxy groups, C6~C 20 It contains one or more of the following: aromatic oxygen group, sulfonic acid group, cyano group, nitro group, and halogen.

[0008] In some specific implementations, the substituent having α-H is selected from substituted or unsubstituted C1~C1 groups. 12 Alkyl, substituted or unsubstituted C8~C 16 cycloalkyl, substituted or unsubstituted C2~C 10 Heterocyclic alkyl groups, substituted or unsubstituted C2~C 10 heteroaryl, substituted or unsubstituted C6~C 10aryl, substituted or unsubstituted C3-C8 alkynyl or substituted or unsubstituted C3-C8 alkenyl; The substituents are selected from C6~C6. 12 aryl, C1~C 10 The carboxyl group, C1~C 10 ester group, C1~C 10 alkoxy groups, C6~C 12 It contains one or more of the following: aromatic oxygen group, sulfonic acid group, cyano group, nitro group, and halogen.

[0009] In some specific implementations, the organic primary amine drug is selected from DNA topoisomerase inhibitors, imidazoquinoline Toll-like receptor agonists, immunomodulators, pyrimidine drugs, folic acid antagonists, or anthracycline antibiotics; The organic secondary amine drugs are selected from tyrosine kinase inhibitors, Sting agonists, DNA topoisomerase inhibitors, pyrimidine drugs, purine drugs, or microtubule inhibitors.

[0010] In some specific implementations, the organic primary amine drug is selected from eczemab, amenophenate, ralsimod, imiquimod, pomalidomide, 9-aminoacridine, or methotrexate; The organic secondary amine drug is selected from alectinib, acridinone, belotecone, monomethylolpropionate E, or rucapranib.

[0011] In some specific implementations, the ultrasonically responsive compound has the structure shown in formula (Ⅰ-1); Equation (Ⅰ-1); R2, R3, R5, and R6 are each independently selected from H, substituted or unsubstituted C2~C. 20 Alkyl, substituted or unsubstituted C3~C 20 cycloalkyl, substituted or unsubstituted C2~C 20 Heterocyclic alkyl groups, substituted or unsubstituted C2~C 20 heteroaryl, substituted or unsubstituted C6~C 20 aryl, substituted or unsubstituted C3~C 20 The alkynyl group or substituted or unsubstituted C2~C 20 alkenyl; The substituents are selected from C6~C6. 12 aryl, C1~C 10 The carboxyl group, C1~C 10 ester group, C1~C 10 alkoxy groups, C6~C 12 It contains one or more of the following: aromatic oxygen group, sulfonic acid group, cyano group, nitro group, and halogen.

[0012] In some specific implementations, the ultrasonically responsive compound has the structure shown in formula (I-1a), formula (I-1b), or formula (I-1c); Equation (Ⅰ-1a); Equation (Ⅰ-1b); Equation (Ⅰ-1c); R5 and R6 are each independently selected from H, substituted or unsubstituted C2~C. 20 Alkyl, substituted or unsubstituted C3~C 20 cycloalkyl, substituted or unsubstituted C2~C 20 Heterocyclic alkyl groups, substituted or unsubstituted C2~C 20 heteroaryl, substituted or unsubstituted C6~C 20 aryl, substituted or unsubstituted C3~C 20 The alkynyl group or substituted or unsubstituted C2~C 20 alkenyl; The substituents are selected from C6~C6. 12 aryl, C1~C 10 The carboxyl group, C1~C 10 ester group, C1~C 10 alkoxy groups, C6~C 12 One or more of the following: aromatic oxygen group, sulfonic acid group, cyano group, nitro group, and halogen; The R7 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, cyano, or sulfonic acid group.

[0013] In some specific implementations, the ultrasonically responsive compound has any of the following structures: , , , , , , , , , , , , , , , , , , , , , .

[0014] This application also provides a pharmaceutical composition for ultrasound-activated therapy, comprising the compound described in any one of the above technical solutions, and one or more pharmaceutical carriers or excipients.

[0015] This application also provides the use of the compounds described in any of the above technical solutions in the preparation of medicaments for diagnosing and / or treating diseases or conditions; The disease or condition is selected from tumors, infectious diseases, hematological diseases, metabolic diseases, or inflammation; The tumor is selected from cancer, lymphoma, lymphoid tumor, blastoma, sarcoma, or leukemia; The cancers mentioned are selected from breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, liver cancer, stomach cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, urethral cancer, hepatocellular carcinoma, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, anal cancer, penile cancer, melanoma, multiple myeloma, brain cancer, gallbladder cancer, esophageal cancer, bile duct cancer, head and neck cancer, bladder cancer, thyroid cancer, or nasopharyngeal carcinoma.

[0016] This application provides an ultrasound-responsive compound having the structure of formula (I) or formula (II), its geometric isomers, optical isomers, salts, hydrates, solvates, or polymorphs. This compound can be stably converted into a corresponding imine intermediate in an aqueous environment through ultrasound, and then hydrolyzed to release a therapeutically active drug. This enables controllable activation of the prodrug in both time and space, and significantly reduces the potential toxicity of the prodrug system in non-target regions. By introducing a monovalent substituent containing α-hydrogen onto the nitrogen atom of the organic amine, this application results in a prodrug with outstanding advantages such as simple structure, ease of synthesis, high safety, and wide applicability. It exhibits good chemical stability under physiological conditions, undergoing conversion activation only under specific ultrasound stimulation, effectively avoiding premature drug release in systemic circulation. This allows for further application in the modification of various amine-containing active molecules. It provides a robust and controllable drug release pathway for precision medicine, while its controllable activation characteristics help broaden the therapeutic window and increase local drug concentration at the lesion site, thereby optimizing the balance between efficacy and safety, laying the foundation for the expanded application of related drugs in clinical practice. Attached Figure Description

[0017] Figure 1 High-performance liquid chromatograms of compounds 8 and 10 after sonication. Figure 1 In Figure 'a', the high-performance liquid chromatogram of compound 10 (N-phenylglycine) is shown. Figure 1 b is the high-performance liquid chromatogram of compound 8 (N-methyl-p-hydroxyaniline); Figure 2 The high-performance liquid chromatograms of compounds 14 and 15 after sonication are shown. Figure 2In Figure 'a', the high-performance liquid chromatogram of compound 14 (N-methyl-N-phenylglycine) is shown. Figure 2 b is the high-performance liquid chromatogram of compound 15 (N-carboxymethylpyrrole); Figure 3 The high-performance liquid chromatograms of compounds I-VIII prepared in Examples 3-10 are obtained by ultrasound. Figure 3 In Figure a, the high-performance liquid chromatogram of compound I after ultrasonic reduction is shown. Figure 3 b is the high-performance liquid chromatogram of compound II after ultrasonic reduction. Figure 3 In the middle, c is the high-performance liquid chromatogram of the ultrasonic reduction of compound III. Figure 3 In the figure, d represents the high-performance liquid chromatogram of compound IV after ultrasonic reduction. Figure 3 In the image, 'e' represents the high-performance liquid chromatogram of compound V after ultrasonic reduction. Figure 3 f is the high-performance liquid chromatogram of compound VI after ultrasonic reduction. Figure 3 g is the high-performance liquid chromatogram of compound VII after ultrasonic reduction. Figure 3 h represents the high-performance liquid chromatogram of the ultrasonic reduction of compound VIII; Figure 4 Graph showing changes in the concentration of various cytokines in the blood of healthy mice after drug administration; Figure 5 Flow cytometry results of in vitro ultrasound-activated DC cells using compound I; Figure 6 The experimental protocol roadmap for the tumor suppression experiment; Figure 7 This is a tumor growth curve for mice. Figure 8 This is a graph showing the changes in the mouse's body weight. Detailed Implementation

[0018] It should be understood that the expression “one or more of…” individually includes each of the objects described after the expression, as well as various different combinations of two or more of the described objects, unless otherwise understood from the context and usage. The expression “and / or” combined with three or more described objects should be understood to have the same meaning, unless otherwise understood from the context.

[0019] The terms “including,” “having,” or “containing,” including the use of their grammatical synonyms, should generally be understood as open-ended and non-restrictive, for example, not excluding other unstated elements or steps, unless otherwise specifically stated or understood from the context.

[0020] It should be understood that the order of steps or the sequence of actions is not important as long as this application remains operational. Furthermore, two or more steps or actions may be performed simultaneously.

[0021] The use of any and all instances or exemplary language such as “e.g.” or “including” herein is merely intended to better illustrate the application and does not constitute a limitation on the scope of the application unless the claims are made. No language in this specification should be construed as indicating that any unclaimed element is essential to the practice of this application.

[0022] Furthermore, the numerical ranges and parameters used to define this application are approximate values, and the relevant values ​​in the specific embodiments have been presented as precisely as possible. However, any numerical value inevitably contains standard deviations due to individual test methods. Therefore, unless otherwise explicitly stated, it should be understood that all ranges, quantities, values, and percentages used in this disclosure are modified with the word "approximately." Here, "approximately" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a specific value or range.

[0023] This application provides an ultrasonically responsive compound having a structure of formula (I) or formula (II), its geometric isomers, optical isomers, salts, hydrates, solvates, or polymorphs; Formula (I); Formula (II); In formula (I), R1 is an organic primary amine drug residue after deamination, and R2 is selected from H or a substituent having α-H; In formula (I), R1 and R2 are two residues of an organic secondary amine drug that have been deaminoked; The R3 is selected from substituents having α-H; The To remove hydrogen residues from the ring A of organic secondary amine drugs containing ring A.

[0024] In this application, R1 in formula (I) is an organic primary amine drug residue after deamination, and R2 is selected from H or a substituent having α-H.

[0025] In some specific implementations, the organic primary amine drug is selected from DNA topoisomerase inhibitors, imidazoquinoline Toll-like receptor agonists, immunomodulators, pyrimidine drugs, folic acid antagonists, or anthracycline antibiotics, preferably eczemab, amenophenate, ralsimod, imiquimod, pomalidomide, 9-aminoacridine, or methotrexate. This application does not restrict the source of the organic primary amine drug; it can be purchased through commercial channels. Those skilled in the art will understand that when an organic primary amine drug contains multiple amino groups, any one amino group in the structural formula can be removed.

[0026] Specifically, R1 in this application is selected from amino-containing DNA topoisomerase inhibitors with deamino residues, amino-containing imidazoquinoline Toll-like receptor agonists with deamino residues, amino-containing immunomodulators with deamino residues, amino-containing pyrimidine drugs with deamino residues, amino-containing folic acid antagonists with deamino residues, or amino-containing anthracycline antibiotics with deamino residues.

[0027] In some specific implementations, R1 is a residue of eczetidine, aminophenate, resimilate, imiquimod, pomalidomide, 9-aminoacridine, or methotrexate, preferably a residue of eczetidine, aminophenate, resimilate, pomalidomide, 9-aminoacridine, or methotrexate.

[0028] The R2 is selected from H or a substituent having α-H.

[0029] Specifically, the substituent having α-H is selected from substituted or unsubstituted C2~C. 20 Alkyl, substituted or unsubstituted C3~C 20 cycloalkyl, substituted or unsubstituted C2~C 20 Heterocyclic alkyl groups, substituted or unsubstituted C2~C 20 heteroaryl, substituted or unsubstituted C6~C 20 aryl, substituted or unsubstituted C3~C 20 The alkynyl group or substituted or unsubstituted C2~C 20 Alkenyl; the substituents are selected from C6~C6. 20 aryl, C1~C 20 The carboxyl group, C1~C 20 ester group, C1~C 20 alkoxy groups, C6~C 20 It contains one or more of the following: aromatic oxygen group, sulfonic acid group, cyano group, nitro group, and halogen.

[0030] Preferably, the substituent having α-H is selected from substituted or unsubstituted C2~C groups. 12 Alkyl, substituted or unsubstituted C8~C 16 cycloalkyl, substituted or unsubstituted C2~C 10 Heterocyclic alkyl groups, substituted or unsubstituted C2~C 10 heteroaryl, substituted or unsubstituted C6~C 10 The aryl, substituted or unsubstituted C3-C8 alkynyl, or substituted or unsubstituted C3-C8 alkenyl groups; wherein the substituted substituents are selected from C6-C6.12 aryl, C1~C 10 The carboxyl group, C1~C 10 ester group, C1~C 10 alkoxy groups, C6~C 12 It contains one or more of the following: aromatic oxygen group, sulfonic acid group, cyano group, nitro group, and halogen.

[0031] More preferably, the substituent having α-H is selected from substituted or unsubstituted C2-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C8 heterocycloalkyl, substituted or unsubstituted C2-C8 heteroaryl, substituted or unsubstituted C6-C8 aryl, substituted or unsubstituted C3-C7 alkynyl, or substituted or unsubstituted C3-C7 alkenyl; the substituted substituent is selected from one or more of C6-C8 aryl, C1-C3 carboxyl, C3-C7 ester, C1-C4 alkoxy, C6-C8 aromatic oxy, sulfonic acid, cyano, nitro, and halogen.

[0032] More preferably, the substituent having α-H is selected from -CH2CH3, -CH(CH3)CH3, -CH2C=CH2, -CH2C6H5, -CH2CH2COOH, -CH(COOCH2CH3)COOCH2CH3, -CH2COOH or -CH2COOCH2CH3.

[0033] The aforementioned cycloalkyl groups refer to saturated hydrocarbon groups that contain one or more rings in their molecular structure.

[0034] The aforementioned heterocyclic alkyl group refers to a group in which at least one carbon atom of the cycloalkyl group is replaced by a heteroatom N, O, P, or S. The number of carbon atoms used for cyclization in the heterocyclic alkyl group can be from 1 to 20, specifically 2, 4, 8, or 20, without any particular limitation.

[0035] The aforementioned aryl group refers to any optional functional group or substituent derived from an aromatic hydrocarbon ring, including monocyclic and polycyclic aryl groups. In other words, an aryl group can be a monocyclic aryl group, a fused-ring aryl group, two or more monocyclic aryl groups conjugated by carbon-carbon bonds, monocyclic and fused-ring aryl groups conjugated by carbon-carbon bonds, or two or more fused-ring aryl groups conjugated by carbon-carbon bonds. That is, two or more aromatic groups conjugated by carbon-carbon bonds can also be considered as the aryl group in this application. The aryl group does not contain heteroatoms such as B, N, O, S, or P. The number of carbon atoms in the aryl group can be from 6 to 20, specifically 6, 8, 12, 16, or 20, without any particular limitation.

[0036] The aforementioned heteroaryl group refers to a group in which at least one carbon atom of the aryl group is replaced by a heteroatom N, O, P, S, or Si. The number of carbon atoms in the heteroaryl group can be from 1 to 20, specifically 2, 8, 12, 16, or 20, without any particular limitation.

[0037] For example, the aforementioned substituted aryl group refers to an aryl group in which one or more hydrogen atoms are replaced by other groups. For example, at least one hydrogen atom may be replaced by an aryl, carboxyl, ester, alkoxy, aromatic oxy, sulfonic acid, cyano, nitro, halogen, or other group. It is understood that an aryl group with 20 substituted carbon atoms refers to an aryl group and its substituents having a total of 20 carbon atoms.

[0038] In this application, R1 and R2 in formula (I) are two residues of an organic secondary amine drug after the removal of an imino group. Those skilled in the art will understand that when an organic secondary amine drug contains multiple imino groups, any one imino group in the structural formula can be removed. After the removal of the imino group from the organic secondary amine drug, two residual groups appear, namely R1 and R2, and R1 and R2 are not the same.

[0039] In some specific implementations, the organic secondary amine drug is selected from tyrosine kinase inhibitors, Sting agonists, DNA topoisomerase inhibitors, pyrimidine drugs, purine drugs, or microtubule inhibitors, preferably alectinib, acridinone, belotecone, monomethylolpropionate E, or rucapranib, more preferably monomethylolpropionate E, belotecone, or rucapranib. This application does not restrict the source of the organic secondary amine drug; it can be purchased through commercial channels. Those skilled in the art will understand that when the organic secondary amine drug contains multiple imino groups, any one imino group in the structural formula can be removed.

[0040] Specifically, R1 and R2 in this application are selected from residues of tyrosine kinase inhibitors containing secondary amines that have lost an imino group, residues of Sting agonists containing secondary amines that have lost an imino group, residues of DNA topoisomerase inhibitors containing secondary amines that have lost an imino group, residues of pyrimidine drugs containing secondary amines that have lost an imino group, residues of purine drugs containing secondary amines that have lost an imino group, or residues of tubulin inhibitors containing secondary amines that have lost hydrogen.

[0041] In some specific implementations, R1 and R2 are residues of alectinib (without imino), acridinone (without imino), belotecone (without imino), monomethyl olritatin E (without imino), or rucapanib (without imino).

[0042] In this application, R3 is selected from substituents having α-H.

[0043] In some specific implementations, the substituent having α-H is selected from substituted or unsubstituted C2~C. 20 Alkyl, substituted or unsubstituted C3~C 20 cycloalkyl, substituted or unsubstituted C2~C 20 Heterocyclic alkyl groups, substituted or unsubstituted C2~C 20 heteroaryl, substituted or unsubstituted C6~C 20 aryl, substituted or unsubstituted C3~C 20 The alkynyl group or substituted or unsubstituted C2~C 20 Alkenyl; the substituents are selected from C6~C6. 20 aryl, C1~C 20 The carboxyl group, C1~C 20 ester group, C1~C 20 alkoxy groups, C6~C 20 It contains one or more of the following: aromatic oxygen group, sulfonic acid group, cyano group, nitro group, and halogen.

[0044] Preferably, the substituent having α-H is selected from substituted or unsubstituted C2~C groups. 12 Alkyl, substituted or unsubstituted C8~C 16 cycloalkyl, substituted or unsubstituted C2~C 10 Heterocyclic alkyl groups, substituted or unsubstituted C2~C 10 heteroaryl, substituted or unsubstituted C6~C 10 The aryl, substituted or unsubstituted C3-C8 alkynyl, or substituted or unsubstituted C3-C8 alkenyl groups; wherein the substituted substituents are selected from C6-C6. 12 aryl, C1~C 10 The carboxyl group, C1~C 10 ester group, C1~C 10 alkoxy groups, C6~C 12 It contains one or more of the following: aromatic oxygen group, sulfonic acid group, cyano group, nitro group, and halogen.

[0045] More preferably, the substituent having α-H is selected from substituted or unsubstituted C2-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C8 heterocycloalkyl, substituted or unsubstituted C2-C8 heteroaryl, substituted or unsubstituted C6-C8 aryl, substituted or unsubstituted C3-C7 alkynyl, or substituted or unsubstituted C3-C7 alkenyl; the substituted substituent is selected from one or more of C6-C8 aryl, C1-C3 carboxyl, C3-C7 ester, C1-C4 alkoxy, C6-C8 aromatic oxy, sulfonic acid, cyano, nitro, and halogen.

[0046] More preferably, the substituent having α-H is selected from -CH2CH3, -CH(CH3)CH3, -CH2C=CH2, -CH2C6H5, -CH2CH2COOH, -CH(COOCH2CH3)COOCH2CH3, -CH2COOH or -CH2COOCH2CH3.

[0047] In this application, the stated To remove hydrogen residues from the ring A of organic secondary amine drugs containing ring A, in this application, " "" indicates the connection position. Those skilled in the art will understand that when an organic secondary amine drug contains multiple ring A, the hydrogen on any one of the ring A in the structural formula is removed.

[0048] In some specific implementations, the organic secondary amine drug containing ring A is selected from tyrosine kinase inhibitors, Sting agonists, DNA topoisomerase inhibitors, pyrimidine drugs, purine drugs, or microtubule inhibitors, preferably alectinib or acridinone. This application does not restrict the source of the organic secondary amine drug; it can be purchased through commercial channels.

[0049] Specifically, the organic secondary amine drug containing ring A described in this application is selected from the dehydrogenated residues of tyrosine kinase inhibitors containing secondary amines, the dehydrogenated residues of Sting agonists containing secondary amines, the dehydrogenated residues of DNA topoisomerase inhibitors containing secondary amines, the dehydrogenated residues of pyrimidine drugs containing secondary amines, the dehydrogenated residues of purine drugs containing secondary amines, or the dehydrogenated residues of tubulin inhibitors containing secondary amines.

[0050] In some specific implementations, the organic secondary amine drug containing ring A is selected from the dehydrogenated residues of alectinib or the dehydrogenated residues of acridinone.

[0051] In this application, the ultrasonically responsive compound has the structure shown in formula (I-1); Equation (Ⅰ-1); R2, R3, R5, and R6 are each independently selected from H, substituted or unsubstituted C2~C. 20 Alkyl, substituted or unsubstituted C3~C 20 cycloalkyl, substituted or unsubstituted C2~C 20 Heterocyclic alkyl groups, substituted or unsubstituted C2~C 20 heteroaryl, substituted or unsubstituted C6~C 20 aryl, substituted or unsubstituted C3~C 20 The alkynyl group or substituted or unsubstituted C2~C 20 Alkenyl; the substituents are selected from C6~C6. 12aryl, C1~C 10 The carboxyl group, C1~C 10 ester group, C1~C 10 alkoxy groups, C6~C 12 It contains one or more of the following: aromatic oxygen group, sulfonic acid group, cyano group, nitro group, and halogen.

[0052] Preferably, R2, R3, R5, and R6 are each independently selected from H, substituted or unsubstituted C2~C. 12 Alkyl, substituted or unsubstituted C8~C 16 cycloalkyl, substituted or unsubstituted C2~C 10 Heterocyclic alkyl groups, substituted or unsubstituted C2~C 10 heteroaryl, substituted or unsubstituted C6~C 10 The aryl, substituted or unsubstituted C3-C8 alkynyl, or substituted or unsubstituted C3-C8 alkenyl groups; wherein the substituted substituents are selected from C6-C6. 12 aryl, C1~C 10 The carboxyl group, C1~C 10 ester group, C1~C 10 alkoxy groups, C6~C 12 It contains one or more of the following: aromatic oxygen group, sulfonic acid group, cyano group, nitro group, and halogen.

[0053] More preferably, R2, R3, R5 and R6 are each independently selected from H, substituted or unsubstituted C2-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C8 heterocycloalkyl, substituted or unsubstituted C2-C8 heteroaryl, substituted or unsubstituted C6-C8 aryl, substituted or unsubstituted C3-C7 alkynyl or substituted or unsubstituted C3-C7 alkenyl; the substituted substituents are selected from one or more of C6-C8 aryl, C1-C3 carboxyl, C3-C7 ester, C1-C4 alkoxy, C6-C8 aromatic oxy, sulfonic acid, cyano, nitro and halogen.

[0054] More preferably, R2, R3, R5 and R6 are each independently selected from H, -CH2CH3, -CH(CH3)CH3, -CH2C=CH2, -CH2C6H5, -CH2CH2COOH, -CH(COOCH2CH3)COOCH2CH3, -CH2COOH or -CH2COOCH2CH3.

[0055] In some specific implementations, the compound has the structure shown in formula (I-1a), formula (I-1b), or formula (I-1c); Equation (Ⅰ-1a); Equation (Ⅰ-1b); Equation (Ⅰ-1c); R5 and R6 are each independently selected from H, substituted or unsubstituted C1~C. 20 Alkyl, substituted or unsubstituted C3~C 20 cycloalkyl, substituted or unsubstituted C2~C 20 Heterocyclic alkyl groups, substituted or unsubstituted C2~C 20 heteroaryl, substituted or unsubstituted C6~C 20 aryl, substituted or unsubstituted C3~C 20 The alkynyl group or substituted or unsubstituted C2~C 20 Alkenyl; the substituents are selected from C6~C6. 12 aryl, C1~C 10 The carboxyl group, C1~C 10 ester group, C1~C 10 alkoxy groups, C6~C 12 One or more of the following: aromatic oxygen group, sulfonic acid group, cyano group, nitro group, and halogen; Preferably, R5 and R6 are each independently selected from H, substituted or unsubstituted C2~C. 12 Alkyl, substituted or unsubstituted C8~C 16 cycloalkyl, substituted or unsubstituted C2~C 10 Heterocyclic alkyl groups, substituted or unsubstituted C2~C 10 heteroaryl, substituted or unsubstituted C6~C 10 The aryl, substituted or unsubstituted C3-C8 alkynyl, or substituted or unsubstituted C3-C8 alkenyl groups; wherein the substituted substituents are selected from C6-C6. 12 aryl, C1~C 10 The carboxyl group, C1~C 10 ester group, C1~C 10 alkoxy groups, C6~C 12 It contains one or more of the following: aromatic oxygen group, sulfonic acid group, cyano group, nitro group, and halogen.

[0056] More preferably, R5 and R6 are each independently selected from H, substituted or unsubstituted C2-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C8 heterocycloalkyl, substituted or unsubstituted C2-C8 heteroaryl, substituted or unsubstituted C6-C8 aryl, substituted or unsubstituted C3-C7 alkynyl, or substituted or unsubstituted C3-C7 alkenyl; the substituent is selected from one or more of C6-C8 aryl, C1-C3 carboxyl, C3-C7 ester, C1-C4 alkoxy, C6-C8 aromatic oxy, sulfonic acid, cyano, nitro, and halogen.

[0057] Wherein, R7 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, cyano or sulfonic acid group.

[0058] Preferably, R7 is selected from H, substituted or unsubstituted C1-C4 alkyl, C1-C4 alkoxy or cyano groups.

[0059] In this application, the ultrasonically responsive compound has any of the following structures: , , , , , , , , , , , , , , , , , , , , , .

[0060] The ultrasonic-responsive compound provided in this application can be stably converted into the corresponding imine intermediate through ultrasonic action in an aqueous environment, and then hydrolyzed to release a drug with therapeutic activity. This enables controllable activation of the prodrug in time and space, and significantly reduces the potential toxicity of the prodrug system in non-target areas.

[0061] This application also provides a method for preparing an ultrasonically responsive compound, comprising: Organic amine drugs react with aldehydes / ketones and borohydrides to yield ultrasonically responsive compounds; Alternatively, organic amine drugs can react with organic halides to yield ultrasonically responsive compounds.

[0062] Furthermore, this application does not impose any restrictions on the preparation method of the ultrasonically responsive compound, as long as it is known to those skilled in the art.

[0063] This application uses organic amine drugs, aldehydes or ketones, and borohydrides to first undergo a dehydration condensation reaction, followed by a reductive amination reaction, to obtain an ultrasonically responsive compound.

[0064] Specifically, an organic amine drug is dissolved in an organic solvent, and an aldehyde / ketone organic solvent is added to perform a dehydration condensation reaction to obtain an intermediate product. This application does not restrict the source of the organic amine drug, aldehyde / ketone, and organic solvent; they can be purchased through commercial channels. In some specific implementations, the organic amine drug is selected from amino-containing DNA topoisomerase inhibitors, amino-containing imidazoquinoline Toll-like receptor agonists, amino-containing immunomodulators, amino-containing pyrimidine drugs, amino-containing folic acid antagonists, or amino-containing anthracycline antibiotics, preferably eczemab, amphenafletin, ralsimod, imiquimod, pomalidomide, or methotrexate or 9-aminoacridine, more preferably eczemab, amphenafletin, ralsimod, pomalidomide, or 9-aminoacridine. In some specific implementations, the aldehyde is one or more selected from glyoxylic acid monohydrate, acetaldehyde, benzaldehyde, ethyl acetate, and tert-butyl acetate, preferably acetaldehyde, ethyl acetate, and tert-butyl acetate, and more preferably glyoxylic acid monohydrate. In some specific implementations, the ketone is one or more selected from acetone, butanone, 2-pentanone, 3-pentanone, cyclohexanone, acetophenone, methyl isobutyl ketone, and diisobutyl ketone, preferably acetone, butanone, and 2-pentanone, and more preferably acetone and butanone. In some specific implementations, the organic solvent is one or more selected from N,N-dimethylformamide, methanol, ethanol, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, dimethyl sulfoxide, ethyl acetate, diethyl ether, methyl tert-butyl ether, petroleum ether, n-butane, acetonitrile, and toluene, preferably anhydrous N,N-dimethylformamide, ethanol, dichloromethane, tetrahydrofuran, ethyl acetate, diethyl ether, acetonitrile, or toluene, and more preferably anhydrous N,N-dimethylformamide.

[0065] In some specific implementations, the molar ratio of the organic amine drug to the aldehyde / ketone is (0.01~5):1, preferably (0.1~3):1, and more preferably (0.4~2):1. In some specific implementations, a dehydration condensation reaction preferably involves the addition of a dehydrating agent to remove the water generated in the reaction; the dehydrating agent includes, but is not limited to, molecular sieves. In some specific implementations, the temperature of the dehydration condensation reaction is 10℃~80℃, preferably 20℃~60℃, and more preferably 30℃~50℃. In some specific implementations, the time of the dehydration condensation reaction is 1 h~72 h, preferably 1 h~36 h, and more preferably 2 h.

[0066] After obtaining the intermediate product, borohydride was added to the system after the dehydration condensation reaction to carry out a reducing amination reaction. After the reaction was completed, impurities were removed to obtain the ultrasonically responsive compound.

[0067] In some specific implementations, the borohydride is one or more of sodium triacetoxyborohydride, sodium borohydride, and sodium cyanoborohydride, preferably sodium triacetoxyborohydride. In some specific implementations, the reductive amination reaction is preferably carried out under anhydrous and oxygen-free conditions. In some specific implementations, the reductive amination reaction time is 12 h to 84 h, preferably 26 h to 72 h, more preferably 24 h to 48 h. In some specific implementations, the method for removing impurities is preferably liquid chromatography or recrystallization. This application does not have any special limitations on the method for removing impurities; any method well known to those skilled in the art is acceptable.

[0068] This application uses organic amine drugs and organic halides to react and obtain ultrasonically responsive compounds.

[0069] Specifically, this application uses organic amine drugs and organohalides as raw materials to prepare ester-protected compounds, thereby obtaining ester-protected compounds. This application does not restrict the source of the organic amine drugs and organohalides; they can be purchased through commercial channels. In some specific implementations, the organic amine drugs are selected from secondary amine-containing tyrosine kinase inhibitors, secondary amine-containing Sting agonists, secondary amine-containing DNA topoisomerase inhibitors, secondary amine-containing pyrimidine drugs, secondary amine-containing purine drugs, or secondary amine-containing microtubule inhibitors, preferably alectinib, acridinone, belotecone, monomethylolpropionate E, or rucapranib, more preferably alectinib, acridinone, monomethylolpropionate E, or rucapranib. In some specific implementations, the organohalide is selected from one or more of tert-butyl bromoacetate, ethyl bromoacetate, tert-butyl iodoacetate, ethyl iodoacetate, tert-butyl chloroacetate, ethyl chloroacetate, bromoethane, benzyl bromide, 2-bromopropane, iodoethane, benzyl iodide, 2-iodopropane, chloroethane, benzyl chloride, and 2-chloropropane, preferably tert-butyl bromoacetate, ethyl bromoacetate, 2-bromopropane, benzyl iodide, chloroethane, benzyl chloride, and 2-chloropropane, and more preferably tert-butyl bromoacetate.

[0070] The above reaction is carried out in an organic solvent. In some specific implementations, the organic solvent is one or more selected from dichloromethane, trichloromethane, carbon tetrachloride, acetonitrile, acetone, dimethyl sulfoxide, tetrahydrofuran, and toluene, preferably dichloromethane, trichloromethane, and acetone, and more preferably dichloromethane. In some specific implementations, the molar ratio of the organic amine drug to the organohalide is (0.01~4):1, preferably (0.3~2):1, and more preferably (0.5~1.2):1. In some specific implementations, the reaction preferably involves the addition of an alkaline substance to neutralize the generated hydrogen halide, the alkaline substance being one or more selected from anhydrous sodium carbonate, cesium carbonate, sodium tert-butoxide, and strontium carbonate, preferably anhydrous sodium carbonate. In some specific implementations, the molar ratio of the alkaline substance to the organic amine drug is (0.02~10):1, preferably (0.5~5):1, and more preferably (1~2):1. In some specific implementations, the reaction temperature is 0℃~50℃, preferably 10℃~40℃, more preferably 20℃~30℃. In some specific implementations, the reaction time is 1 h~36 h, preferably 1 h~24 h, more preferably 2 h~12 h. In some specific implementations, the method for removing impurities is preferably liquid chromatography. This application does not limit the method for removing impurities.

[0071] After obtaining the ester-protected compound, the protection is removed, and the compound undergoes post-treatment to obtain the ultrasonically responsive compound. In some specific implementations, the deprotecting agent in the reaction is one or more of trifluoroacetic acid, hydrogen chloride, sulfuric acid, formic acid, p-toluenesulfonic acid, and methanesulfonic acid, preferably trifluoroacetic acid-formic acid, p-toluenesulfonic acid, and methanesulfonic acid, and more preferably trifluoroacetic acid. In some specific implementations, the reaction time is 0.1 h to 10 h, preferably 0.3 h to 5 h, and more preferably 0.5 h to 2 h. In some specific implementations, the post-treatment includes, but is not limited to, rotary evaporation and recrystallization. This application does not limit the post-treatment method.

[0072] In a typical example, ultrasonically responsive compound I can be prepared using a 7-step method, as follows: Step 1: 2,4-Dihydroxyquinoline and glacial acetic acid are mixed, and concentrated nitric acid is added dropwise. The mixture is reacted at 65℃~85℃ for 1 h~3 h. After the reaction is complete, the reaction solution is cooled to room temperature, and then dropped into ice water. After filtration, Int1 is obtained. Step 2: After mixing Int1 obtained in Step 1 with phosphorus oxychloride, triethylamine was added dropwise and the mixture was reacted at 100℃~110℃ for 2h~4h. After the reaction was completed, the reaction solution was cooled to room temperature, and then quenched by dropping the reaction solution into ice water to obtain a solid. The solid was then extracted with dichloromethane, washed successively with saturated sodium bicarbonate solution and saturated brine to remove the solvent, and Int2 was obtained. Step 3: The Int2 obtained in Step 2, triethylamine, dichloromethane, and 1-amino-2-methylprop-2-ol were refluxed and stirred at 35℃~55℃ for 5 h~6 h. After the reaction was completed, the reaction solution was cooled to room temperature and then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain Int3; Step 4: The Int3 obtained in Step 3, ethyl acetate, and 10% Pt / C were hydrogenated overnight at room temperature and pressure. After the reaction was complete, the reaction solution was filtered through diatomaceous earth to remove the solvent, yielding Int4; Step 5: After mixing Int4 obtained in Step 4, triethylamine and dichloromethane, the mixture was cooled in an ice bath and stirred until homogeneous. Then, an ethoxyacetyl chloride solution in dichloromethane was added dropwise over 16 minutes using a constant pressure dropping funnel. The reaction system was first stirred at 10℃~15℃ for 3 h~4 h, and then heated to 27℃~35℃ and stirred for another 2 h~4 h. After the reaction was completed, the reaction solution was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain Int5. Step 6: Add the Int5 obtained in Step 5 to a high-pressure reactor, add 50 mL of methanol, seal and heat. First, control the temperature inside the reactor at 120℃~130℃ and react for 1 hour, then adjust the temperature to 135℃ and react for 4 hours. Maintain the system pressure at 0.75 MPa. After the reaction is complete, allow it to cool naturally to room temperature, then release the pressure and open the reactor. Concentrate the reaction solution under reduced pressure to remove the solvent, obtaining Int6; Step 7: Add the Int6 obtained in Step 6 to a high-pressure reactor, then add ethanol, triethylamine, and glycine ethyl ester hydrochloride. Purge with nitrogen gas for 30 min. Heat and control the reactor temperature at 145℃ for 6 h. After the reaction is complete, allow it to cool naturally to room temperature, then release the pressure and open the reactor. Purify the reaction solution by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain the ethyl ester intermediate. Mix the ethyl ester intermediate with 1,4-dioxane, add sodium hydroxide dropwise, and react at 50℃ for 30 min. After the reaction is complete, purify the reaction solution by silica gel column chromatography (dichloromethane / methanol = 4:1) to obtain compound I. Compound I.

[0073] The method for preparing ultrasound-responsive compounds provided in this application, through the design of introducing a monovalent substituent containing α-hydrogen onto the nitrogen atom of an organic amine, results in compounds with outstanding advantages such as simple structure, ease of synthesis, high safety, and wide applicability. This method can also be used to prepare ultrasound-responsive prodrugs, achieving precise spatiotemporal control of drug activity at the molecular level. This allows for the on-demand release of potent active drugs only at the lesion site, minimizing toxic side effects on normal tissues throughout the body, and achieving safer, more efficient, and intelligent precision treatment.

[0074] This application provides an ultrasound-activated compound system, including the ultrasound-responsive compound described in any of the above technical solutions.

[0075] In some specific implementations, the power density of the ultrasound is 0.2 W / cm². 2 ~60 W / cm 2 The preferred value is 0.5 W / cm 2 ~35 W / cm 2 More preferably 1.0 W / cm 2 ~20 W / cm 2 .

[0076] In some specific implementations, the duty cycle of the ultrasound is 5% to 100%, preferably 20% to 95%, and more preferably 30% to 70%.

[0077] In some specific implementations, the frequency of the ultrasound is 0.01 MHz to 50 MHz, preferably 0.1 MHz to 25 MHz, and more preferably 0.1 MHz to 5 MHz.

[0078] In some specific implementations, the ultrasound duration is 1 min to 40 min, preferably 2 min to 30 min, and more preferably 2 min to 18 min.

[0079] Those skilled in the art will understand that this application can be ultrasonically activated under the above-described system, and the ultrasonic activation effect of the compound can be evaluated by the conversion rate of the reactants and the yield of the product. The conversion rate refers to the percentage of a specific reactant consumed (usually a limiting reactant) within a given reaction time relative to its initial amount. The yield refers to the percentage of a specific target product generated relative to the theoretical maximum yield of that product, where the theoretical maximum yield is based on the amount that can be produced based on the complete conversion of the limiting reactant. The selectivity refers to the proportion of consumed reactants converted to the target product, measuring the specificity of the reaction pathway.

[0080] The ultrasound-responsive compound provided in this application can undergo transformation and activation under specific ultrasound stimulation. In an aqueous environment, the compound can be stably transformed into the corresponding imine intermediate through ultrasound, and then hydrolyzed to release the active molecule. This allows for controllable activation of the compound in time and space, and has advantages such as non-invasiveness, strong tissue penetration, high spatiotemporal precision, and external controllability. It can overcome the uncertainties caused by the aforementioned physiological differences and can be further extended to the modification of various amine-containing active molecules, providing a robust and controllable drug release pathway for achieving precision medicine. At the same time, its controllable activation characteristics help to broaden the therapeutic window of drugs and increase the local drug concentration at the lesion, thereby optimizing the balance between efficacy and safety, and laying the foundation for the expanded application of related drugs in clinical practice.

[0081] This application also provides a pharmaceutical composition for ultrasound-activated therapy, comprising the compound described in any one of the above technical solutions, and one or more pharmaceutical carriers or excipients.

[0082] This application also provides the use of the compounds described in any of the above technical solutions in the preparation of medicaments for diagnosing and / or treating diseases or conditions; The disease or condition is selected from tumors, infectious diseases, hematological diseases, metabolic diseases, or inflammation; The tumor is selected from cancer, lymphoma, lymphoid tumor, blastoma, sarcoma, or leukemia; The cancers mentioned are selected from breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, liver cancer, stomach cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, urethral cancer, hepatocellular carcinoma, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, anal cancer, penile cancer, melanoma, multiple myeloma, brain cancer, gallbladder cancer, esophageal cancer, bile duct cancer, head and neck cancer, bladder cancer, thyroid cancer, or nasopharyngeal carcinoma.

[0083] The ultrasound-responsive compound provided in this application can improve the solubility of amine-containing drugs and improve the distribution of drugs in tissues or cells, wherein the drugs are rheumatoid arthritis treatment drugs, tuberculosis treatment drugs, antibacterial treatment drugs, or tumor treatment drugs.

[0084] This application provides an ultrasound-responsive compound having the structure of formula (I) or formula (II), its geometric isomers, optical isomers, salts, hydrates, solvates, or polymorphs. This compound can be stably converted into the corresponding imine intermediate in an aqueous environment through ultrasound, followed by hydrolysis to release the active molecule, enabling controllable activation of the compound in both time and space. By introducing a monovalent substituent containing α-hydrogen onto the nitrogen atom of the organic amine, this application results in a compound with outstanding advantages such as simple structure, ease of synthesis, high safety, and wide applicability. The compound exhibits good chemical stability and undergoes conversion activation under specific ultrasound stimulation, allowing for further application in the modification of various amine-containing active molecules. It provides a robust and controllable drug release pathway for precision medicine, while its controllable activation characteristics help broaden the therapeutic window and increase local drug concentration at the lesion site, thereby optimizing the balance between efficacy and safety, laying the foundation for the expanded application of related drugs in clinical practice.

[0085] The present application is further illustrated below with reference to embodiments. The scope of protection of the present application is not limited to the following embodiments.

[0086] The experimental materials used in the following embodiments of this application are all commercially available products.

[0087] Example 1

[0088] The organic secondary amine compounds shown in Table 1 were dissolved in 0.1% DMSO to prepare 100 μM aqueous solutions. The aqueous solutions were then subjected to ultrasonic treatment at 1.8 W / cm², 1.0 MHz, and a duty cycle of 50% to induce a reduction reaction. The reduction rates after 5 min of ultrasonic treatment are shown in Table 1. The high-performance liquid chromatograms of compounds 8 (N-methyl-p-hydroxyaniline) and 10 (N-phenylglycine) after 5 min of ultrasonic treatment in Table 1 are shown in [reference needed]. Figure 1 , Figure 1 In Figure 'a', the high-performance liquid chromatogram of compound 10 (N-phenylglycine) is shown. Figure 1 b is the high performance liquid chromatogram of compound 8 (N-methyl-p-hydroxyaniline).

[0089] Experimental results show that primary amine products can be obtained from compounds 1 to 11 after ultrasonication, and the yield of the primary amine product of compound 10 reaches 52.92%, indicating that the compounds provided in this application can be activated by ultrasonication.

[0090] Table 1

[0091] Example 2

[0092] The organic tertiary amine compounds shown in Table 2 were dissolved in 0.1% DMSO to prepare 100 μM aqueous solutions. The solutions were then subjected to ultrasonic treatment at 1.8 W / cm². 2 Under conditions of 1.0 MHz and a duty cycle of 50%, the above-mentioned organic tertiary amine aqueous solution was subjected to ultrasonic treatment to induce a reduction reaction. The reduction rates after 5 min of ultrasonic treatment are shown in Table 2. The high-performance liquid chromatograms of compounds 14 (N-methyl-N-phenylglycine) and 15 (N-carboxymethylpyrrole) after 5 min of ultrasonic treatment in Table 2 are shown below. Figure 2 , Figure 2 In Figure 'a', the high-performance liquid chromatogram of compound 14 (N-methyl-N-phenylglycine) is shown. Figure 2 b is the high performance liquid chromatogram of compound 15 (N-carboxymethylpyrrole).

[0093] Experimental results show that compounds 12-15 can be sonicated to obtain secondary amine products, and compounds 11-14 can be sonicated to obtain primary amine products. The yield of the secondary amine product of compound 14 is 86.88%, and the yield of the primary amine product of compound 15 is 87.88%. That is, the compounds provided in this application have high activation activity and accessibility.

[0094] Table 2

[0095] Example 3: Preparation and characterization of compound I

[0096] Compound I was prepared by reacting glyoxylic acid with ressimode (R848) as follows: 314.39 mg of resimilarto (1.0 mmol) was dissolved in 10 mL of anhydrous dimethylformamide. 5 mL of anhydrous dimethylformamide solution containing 138.08 mg of glyoxylic acid monohydrate (1.5 mmol) and 6 molecular sieves for dehydration were added, and the reaction was carried out at 40 °C for 2 h. Then, 317.91 mg of sodium triacetoxyborohydride (1.5 mmol) of anhydrous dimethylformamide solution was added, and the reaction was carried out for two days under anhydrous and oxygen-free conditions at 40 °C. After the reaction was complete, impurities were removed by liquid chromatography (methanol:dichloromethane = 8:92), and the mobile phase ratio was increased to methanol:dichloromethane = 20:80 to obtain compound I, with the following structural formula: Compound I.

[0097] Using deuterated DMSO as a solvent, the products were analyzed by nuclear magnetic resonance spectroscopy. 1 H NMR testing, corresponding to 400 M 1 HNMR, the spectral data are as follows: δ 13.03 (s, 1H), 9.10 (s, 1H), 8.13 (dd, J=7.5, 1.5Hz, 1H), 7.81 (dd, J=7.5, 1.5Hz, 1H), 7.67 (td, J=7.5, 1.5Hz, 1H), 7.56 (td, J=7.5, 1.5Hz, 1H), 4.63 (t, J=7.0Hz, 2H), 4.49 (s, 1H), 4.00 (s, 2H), 3.80 (s, 2H), 3.58 (q, J=7.0Hz, 2H), 1.26 (s, 6H), 1.18 (t, J=7.0Hz, 3H). C 19 H 24 ESI m / z of N4O4 ([M+H) + The value was 373.18, but the actual measurement found it to be 373.19.

[0098] Example 4: Preparation and characterization of compound II

[0099] Compound II was prepared by reacting glyoxylic acid with aminonaphthyl filtrate, as follows: 283.33 mg of aminonaphthyl ether (1.0 mmol) was dissolved in 10 mL of anhydrous dimethylformamide. 5 mL of anhydrous dimethylformamide solution containing 138.08 mg of glyoxylic acid monohydrate (1.5 mmol) and 6 molecular sieves for dehydration were added, and the reaction was carried out at 40 °C for 2 h. Then, 317.91 mg of sodium triacetoxyborohydride (1.5 mmol) of anhydrous dimethylformamide solution was added, and the reaction was carried out overnight at 40 °C under anhydrous and oxygen-free conditions. After the reaction was complete, recrystallization in methanol yielded compound II, with the structural formula shown below: Compound II.

[0100] Using deuterated DMSO as a solvent, the products were analyzed by nuclear magnetic resonance spectroscopy. 1 H NMR testing, corresponding to 400 M 1 HNMR is: δ13.03 (s, 1H), 8.31 (dd, J=7.5, 1.5Hz, 1H), 8.25 (dd, J=7.5, 1.5Hz, 1H), 8.11 (d, J=1.5Hz, 1H), 7.60 (t, J=7.5Hz, 1H), 7.08 (t, J=1.5Hz, 1H), 6.28 (s, 1H), 4.00 (s, 2H), 3.16 (t, J=7.1Hz, 2H), 2.57 (t, J=7.1Hz, 2H), 2.21 (s, 6H). C 18 H 19 ESI m / z of N3O4 ([MH) - The value was 340.14, but the actual measurement found it to be 340.13.

[0101] Example 5: Preparation and characterization of compound III

[0102] The reaction of glyoxylic acid and pomalidomide to prepare compound III follows the steps below: 273.24 mg of pomalidomide (1.0 mmol) was dissolved in 10 mL of anhydrous dimethylformamide, and 5 mL of anhydrous dimethylformamide solution containing 138.08 mg of glyoxylic acid monohydrate (1.5 mmol) and 6 molecular sieves for dehydration were added. The reaction was carried out at 40 °C for 2 h. Then, 317.91 mg of sodium triacetoxyborohydride (1.5 mmol) of anhydrous dimethylformamide solution was added, and the reaction was carried out overnight at 40 °C under anhydrous and oxygen-free conditions. After the reaction was completed, the product was recrystallized in methanol to give compound III, the structure of which is shown below: Compound III.

[0103] Using deuterated DMSO as a solvent, the products were analyzed by nuclear magnetic resonance spectroscopy. 1 H NMR testing, corresponding to 400 M 1 HNMR is: δ13.03 (s, 1H), 11.06 (s, 1H), 7.59 (t, J=7.5Hz, 1H), 7.25 (dd, J=7.5,1.5Hz, 1H), 6.98 (dd, J=7.5, 1.5Hz, 1H), 5.74 (s, 1H), 4.44 (t, J=7.0Hz, 1H), 4.00 (s, 2H), 2.27 (dd, J=7.1, 7.0Hz, 1H), 2.21 (d, J=7.1Hz, 1H), 2.11 (d, J=7.1Hz, 1H), 2.02 (dd, J=7.1, 7.0Hz, 1H). C 15 H 13 ESI m / z of N3O6 ([M+H) + The value was 332.08, and the actual measurement found it to be 332.08.

[0104] Example 6: Preparation and characterization of compound IV

[0105] The reaction of glyoxylic acid and eczematen yields compound IV, as follows: 435.45 mg of eczema (1.0 mmol) was dissolved in 10 mL of anhydrous dimethylformamide, and 5 mL of anhydrous dimethylformamide solution containing 138.08 mg of glyoxylic acid monohydrate (1.5 mmol) and 6 molecular sieves for dehydration were added. The reaction was carried out at 40 °C for 2 h. Then, 317.91 mg of sodium triacetoxyborohydride (1.5 mmol) of anhydrous dimethylformamide solution was added, and the reaction was carried out overnight at 40 °C under anhydrous and oxygen-free conditions. After the reaction was completed, the compound IV was recrystallized in methanol, with the following structural formula: Compound IV.

[0106] Using deuterated DMSO as a solvent, the products were analyzed by nuclear magnetic resonance spectroscopy. 1 H NMR testing, corresponding to 400 M 1HNMR is: δ13.03 (s, 1H), 7.23 (d, J=8.0 Hz, 1H), 6.74 (s, 1H), 4.77 (s, 1H), 4.76 (d, J=12.4 Hz, 1H), 4.74 (d, J=12.4 Hz, 1H), 4.22 (s, 2H), 4.16 (s, 1H), 3.81 (t, J=7.0 Hz, 1H), 3.49 (s, 2H), 2.85 (d, J=12.4 Hz, 1H), 2.75 (d, J=12.4 Hz, 1H), 2.33 (s, 3H), 2.17 (d, J=12.4 Hz, 1H), 1.92 (d, J=12.4 Hz, 1H), 1.87 (t, J=8.0 Hz, 2H), 0.89 (t, J=8.0 Hz, 3H). C 26 H 24 ESI m / z of FN3O6 ([MH) - The value was 492.16, but the actual measurement found it to be 492.37.

[0107] Example 7: Preparation and characterization of compound V

[0108] Compound V was prepared by reacting tert-butyl bromoacetate with monomethyl guanylate E (MMAE) in the following steps: 717.50 mg of monomethyl guanylate E (1.0 mmol) was dissolved in 10 mL of anhydrous dichloromethane. 5 mL of anhydrous dimethylformamide solution containing 234.06 mg of tert-butyl bromoacetate (1.2 mmol) and 158.98 mg of anhydrous sodium carbonate (1.5 mmol) were added. The reaction was carried out at room temperature for 4 h. After the reaction was complete, impurities were removed by liquid chromatography (methanol:dichloromethane = 10:90) to obtain the tert-butyl-protected compound. The protection was then removed by reacting in trifluoroacetic acid for 1 h, and the solution was evaporated to dryness and recrystallized in methanol to give compound V, with the following structural formula: Compound V.

[0109] Using deuterated DMSO as a solvent, the products were analyzed by nuclear magnetic resonance spectroscopy. 1 H NMR testing, corresponding to 400 M 1HNMR is: δ13.03 (s, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.32 (d, J=7.5 Hz, 2H), 7.25 (m, 3H), 5.40 (d, J=7.0 Hz, 1H), 5.17 (s, 1H), 4.34 (dd, 1H), 4.12 (m,1H), 4.08 (m, 1H), 4.02 (m, 1H), 3.56 (m, 1H),3.51(m, 1H), 3.50 (dd, 1H),3.46 (d, J=12.4 Hz, 1H), 3.41 (m, 1H), 3.41 (s, 6H), 3.37 (d, 1H), 3.30 (s,2H), 3.27 (s, 3H), 2.73 (m, 1H), 2.64 (m, 1H), 2.42 (d, J=12.4 Hz, 1H), 2.29(d, J=12.4 Hz, 1H), 2.26 (s, 3H), 2.17 (d, 1H), 2.06 (m, 1H), 2.02 (m, 1H), 1.97 (d, J=12.4 Hz, 1H), 1.92 (d, J=12.4 Hz, 1H), 1.55 (m, 2H), 1.26 (d, J=6.8 Hz, 3H), 1.12 (d, J=6.8 Hz, 3H), 0.99 (d, J=8.0 Hz, 3H), 0.96 (d, J=6.8Hz, 12H), 0.88 (d, J=6.8Hz, 3H). C 41 H 69 ESI m / z of N5O9 ([M+H) + The value was 776.51, and the actual measurement found it to be 776.51.

[0110] Example 8: Preparation and characterization of compound VI

[0111] Compound VI was prepared by reacting tert-butyl bromoacetate with acridinium, as follows: 195.22 mg of acridinium (1.0 mmol) was dissolved in 10 mL of anhydrous dichloromethane. 5 mL of anhydrous dimethylformamide solution containing 234.06 mg of tert-butyl bromoacetate (1.2 mmol) and 158.98 mg of anhydrous sodium carbonate (1.5 mmol) were added. The reaction was carried out at room temperature for 4 h. After the reaction was complete, impurities were removed by liquid chromatography (methanol:dichloromethane = 10:90) to obtain the tert-butyl-protected compound. The protection was then removed by reacting in trifluoroacetic acid for 1 h, and the solution was evaporated to dryness and recrystallized in methanol to give compound VI, with the structure shown below: Compound VI.

[0112] Using deuterated DMSO as a solvent, the products were analyzed by nuclear magnetic resonance spectroscopy. 1 H NMR testing, corresponding to 400 M 1 HNMR is: δ13.03 (s,1H), 7.70 (d,J=7.5 Hz,2H), 7.48 (m,2H), 7.28 (d,J=7.5 Hz,2H), 7.18 (m,2H), 4.00 (s,2H). C 15 H 11 ESI m / z of NO3 ([M+H) + The value was 254.07, but the actual measurement found it to be 254.09.

[0113] Example 9: Preparation and characterization of compound VII

[0114] Compound VII was prepared by reacting tert-butyl bromoacetate with alectinib, as follows: 482.62 mg of alectinib (1.0 mmol) was dissolved in 10 mL of anhydrous dichloromethane. 5 mL of anhydrous dimethylformamide solution containing 234.06 mg of tert-butyl bromoacetate (1.2 mmol) and 158.98 mg of anhydrous sodium carbonate (1.5 mmol) were added. The reaction was carried out at room temperature for 4 h. After the reaction was complete, impurities were removed by liquid chromatography (methanol:dichloromethane = 10:90) to obtain the tert-butyl-protected compound. The protection was then removed by reacting in trifluoroacetic acid for 1 h, and the solution was evaporated to dryness and recrystallized in methanol to give compound VII, with the structural formula shown below: Compound VII.

[0115] Using deuterated DMSO as a solvent, the products were analyzed by nuclear magnetic resonance spectroscopy. 1 H NMR testing, corresponding to 400 M 1HNMR is: δ12.22 (s,1H), 8.23 ​​(d,J=7.5 Hz,1H), 7.83 (m,2H), 7.52 (d,J=7.5 Hz,1H), 7.01 (d,J=7.5 Hz,1H), 4.79 (s,2H), 3.57 (t,J=7.1 Hz,4H), 3.14 (d,J=12.4 Hz,2H), 3.04 (d,J=12.4 Hz,2H), 2.63 (m,1H), 2.58 (t,J=8.0 Hz,2H), 2.48 (t,J=7.1Hz,4H), 1.75 (s,6H), 1.69 (d,J=12.4 Hz,2H), 1.44 (d,J=12.4 Hz,2H), 1.12 (d,J=8.0 Hz,3H). C 32 H 36 ESI m / z of N4O4 ([M+H) + The value was 541.27, but the actual measurement found it to be 541.28.

[0116] Example 10: Preparation and characterization of compound VIII

[0117] Compound VIII was prepared by reacting tert-butyl bromoacetate with rucapranil, as follows: 323.51 mg of rucapranib (1.0 mmol) was dissolved in 10 mL of anhydrous dichloromethane. 5 mL of anhydrous dimethylformamide solution containing 234.06 mg of tert-butyl bromoacetate (1.2 mmol) and 158.98 mg of anhydrous sodium carbonate (1.5 mmol) were added. The reaction was carried out at room temperature for 4 h. After the reaction was complete, impurities were removed by liquid chromatography (ethyl acetate: n-hexane = 70:30) to obtain the tert-butyl-protected compound. The protection was then removed by reacting in trifluoroacetic acid for 1 h, and the solution was evaporated to dryness and recrystallized in methanol to give compound VIII, with the structural formula shown below: Compound VIII.

[0118] Using deuterated DMSO as solvent, the product was analyzed by 1H NMR spectroscopy at 400 M. 1HNMR is: δ13.03 (s, 1H), 11.49 (s, 1H), 8.04 (s, 1H), 7.75 (dd, J=8.0, 1.5 Hz,1H), 7.67 (m, 2H), 7.47 (m, 2H), 7.31 (dd, J=8.0, 1.5 Hz, 1H), 3.66 (q, J=7.1Hz, 2H), 3.47 (t, J=7.1 Hz, 2H), 3.30 (s, 2H), 2.73 (t, J=7.1 Hz, 2H), 2.26 (t, J=7.1 Hz, 3H). ESI m / z([M+H] of C21H20FN3O3 + The value was 382.15, but the actual measurement found it to be 382.16.

[0119] Example 11: Preparation and characterization of compound IX

[0120] Compound IX was prepared by reacting glyoxylic acid with 9-aminoacridine, as follows: 194.23 mg of 9-aminoacridine (1.0 mmol) was dissolved in 10 mL of anhydrous dimethylformamide. 5 mL of anhydrous dimethylformamide solution containing 138.08 mg of glyoxylic acid monohydrate (1.5 mmol) and 6 molecular sieves for dehydration were added. The reaction was carried out at 40 °C for 2 h. Then, 317.91 mg of sodium triacetoxyborohydride (1.5 mmol) of anhydrous dimethylformamide solution was added, and the reaction was carried out overnight at 40 °C in an anhydrous and oxygen-free environment. After the reaction was complete, the compound IX was recrystallized in methanol, with the structural formula shown below: Compound IX.

[0121] Using deuterated DMSO as a solvent, the products were analyzed by nuclear magnetic resonance spectroscopy. 1 H NMR testing, corresponding to 400 M 1 HNMR is: δ13.03 (s,1H), 8.25 (dd, J = 7.5 Hz, 2H), 7.81 (dd, J = 7.5 Hz, 2H), 7.62 (ddd, J = 7.5 Hz, 2H), 7.45 (ddd, J = 7.5 Hz, 2H), 5.03 (s, 1H), 4.00(s, 2H). C 15 H 12 ESI m / z of N2O2 ([MH) - The value was 251.09, but the actual measurement found it to be 251.11.

[0122] Example 12: Preparation and characterization of compound I

[0123] Compound I was prepared from 2,4-dihydroxyquinoline through a 7-step reaction, as follows: Step 1: Weigh 31 mmol of 2,4-dihydroxyquinoline and add it to 1.08 mol of glacial acetic acid, stirring until homogeneous. Then, slowly add 101 mmol of concentrated nitric acid dropwise, continuing stirring for 10 min. Heat to 75 °C and stir for 1 h. Cool the reaction solution to room temperature and slowly add it dropwise to 150 mL of ice water, filtering to obtain Int1. This product was analyzed by 1H NMR spectroscopy (1H NMR spectroscopy). 1 The structure was confirmed by H NMR characterization. 1 H NMR (600 MHz, DMSO) δ 11.94 (s, 1H), 8.03 (dd, J = 8.2, 1.6Hz, 1H), 7.64 (ddd, J = 8.4, 7.1, 1.5 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.27(ddd, J = 8.3, 7.2, 1.2 Hz, 1H).

[0124] Step 2: Int1 (9.6 mmol) was added to phosphorus oxychloride (29 mL), stirred, and triethylamine (9.6 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 5 min, then heated to 105 °C and stirred for 3 h. The reaction solution was then cooled to room temperature and quenched by slowly adding it dropwise to 300 mL of ice water, precipitating a solid. The solid was extracted with dichloromethane and washed successively with saturated sodium bicarbonate solution and saturated brine to remove the solvent, yielding Int2. The structure of this product was confirmed by 1H NMR spectroscopy. 1 H NMR (600MHz, DMSO) δ 8.34 (dd, J = 8.4, 2.1 Hz, 1H), 8.17 (d, J = 7.2 Hz, 1H), 8.12 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.98 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H).

[0125] Step 3: Int2 (7.88 mmol) and triethylamine (9.88 mmol) were added to 50 mL of dichloromethane, followed by 1-amino-2-methylprop-2-ol (7.88 mmol). The mixture was heated to 45 °C and refluxed with stirring for 5 h. The reaction solution was then cooled to room temperature and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain Int3. The structure of this product was confirmed by 1H NMR spectroscopy. 1H NMR (600 MHz, DMSO) δ 8.36 (d, J = 9.5 Hz, 1H), 7.87–7.83 (m, 2H), 7.68 (ddd, J = 8.3, 6.1, 2.2 Hz, 1H), 7.27 (t, J = 5.5 Hz, 1H), 5.02 (s, 1H), 3.10 (d, J = 5.5 Hz, 2H), 1.14 (s, 6H).

[0126] Step 4: Int3 (3.38 mmol) was added to 100 mL of ethyl acetate, followed by 10% Pt / C (136 mg). The mixture was hydrogenated overnight at room temperature and pressure. After the reaction was complete, the solvent was removed by filtration with diatomaceous earth to obtain Int4. The structure of this product was confirmed by 1H NMR spectroscopy. 1 H NMR (600 MHz, DMSO) δ 8.07–8.04 (m, 1H), 7.69–7.66 (m,1H), 7.43–7.40 (m, 2H), 5.14 (s, 2H), 5.09 (t, J = 6.6 Hz, 1H), 4.83 (s, 1H), 3.18 (d, J = 6.7 Hz, 2H), 1.15 (s, 6H).

[0127] Step 5: Int4 (1.51 mmol) and triethylamine (3.01 mmol) were added to 35 mL of dichloromethane, and the mixture was cooled in an ice bath and stirred until homogeneous. Ethoxyacetyl chloride (1.18 mmol) was dissolved in 5 mL of dichloromethane and added dropwise to the reaction system over 16 min using a constant-pressure dropping funnel, and stirred until homogeneous. The reaction was then stirred at 13 °C for 3 h, and then heated to 27 °C and stirred for another 2 h. After the reaction was complete, the product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain Int5. The structure of this product was confirmed by 1H NMR spectroscopy. 1H NMR (600 MHz, DMSO) δ 9.52 (s, 1H), 8.18 (d, J = 9.9 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.69 (t, J = 8.3 Hz, 1H), 7.52 (t, J = 8.4 Hz, 1H), 6.29 (t, J = 5.6 Hz, 1H), 4.94 (s, 1H), 4.08 (s, 2H), 3.65 (q, J = 7.0 Hz, 2H), 3.48 (d, J = 5.5 Hz, 2H), 1.23 (t, J = 7.0 Hz, 3H), 1.15 (s, 6H).

[0128] Step 6: Add Int5 (0.85 mmol) to the high-pressure reactor, add 50 mL of methanol, seal and heat. First, maintain the internal temperature at 120℃ for 1 h, then adjust the temperature to 135℃ and react for 4 h, maintaining the system pressure at 0.75 MPa. After the reaction is complete, allow it to cool naturally to room temperature, then release the pressure and open the reactor. Concentrate the reaction solution under reduced pressure to remove the solvent, yielding Int6. The structure of this product was confirmed by 1H NMR spectroscopy. 1 H NMR (600 MHz, DMSO) δ 8.65 (d, J = 8.4 Hz, 1H), 8.05 (d, J= 9.7 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 4.92 (s,1H), 4.80 (s, 2H), 3.55 (q, J = 7.0 Hz, 2H), 3.33 (s, 2H), 1.15 (t, J = 7.0Hz, 9H).

[0129] Step 7: Add Int6 (0.741 mmol) to a high-pressure reactor, add 50 mL of ethanol, then add triethylamine (1.482 mmol) and glycine ethyl ester hydrochloride (1.482 mmol) sequentially, and purge with nitrogen gas for 30 min. Maintain the internal temperature at 145℃ and react for 6 h. After the reaction is complete, allow it to cool naturally to room temperature, then release the pressure and open the reactor. Purify by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain the ethyl ester intermediate. Add the ethyl ester intermediate (0.472 mmol) to 5 mL of 1,4-dioxane, and add 0.4 mL of sodium hydroxide dissolved in deionized water (0.942 mmol) dropwise. React at 50℃ for 30 min. After the reaction is complete, purify by silica gel column chromatography (dichloromethane / methanol = 4:1) to obtain compound I; Compound I.

[0130] Using deuterated DMSO as a solvent, the products were analyzed by nuclear magnetic resonance spectroscopy. 1 H NMR testing, corresponding to 600 M 1 HNMR is: δ13.03 (s, 1H), 9.10 (s, 1H), 8.13 (dd, J=7.5, 1.5Hz, 1H), 7.81 (dd, J=7.5, 1.5Hz, 1H), 7.67 (td, J=7.5, 1.5Hz, 1H), 7.56 (td, J=7.5, 1.5Hz, 1H), 4.63 (t, J=7.0Hz, 2H), 4.49 (s, 1H), 4.00 (s, 2H), 3.80 (s, 2H), 3.58 (q, J=7.0Hz, 2H), 1.26 (s, 6H), 1.18 (t, J=7.0Hz, 3H). C 19 H 24 ESI m / z of N4O4 ([M+H) + The value was 373.18, but the actual measurement found it to be 373.19.

[0131] Experimental Example 1: Ultrasonic Activation Test

[0132] Compounds I, II, III, IV, V, VI, VII, VIII, and IX prepared in Examples 3-11 were each independently dissolved in 0.1% DMSO to prepare 100 μM aqueous solutions. The solutions were then sonicated at 1.8 W / cm². 2 The above aqueous solution was subjected to ultrasonic treatment at 1.0 MHz and a duty cycle of 50% for 5 min.

[0133] The ultrasonic reduction effect after ultrasonication was detected by high performance liquid chromatography (HPLC). See [reference needed]. Figure 3 The result is as follows Figure 3 As shown, where, Figure 3 In the image, 'a' is the high-performance liquid chromatogram of compound I after ultrasonic reduction; Figure 3 b is the high-performance liquid chromatogram of the ultrasonic reduction of compound II; Figure 3 c is the high-performance liquid chromatogram of the ultrasonic reduction of compound III; Figure 3 In the image, d represents the high-performance liquid chromatogram of the ultrasonic reduction of compound IV; Figure 3 In the image, 'e' represents the high-performance liquid chromatogram of compound V after ultrasonic reduction. Figure 3 f is the high-performance liquid chromatogram of compound VI after ultrasonic reduction; Figure 3g is the high-performance liquid chromatogram of the ultrasonic reduction of compound VII; Figure 3 In the figure, h represents the high-performance liquid chromatogram of compound VIII after ultrasonic reduction. The yield, conversion, and selectivity were calculated using structural analysis, and the results are shown in Table 3.

[0134] Table 3

[0135] Experimental Example 2: In vivo toxicity assessment of compound I

[0136] Twenty-seven healthy female mice were divided into three groups. Each group of mice was injected intravenously with PBS, 10 mg / kg to 70 mg / kg of rethimod (R848), and 10 mg / kg to 70 mg / kg of compound I, respectively, and then in vivo toxicity was assessed in mice.

[0137] See the experimental results. Figure 4 , Figure 4 A graph showing the changes in the concentration of various cytokines in the blood of healthy mice after drug administration. Figure 4 It was found that compound I at doses ranging from 10 mg / kg to 70 mg / kg did not cause a significant increase in cytokine concentrations in mouse blood. Conversely, the small molecule active drug R848 at doses ranging from 10 mg / kg to 70 mg / kg caused a significant increase in cytokine concentrations in mouse blood. These experimental results demonstrate the strong potential of compound I as a prodrug in mitigating the systemic toxicity of the active drug.

[0138] Experimental Example 3: In vitro ultrasonic reduction assessment of compound I

[0139] Dendritic cells derived from the bone marrow of 4-6 week old black mice were added to PBS, 30 μM retimide (R848), and compound I, respectively, and subjected to ultrasound at a power of 1.8 W / cm². 2 After sonication at a duty cycle of 50% for 2 min, the cells were cultured for 24 h, and the proportion of mature cells was determined by flow cytometry.

[0140] See the experimental results. Figure 5 , Figure 5 This is a flow cytometry analysis of the in vitro ultrasound-activated dendritic cells (DCs) results of compound I. The experimental results show that compound I cannot activate DCs without ultrasound. Under ultrasound conditions, compound I promotes DC maturation. The results indicate that ultrasound can activate compound I, allowing it to function as a TLR7 / 8 agonist.

[0141] Experimental Example 4: Evaluation of the antitumor effect of compound I on the Balb / c mouse CT26 tumor model

[0142] See dosing regimen Figure 6 , Figure 6 This is the experimental protocol roadmap for the tumor suppression experiment, specifically showing that on days 0, 2, and 4, tumors with a volume of 100 cm³ were targeted according to group assignments. 3 Mice with tumors were injected via tail vein with the appropriate dose and type of drug, and ultrasound was not used. Mice were then sacrificed on day 14, tumors were isolated, and the tumor-suppressing effects and weight changes of the mice over 14 days were compared between the groups. (See [link to relevant documentation]). Figure 7 and Figure 8 , Figure 7 This is a tumor growth curve in mice. Figure 8 This is a graph showing the changes in the mouse's body weight.

[0143] Experimental results showed that the combined use of compound I and ultrasound significantly inhibited tumor growth. Furthermore, no significant weight loss was observed in mice after treatment, demonstrating the low toxicity and safety of compound I.

[0144] The above description is merely a preferred embodiment of this application, but the scope of protection of this application is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in this application, based on the technical solution and inventive concept of this application, should be included within the scope of protection of this application.

Claims

1. An ultrasonically responsive compound, characterized in that, Having a structure of formula (I) or formula (II), its geometric isomers, optical isomers, salts, hydrates, solvates or polymorphs; Formula (I); Formula (II); In formula (I), R1 is an organic primary amine drug residue after deamination, and R2 is selected from H or a substituent having α-H; In formula (I), R1 and R2 are two residues of an organic secondary amine drug that have been deaminoked; The R3 is selected from substituents having α-H; The To remove hydrogen residues from the ring A of organic secondary amine drugs containing ring A.

2. The ultrasonically responsive compound according to claim 1, characterized in that, The substituents having α-H are selected from substituted or unsubstituted C2~C. 20 Alkyl, substituted or unsubstituted C3~C 20 cycloalkyl, substituted or unsubstituted C2~C 20 Heterocyclic alkyl groups, substituted or unsubstituted C2~C 20 heteroaryl, substituted or unsubstituted C6~C 20 aryl, substituted or unsubstituted C3~C 20 The alkynyl group or substituted or unsubstituted C2~C 20 alkenyl; The substituents are selected from C6~C6. 20 aryl, C1~C 20 The carboxyl group, C1~C 20 ester group, C1~C 20 alkoxy groups, C6~C 20 It contains one or more of the following: aromatic oxygen group, sulfonic acid group, cyano group, nitro group, and halogen.

3. The ultrasonically responsive compound according to claim 2, characterized in that, The substituents having α-H are selected from substituted or unsubstituted C2~C. 12 Alkyl, substituted or unsubstituted C8~C 16 cycloalkyl, substituted or unsubstituted C2~C 10 Heterocyclic alkyl groups, substituted or unsubstituted C2~C 10 heteroaryl, substituted or unsubstituted C6~C 10 aryl, substituted or unsubstituted C3-C8 alkynyl or substituted or unsubstituted C3-C8 alkenyl; The substituents are selected from C6~C6. 12 aryl, C1~C 10 The carboxyl group, C1~C 10 ester group, C1~C 10 alkoxy groups, C6~C 12 It contains one or more of the following: aromatic oxygen group, sulfonic acid group, cyano group, nitro group, and halogen.

4. The ultrasonically responsive compound according to claim 1, characterized in that, The organic primary amine drugs are selected from DNA topoisomerase inhibitors, imidazoquinoline Toll-like receptor agonists, immunomodulators, pyrimidine drugs, folic acid antagonists, or anthracycline antibiotics; The organic secondary amine drugs are selected from tyrosine kinase inhibitors, Sting agonists, DNA topoisomerase inhibitors, pyrimidine drugs, purine drugs, or microtubule inhibitors.

5. The ultrasonically responsive compound according to claim 4, characterized in that, The organic primary amine drugs are selected from eczemab, amphenifet, ralsimod, imiquimod, pomalidomide, 9-aminoacridine, or methotrexate; The organic secondary amine drug is selected from alectinib, acridinone, belotecone, monomethylolpropionate E, or rucapranib.

6. The ultrasonically responsive compound according to claim 1, characterized in that, It has the structure shown in equation (Ⅰ-1); Equation (Ⅰ-1); R2, R3, R5, and R6 are each independently selected from H, substituted or unsubstituted C2~C. 20 Alkyl, substituted or unsubstituted C3~C 20 cycloalkyl, substituted or unsubstituted C2~C 20 Heterocyclic alkyl groups, substituted or unsubstituted C2~C 20 heteroaryl, substituted or unsubstituted C6~C 20 aryl, substituted or unsubstituted C3~C 20 The alkynyl group or substituted or unsubstituted C2~C 20 alkenyl; The substituents are selected from C6~C6. 12 aryl, C1~C 10 The carboxyl group, C1~C 10 ester group, C1~C 10 alkoxy groups, C6~C 12 It contains one or more of the following: aromatic oxygen group, sulfonic acid group, cyano group, nitro group, and halogen.

7. The ultrasonically responsive compound according to claim 6, characterized in that, It has the structure shown in formula (Ⅰ-1a), formula (Ⅰ-1b) or formula (Ⅰ-1c); Equation (Ⅰ-1a); Equation (Ⅰ-1b); Equation (Ⅰ-1c); R5 and R6 are each independently selected from H, substituted or unsubstituted C2~C. 20 Alkyl, substituted or unsubstituted C3~C 20 cycloalkyl, substituted or unsubstituted C2~C 20 Heterocyclic alkyl groups, substituted or unsubstituted C2~C 20 heteroaryl, substituted or unsubstituted C6~C 20 aryl, substituted or unsubstituted C3~C 20 The alkynyl group or substituted or unsubstituted C2~C 20 alkenyl; The substituents are selected from C6~C6. 12 aryl, C1~C 10 The carboxyl group, C1~C 10 ester group, C1~C 10 alkoxy groups, C6~C 12 One or more of the following: aromatic oxygen group, sulfonic acid group, cyano group, nitro group, and halogen; The R7 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, cyano, or sulfonic acid group.

8. The ultrasonically responsive compound according to claim 1, characterized in that, It has any of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 9. A pharmaceutical composition for ultrasound-activated therapy, characterized in that, It comprises the compound according to any one of claims 1 to 8, and one or more pharmaceutical carriers or excipients.

10. The use of the ultrasound-responsive compound according to any one of claims 1 to 8 in the preparation of a medicament for diagnosing and / or treating diseases or conditions; The disease or condition is selected from tumors, infectious diseases, hematological diseases, metabolic diseases, or inflammation; The tumor is selected from cancer, lymphoma, lymphoid tumor, blastoma, sarcoma, or leukemia; The cancers mentioned are selected from breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, liver cancer, stomach cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, urethral cancer, hepatocellular carcinoma, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, anal cancer, penile cancer, melanoma, multiple myeloma, brain cancer, gallbladder cancer, esophageal cancer, bile duct cancer, head and neck cancer, bladder cancer, thyroid cancer, or nasopharyngeal carcinoma.

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