Pyrimido[6,1-a]isoquinolin-4-one derivatives and uses thereof

Abstract

This invention relates to a pyrimido[6,1-a]isoquinoline-4-one derivative and its uses. The structural formula of the pyrimido[6,1-a]isoquinoline-4-one derivative of this invention is shown in formula (I): wherein R1, R2, R3, X, and Y are as described in the specification. The compounds of this invention can simultaneously inhibit PDE3 and PDE4, and exhibit better efficacy compared to existing dual-target inhibitors of PDE3 and PDE4.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a pyrimido[6,1-a]isoquinoline-4-one derivative and its uses. Background Technology

[0002] PDE3 and PDE4 belong to the PDE (phosphodiesterase) superfamily and are the main cAMP hydrolases in lung tissue cells. PDE3 can hydrolyze both cAMP and cGMP, with its cAMP hydrolytic capacity being approximately ten times that of cGMP. Inhibition of PDE3 blocks intracellular cAMP hydrolysis, and the accumulated cAMP can lead to calcium loss in the sarcoplasmic reticulum. 2+ The large-scale release of cAMP promotes bronchial smooth muscle relaxation. PDE4 specifically hydrolyzes cAMP, which plays a major regulatory role in the expression of pro-inflammatory and anti-inflammatory mediators; its inhibition significantly reduces the release of harmful mediators from inflammatory cells. This dual-target inhibition strategy synergistically increases intracellular cAMP / cGMP concentrations, activates downstream signaling pathways, and achieves a dual enhancement of airway relaxation and anti-inflammatory effects, while simultaneously promoting airway clearance.

[0003] WO2000058308A1 discloses a PDE3 / 4 dual-target inhibitor, RPL554, with positive clinical results.

[0004]

[0005] However, research data on RPL554 show that its inhibitory activity against PDE4 is significantly insufficient, while its inhibitory activity against PDE3 still has room for improvement. Summary of the Invention

[0006] To address unmet clinical needs, there is a need to develop more efficient and safer dual-target inhibitors of PDE3 / 4. Therefore, this invention provides a pyrimido[6,1-a]isoquinoline-4-one derivative and its uses.

[0007] Therefore, one object of the present invention is to provide a pyrimido[6,1-a]isoquinoline-4-one derivative as a dual-target inhibitor of PDE3 / 4.

[0008] Another object of the present invention is to provide a pharmaceutical composition comprising the above-described compounds.

[0009] The technical solution of the present invention is implemented by the following approach.

[0010] On the one hand, the present invention provides compounds of general formula (I) or their stereoisomers, tautomers, deuterated derivatives, prodrugs or their chemically acceptable salts:

[0011]

[0012] in,

[0013] R1 is selected from -NR4R5 or cyclone Cy;

[0014] R4 and R5 are independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl;

[0015] Cy is selected from 4-7 heteroaryl and aryl groups containing 1-5 (e.g., 1, 2, 3, 4, or 5) heteroatoms selected from N, O, and S, wherein the 4-7 heteroaryl and aryl groups containing 1-5 heteroatoms selected from N, O, and S are optionally surrounded by 0, 1, 2, 3, 4, or 5 R groups. 1a replace;

[0016] Each R 1a They may be the same or different, and each is independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, hydroxyl, cyano, amino and mercapto;

[0017] R2 is selected from H, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy are optionally substituted by 0, 1, 2, or 3 substituents selected from halogen, hydroxyl, cyano, amino, and mercapto.

[0018] R3 is selected from H, deuterium, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and mercapto.

[0019] X is -(CH2) m -; m is 1, 2, 3, or 4; Y is -(CH2). n -; n is 1, 2, 3 or 4.

[0020] Preferably, the compound has the structure shown in formula (II), formula (III), or formula (IV):

[0021]

[0022] Preferably, R1 is -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl. When it is cycloCy, cycloCy is selected from 4-6 member heteroaryl and aryl groups containing 1-4 (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, and S. The 4-6 member heteroaryl and aryl groups containing 1-4 heteroatoms selected from N, O, and S are optionally surrounded by 0, 1, 2, 3, or 4 R groups. 1a replace;

[0023] Preferably, R1 is -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl. When it is cycloCy, cycloCy is selected from 4-6 member heteroaryl and aryl groups containing 1-3 (e.g., 1, 2, or 3) heteroatoms selected from N, O, and S. The 4-6 member heteroaryl and aryl groups containing 1-3 heteroatoms selected from N, O, and S are optionally surrounded by 0, 1, 2, or 3 R groups. 1a replace;

[0024] Preferably, R1 is -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl. When it is cycloCy, cycloCy is selected from 4-6-membered heteroaryl and aryl groups containing 1-3 (e.g., 1, 2, or 3) heteroatoms selected from N, O, and S. The 4-6-membered heteroaryl and aryl groups containing 1-3 heteroatoms selected from N, O, and S are optionally surrounded by 0, 1, or 2 R groups. 1a replace;

[0025] Preferably, R1 is -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl. When it is cycloCy, cycloCy is selected from 5-6 member heteroaryl and aryl groups containing 1-3 (e.g., 1, 2, or 3) heteroatoms selected from N, O, and S. The 5-6 member heteroaryl and aryl groups containing 1-3 heteroatoms selected from N, O, and S are optionally surrounded by 0, 1, 2, or 3 R groups. 1a replace;

[0026] Preferably, R1 is -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl. When it is cycloCy, cycloCy is selected from 5-6 member heteroaryl and aryl groups containing 1-3 (e.g., 1, 2, or 3) N heteroatoms, wherein the 5-6 member heteroaryl and aryl groups containing 1-3 N heteroatoms are optionally surrounded by 0, 1, or 2 R atoms. 1a replace.

[0027] Preferably, R1 is -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl. When it is cycloCy, cycloCy is selected from...

[0028]

[0029] Where w is 0, 1 or 2, v is 0, 1, 2, 3, 4 or 5, and u is 0, 1, 2 or 3;

[0030] Preferably, R 1a Each is independently selected from H, deuterium, halogen, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy, hydroxyl, cyano, amino and mercapto;

[0031] Preferably, R 1a Each is independently selected from H, deuterium, halogen, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C3-C4 cycloalkoxy, and hydroxyl;

[0032] Preferably, R 1a Each is independently selected from H, deuterium, halogen, C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C3-C4 cycloalkoxy, and hydroxyl;

[0033] Preferably, R 1a Each is independently selected from H, deuterium, F, Cl, Br, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy, and hydroxyl;

[0034] Preferably, R 1a Each is independently selected from H, deuterium, F, Cl, Br, C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C3-C4 cycloalkoxy, and hydroxyl;

[0035] Preferably, R 1a Each is independently selected from H, deuterium, F, Cl, Br, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, and hydroxyl;

[0036] Preferably, R1 is -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl. When it is cycloCy, cycloCy is selected from:

[0037]

[0038] Preferably, R2 is selected from H, hydroxyl, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, and C3-C5 cycloalkoxy, wherein the C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, and C3-C5 cycloalkoxy are optionally substituted by 0, 1, 2, or 3 substituents selected from halogen, hydroxyl, cyano, amino, and mercapto.

[0039] Preferably, R2 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, and C3-C4 cycloalkoxy, wherein the C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, and C3-C4 cycloalkoxy are optionally substituted by 0, 1, 2, or 3 substituents selected from halogen, hydroxyl, cyano, amino, and mercapto.

[0040] Preferably, R2 is selected from methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, and propoxy, wherein the methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, and propoxy groups are optionally substituted by 0, 1, 2, or 3 substituents selected from halogen, hydroxyl, cyano, amino, and mercapto groups.

[0041] Preferably, R3 is selected from H, deuterium, C1-C4 alkyl, and C3-C5 cycloalkyl, wherein the C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted by 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and mercapto.

[0042] Preferably, R3 is selected from C1-C3 alkyl and C3-C4 cycloalkyl, wherein the C1-C3 alkyl and C3-C4 cycloalkyl are optionally substituted by 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and mercapto.

[0043] Preferably, R3 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally substituted by 0, 1, 2, or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino, and mercapto.

[0044] Preferably, X is -(CH2). m -, m is 1, 2 or 3;

[0045] Preferably, X is -(CH2). m -, m is 1 or 2.

[0046] Preferably, X is -(CH2). m -, m is 1.

[0047] Preferably, Y is -(CH2). n -, where n is 1, 2, or 3;

[0048] Preferably, Y is -(CH2). n - where n is 1 or 2.

[0049] In one specific embodiment, in formula (I), formula (II), formula (III) or formula (IV), R1 is -NR4R5 or cycloCy, R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl; cycloCy is selected from 5-6-membered heteroaryl and aryl groups containing 1-3 (e.g., 1, 2 or 3) N heteroatoms, wherein the 5-6-membered heteroaryl and aryl groups containing 1-3 N heteroatoms are optionally surrounded by 0, 1 or 2 R atoms. 1a replace;

[0050] R 1a Each is independently selected from H, deuterium, halogen, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy, hydroxyl, cyano, amino and mercapto;

[0051] R2 is selected from H, hydroxyl, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, and C3-C5 cycloalkoxy, wherein the C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, and C3-C5 cycloalkoxy are optionally substituted by 0, 1, 2, or 3 substituents selected from halogen, hydroxyl, cyano, amino, and mercapto.

[0052] R3 is selected from H, deuterium, C1-C4 alkyl, and C3-C5 cycloalkyl, wherein the C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted by 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and mercapto.

[0053] X is -(CH2) m -, m is 1, 2 or 3;

[0054] Y is -(CH2) n - where n is 1, 2, or 3. In another specific embodiment, in formula (I), formula (II), formula (III), or formula (IV), R1 is -NR4R5 or cycloCy, where R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl; cycloCy is selected from...

[0055]

[0056]

[0057] Where w is 0, 1 or 2, v is 0, 1, 2, 3, 4 or 5, and u is 0, 1, 2 or 3;

[0058] R 1a Each is independently selected from H, deuterium, halogen, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy, hydroxyl, cyano, amino and mercapto;

[0059] R2 is selected from H, hydroxyl, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, and C3-C5 cycloalkoxy, wherein the C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, and C3-C5 cycloalkoxy are optionally substituted by 0, 1, 2, or 3 substituents selected from halogen, hydroxyl, cyano, amino, and mercapto.

[0060] R3 is selected from H, deuterium, C1-C4 alkyl, and C3-C5 cycloalkyl, wherein the C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted by 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and mercapto.

[0061] X is -(CH2) m -, m is 1, 2 or 3;

[0062] Y is -(CH2) n - where n is 1, 2, or 3.

[0063] In another specific embodiment, in formula (I), formula (II), formula (III) or formula (IV), R1 is -NR4R5 or cycloCy, R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl; cycloCy is selected from

[0064]

[0065]

[0066] Where w is 0, 1 or 2, v is 0, 1, 2, 3, 4 or 5, and u is 0, 1, 2 or 3;

[0067] R 1a Each is independently selected from H, deuterium, halogen, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C3-C4 cycloalkoxy, and hydroxyl;

[0068] R2 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, and C3-C4 cycloalkoxy, wherein the C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, and C3-C4 cycloalkoxy are optionally substituted by 0, 1, 2, or 3 substituents selected from halogen, hydroxyl, cyano, amino, and mercapto.

[0069] R3 is selected from C1-C3 alkyl and C3-C4 cycloalkyl, wherein the C1-C3 alkyl and C3-C4 cycloalkyl are optionally substituted by 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and mercapto.

[0070] X is -(CH2) m -, m is 1, 2 or 3;

[0071] Y is -(CH2) n - where n is 1, 2, or 3.

[0072] In another specific embodiment, in formula (I), formula (II), formula (III) or formula (IV), R1 is -NR4R5 or cycloCy, and R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl; cycloCy is selected from:

[0073]

[0074]

[0075] R2 is selected from H, hydroxyl, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, and C3-C5 cycloalkoxy, wherein the C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, and C3-C5 cycloalkoxy are optionally substituted by 0, 1, 2, or 3 substituents selected from halogen, hydroxyl, cyano, amino, and mercapto.

[0076] R3 is selected from H, deuterium, C1-C4 alkyl, and C3-C5 cycloalkyl, wherein the C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted by 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and mercapto.

[0077] X is -(CH2) m -, m is 1, 2 or 3;

[0078] Y is -(CH2) n - where n is 1, 2, or 3.

[0079] In another specific embodiment, in formula (I), formula (II), formula (III) or formula (IV), R1 is -NR4R5 or cycloCy, R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl; cycloCy is selected from:

[0080]

[0081]

[0082] R2 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, and C3-C4 cycloalkoxy, wherein the C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, and C3-C4 cycloalkoxy are optionally substituted by 0, 1, 2, or 3 substituents selected from halogen, hydroxyl, cyano, amino, and mercapto.

[0083] R3 is selected from C1-C3 alkyl and C3-C4 cycloalkyl, wherein the C1-C3 alkyl and C3-C4 cycloalkyl are optionally substituted by 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and mercapto.

[0084] X is -(CH2) m -, m is 1, 2 or 3;

[0085] Y is -(CH2) n - where n is 1, 2, or 3.

[0086] In another specific embodiment, the compound represented by general formula (I) is selected from:

[0087]

[0088]

[0089] The compounds of formula (I) of the present invention can be prepared by chemical synthesis methods known in the art, for example, by retrosynthesis using commercially available raw materials. Specific synthetic examples are provided in the embodiments of the present invention.

[0090] On the other hand, the present invention provides a pharmaceutical composition comprising the above-mentioned compound or its stereoisomers, tautomers, deuterated derivatives, prodrugs or pharmaceutically acceptable salts, and pharmaceutically acceptable excipients, carriers or diluents.

[0091] Compared with existing technologies, the compounds of the present invention, or their stereoisomers, tautomers, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or pharmaceutical compositions thereof, can simultaneously inhibit PDE3 and PDE4. Furthermore, compared with the existing dual-target inhibitor of PDE3 and PDE4, RPL554, the compounds provided by the present invention, or their stereoisomers, tautomers, deuterated derivatives, prodrugs, pharmaceutically acceptable salts, or pharmaceutical compositions thereof, exhibit comparable or superior inhibitory activity against PDE3, significantly higher inhibitory activity against PDE4 than RPL554, and stronger activity against TNF-α and cAMP.

[0092] definition

[0093] Unless otherwise indicated, the meaning and scope of the terminology in this invention are explained below by way of example.

[0094] Indicates the connection site.

[0095] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix (C a-b Alkyl groups are defined as any alkyl group containing one to two carbon atoms ("a" to "b"). Therefore, for example, (C...) 1-6 Alkyl refers to an alkyl group containing 1 to 6 carbon atoms. The alkyl group may be branched or straight-chain.

[0096] The atoms described in this application include their isotopes; for example, hydrogen may be deuterium or tritium.

[0097] "Alkyl" refers to a monovalent straight-chain or branched saturated hydrocarbon group, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and other similar groups. C is preferred. 1-6 Alkyl group. More preferably, C10. 1-4 Alkyl group. More preferably, C10. 1-3 alkyl.

[0098] "Cycloalkyl" refers to a saturated monocyclic, cyclic, spirocyclic, fused, or bridged cycloalkyl group, which may be combined with other groups. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Preferred are 3-6 membered cycloalkyl groups. Preferred are 3-5 membered cycloalkyl groups. Preferred are 3-4 membered cycloalkyl groups.

[0099] "Halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine.

[0100] "Aryl" refers to a substituted or unsubstituted monocyclic or polycyclic aromatic group, including but not limited to phenyl and naphthyl. Preferably, it is a 6-10 membered monocyclic or bicyclic aromatic group. More preferably, it is phenyl or naphthyl. Most preferably, it is phenyl.

[0101] "Heteroaryl" refers to a substituted or unsubstituted 5- or 6-membered mono- or 6-membered heteroaryl ring system, or a substituted or unsubstituted 9- or 10-membered fused or di- or bis- or substituted heteroaryl ring system, containing 1-4 independent heteroatoms selected from N, O, or S, with the remaining ring atoms being carbon atoms. Examples of heteroaryl moieties include, but are not limited to: thiophene, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrroleyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, indolyl, indazole, quinolinyl, isoquinolinyl, benzimidazolyl, or benzothiazolyl.

[0102] "Pharmaceutically acceptable salts" refer to conventional acid-addition or base-addition salts that retain the bioavailability and properties of the compound of formula (I), formed from a suitable nontoxic organic or inorganic acid or organic or inorganic base. Examples of acid-addition salts include those derived from inorganic acids and organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, and nitric acid. Examples of organic acids include acetic acid, propionic acid, glycolic acid, oxalic acid, stearic acid, ascorbic acid, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid, succinic acid, citric acid, maleic acid, hydroxymaleic acid, lactic acid, fumaric acid, tartaric acid, malic acid, hydroxyethylsulfonic acid, benzenesulfonic acid, trifluoroacetic acid, mandelic acid, etc. Examples of base-addition salts include those derived from inorganic acids and organic acids, such as ammonium salts, calcium salts, iron salts, aluminum salts, sodium salts, potassium salts, zinc salts, and magnesium salts. The organic bases include salts of primary, secondary and tertiary amines, such as trimethylamine, triethylamine, tripropylamine, diethanolamine, ethylenediamine, ethanolamine, etc.

[0103] "Prodrug" refers to a prodrug that can be converted in vivo into the structure of the compound involved in this invention and its pharmaceutically acceptable salt. Detailed Implementation

[0104] The technical solution of the present invention will be further described below with reference to specific embodiments. These embodiments are merely illustrative of the present invention and not intended to limit its scope, and the implementation of the present invention is not limited thereto. Any changes, substitutions, modifications, simplifications, etc., made without departing from the technical concept and method principle of the present invention should be considered equivalent substitutions and are included within the protection scope of the present invention.

[0105] Unless otherwise specified, the chemical reagents and apparatus used in the following examples are commercially available.

[0106] Synthesis of intermediates

[0107]

[0108] 1. Synthesis of intermediate Int-A

[0109]

[0110] (1) Synthesis of A-2

[0111] A-1 (30 g, 166.48 mmol) was dissolved in acetic acid (200 mL), and ammonium acetate (32.1 g, 416.45 mmol) was added. The mixture was stirred at 10 °C for 15 minutes. Nitromethane (30.5 g, 499.67 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at 100 °C for 4 hours. After the reaction was complete, the reaction mixture was slowly poured into 500 mL of water. The precipitated solid was filtered, dried, and then slurried with 100 mL of methanol and dried to obtain A-2 (21 g, yellow solid), yield: 57%.

[0112] MSm / z(ESI):224.0[M+H]+.

[0113] (2) Synthesis of A-3

[0114] A-2 (21 g, 94.07 mmol) was dissolved in dimethyl sulfoxide (165 mL) and acetic acid (80 mL). Sodium borohydride (5.34 g, 141.16 mmol) was added in portions at 0 °C, and the mixture was stirred at 10 °C for 1 hour. After the reaction was complete, the reaction solution was slowly poured into 500 mL of water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give A-3 (21 g, yellow gel), yield: 99%.

[0115] MSm / z(ESI): 226.2 [M+H] + .

[0116] 1 H NMR(400MHz,Chloroform-d)δ6.82(d,J=8.2Hz,1H),6.77-6.66(m,2H),4.58(t,J=7.2H z, 2H), 4.08 (q, J = 7.2Hz, 2H), 3.85 (s, 3H), 3.25 (t, J = 7.6Hz, 2H), 1.46 (t, J = 7.2Hz, 3H).

[0117] (3) Synthesis of A-4

[0118] A-3 (20 g, 88.79 mmol) was dissolved in methanol (100 mL), and 5% palladium on carbon (4.44 g) was added under a nitrogen atmosphere. The mixture was purged three times with hydrogen, and stirred at 40 °C for 16 hours under hydrogen (15 psi). After the reaction was complete, the palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain A-4 (17 g, colorless gel), yield: 98%.

[0119] MSm / z(ESI):196.1[M+H]+.

[0120] (4) Synthesis of A-5

[0121] A-4 (17 g, 87.06 mmol) was added to ethyl cyanoacetate (32 mL), and the mixture was stirred at 100 °C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to dichloromethane / methanol = 10 / 1) to obtain A-5 (18 g, pale yellow solid), yield: 79%.

[0122] MSm / z(ESI): 263.1 [M+H] + .

[0123] 1 H NMR(400MHz,Chloroform-d)δ6.83(d,J=7.6Hz,1H),6.73(d,J=7.6Hz,2H),6.10(s,1H),4.10(q,J=7.2 Hz, 2H), 3.86 (s, 3H), 3.54 (q, J = 6.8Hz, 2H), 3.33 (s, 2H), 2.79 (t, J = 7.2Hz, 2H), 1.47 (t, J = 7.2Hz, 3H).

[0124] (5) Synthesis of A-6

[0125] A-5 (18 g, 68.62 mmol) was added in portions to phosphorus oxychloride (180 mL) at 85 °C, and stirred at 85 °C for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove most of the phosphorus oxychloride. The crude product was diluted with dichloromethane, poured into ice water, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The solution was extracted with dichloromethane, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to give intermediate A-6 (16 g, crude product, yellow solid), yield: 95%.

[0126] MSm / z(ESI): 245.2 [M+H] + .

[0127] (6) Synthesis of A-7

[0128] A-6 (16.0 g, 65.50 mmol) was added in portions to concentrated sulfuric acid (160 mL) at 0 °C, and stirred at 10 °C for 3 hours. After the reaction was complete, the reaction solution was slowly poured into ice water, the pH was adjusted to 7 with 4 M sodium hydroxide aqueous solution, and the mixture was extracted with dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give A-7 (11.4 g, yellow solid), yield: 66%.

[0129] MSm / z(ESI):263.2[M+H]+.

[0130] 1 H NMR(400MHz,DMSO-d6)δ9.44(t,J=3.2Hz,1H),7.06(s,1H),6.83(s,1H),6.26(s,2H),5.07(s,1H),4.06 (t,J=7.2Hz,2H),3.78(s,3H),3.27(td,J=6.4,2.8Hz,2H),2.72(t,J=6.4Hz,2H),1.34(t,J=7.2Hz,3H).

[0131] (7) Synthesis of A-8

[0132] Sodium metal (5.81 g, 252.72 mmol) was added in portions to ethanol (200 mL) at 0 °C, and the mixture was stirred until all the sodium metal had reacted. A-7 (11.4 g, 43.46 mmol) was added to freshly prepared sodium ethoxide solution, and the mixture was stirred at 80 °C for 1 hour. Then, diethyl carbonate (15.80 mL) was added to the reaction mixture, and the mixture was stirred at 80 °C for 8 hours. After the reaction was complete, the reaction mixture was slowly poured into ice water, and the pH was adjusted to 7 with 2 M hydrochloric acid. The solid precipitate was filtered and dried under reduced pressure to obtain A-8 (8.5 g, yellow solid), yield: 68%.

[0133] MSm / z(ESI): 289.1 [M+H] + .

[0134] 1 H NMR (400MHz, DMSO-d6) δ11.20(s,1H),7.35(s,1H),6.94(s,1H),6.22(d,J=2.1Hz,1H),4.08(q, J=6.9Hz,2H),3.89(t,J=6.2Hz,2H),3.83(s,3H),2.88(t,J=6.2Hz,2H),1.35(t,J=6.9Hz,3H).

[0135] (8) Synthesis of A-9

[0136] A-8 (8.0 g, 27.75 mmol) was added to phosphorus oxychloride (120 mL), and the mixture was stirred at 100 °C for 3 hours. After the reaction was complete, the filtrate was concentrated under reduced pressure to remove most of the phosphorus oxychloride. The crude product was diluted with dichloromethane, poured into ice water, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to give A-9 (8.0 g, crude product, yellow solid), yield: 94%.

[0137] MSm / z(ESI): 307.1 [M+H] + .

[0138] (9) Synthesis of intermediate Int-A

[0139] A-9 (1.5 g, 4.89 mmol) and A-10 (1.14 g, 7.54 mmol, purchased) were added to isopropanol (30 mL) and stirred at 90 °C for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature, the solid precipitate was filtered, washed with ethyl acetate, and dried under reduced pressure to give intermediate Int-A (2.0 g, yellow solid), yield: 97%.

[0140] MSm / z(ESI):422.2[M+H]+.

[0141] 2. Synthesis of intermediates Int-B to Int-D

[0142] Intermediates Int-B to Int-D were prepared using the same method as intermediate Int-A.

[0143] intermediate <![CDATA[MSm / z(ESI):[M+H] + ]]> Int-B 432.3 Int-C 406.2 Int-D 392.2

[0144] Example 1: Synthesis of Compound 1

[0145]

[0146] Synthesis of Compound 1-1

[0147] Compound Int-D (97.9 mg, 0.25 mmol), compound a (360.2 mg, 1.44 mmol), cesium carbonate (700.5 mg, 2.15 mmol), and sodium iodide (215.8 mg, 1.44 mmol) were added to 10 mL of butanone and stirred at 110 °C for 16 hours under nitrogen protection. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give compound 1-1 (34.1 mg, yellow oil), yield: 24%.

[0148] MSm / z(ESI): 561.4 [M+H] + .

[0149] Synthesis of Compounds 1-2

[0150] Compound 1-1 (34.1 mg, 0.061 mmol) was dissolved in dichloromethane (2 mL), followed by the addition of trifluoroacetic acid (0.5 mL), and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give compound 1-2 (26.7 mg, yellow oil), yield: 95%.

[0151] MSm / z(ESI): 461.4 [M+H] + .

[0152] Synthesis of Compound 1

[0153] Compound b (2.3 mg, 0.02 mmol), HATU (15.2 mg, 0.04 mmol), DIPEA (10.3 mg, 0.08 mmol), and compounds 1-2 (18.4 mg, 0.04 mmol) were added to 1.5 mL of DMF and stirred at 25 °C for 12 hours. After the reaction was completed, the reaction solution was purified by a C18 reverse-phase column (acetonitrile / aqueous solution containing 10 mM ammonium bicarbonate = 20%–50%; purification method: RP4-25 cm; flow rate: 40 mL / min; gradient time: 15 min) to give compound 1 (1.2 mg, yellow solid), yield: 5%.

[0154] MSm / z(ESI): 556.5 [M+H] + .

[0155] 1 H NMR(400MHz,Chloroform-d)δ8.22(s,1H),7.00(d,J=7.6Hz,2H),6.69(d,J=20.8Hz ,2H),5.42(s,1H),4.64(dd,J=13.6,5.2Hz,2H),4.34(dd,J=10.8,5.7Hz,1H),4.29 -4.05(m,3H),3.91(s,3H),3.87(s,1H),3.78(dd,J=10.4,5.6Hz,1H),3.74(s,3H), 3.04(s,1H),2.94(t,J=6.4Hz,2H),2.34(s,3H),2.14(d,J=9.6Hz,6H),1.25(s,1H).

[0156] Example 2: Synthesis of Compound 2

[0157]

[0158] Synthesis of Compound 2

[0159] Compound c (7.3 mg, 0.065 mmol), HATU (36.9 mg, 0.097 mmol), DIPEA (42.0 mg, 0.325 mmol), and compounds 1-2 (29.9 mg, 0.065 mmol) were added to DMF (1.5 mL) and stirred at 25 °C for 12 hours. After the reaction was completed, the reaction solution was purified by a C18 reverse-phase column (acetonitrile / aqueous solution containing 10 mM ammonium bicarbonate = 20%–50%; purification method: RP4-25 cm; flow rate: 40 mL / min; gradient time: 15 min) to give compound 2 (2.2 mg, white solid), yield: 6%.

[0160] MSm / z(ESI) = 555.3 [M+H] + .

[0161] 1 H NMR(400MHz,Chloroform-d)δ11.24(s,1H),7.49(s,1H),6.86(s,2H),6.69(d ,J=16.4Hz,2H),6.61(s,1H),5.46(s,1H),4.59(t,J=6.4Hz,4H),4.32(t,J=9. 6Hz,1H),4.18(dd,J=10.4,6.0Hz,1H),4.08-4.00(m,2H),3.90(s,3H),3.76( s, 3H), 3.45 (p, J = 7.2Hz, 1H), 2.91 (t, J = 6.4Hz, 2H), 2.27 (s, 3H), 2.03 (s, 6H).

[0162] Example 3: Synthesis of Compound 3

[0163]

[0164] Synthesis of compound 3-1

[0165] Compound Int-C (499 mg, 1.23 mmol), compound a (923 mg, 3.69 mmol), cesium carbonate (3.41 g, 10.47 mmol), and sodium iodide (1.05 g, 7.01 mmol) were added to 10 mL of butanone and stirred at 110 °C for 16 hours under nitrogen protection. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give compound 3-1 (427 mg, yellow solid), yield: 60%.

[0166] MSm / z(ESI) = 575.4 [M+H] + .

[0167] Synthesis of compound 3-2

[0168] Compound 3-1 (400 mg, 0.696 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of trifluoroacetic acid (3 mL), and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give compound 3-2 (300 mg, brown solid), yield: 91%.

[0169] MSm / z(ESI) = 475.3 [M+H] + .

[0170] Synthesis of Compound 3

[0171] Compound b (6.8 mg, 0.06 mmol), HATU (34.2 mg, 0.09 mmol), DIPEA (24.6 mg, 0.19 mmol), and compound 3-2 (28.5 mg, 0.06 mmol) were added to DMF (2 mL), and the mixture was stirred at 25 °C for 12 hours. After the reaction was complete, the reaction solution was purified by a C18 reverse-phase column (acetonitrile / aqueous solution containing 10 mM ammonium bicarbonate = 20%–50%; purification method: RP4-25 cm; flow rate: 40 mL / min; gradient time: 15 min) to give compound 3 (2.0 mg, white solid), yield: 6%.

[0172] MSm / z(ESI): 570.4 [M+H] + .

[0173] 1 H NMR (400MHz, Methanol-d4) δ7.95(s,1H),7.17(d,J=4.0Hz,2H),6.95(s,1H),6.69(s,1H),5.56(s,1H),4.63(dd,J=13.6,4.4Hz,1 H),4.14(q,J=6.8Hz,4H),3.83-3.60(m,9H),3.03(t,J=6.4Hz,2H),2.37(s,3H),2.28(s,3H),2.24(s,3H),1.42(t,J=7.2Hz,3H).

[0174] Example 4: Synthesis of Compound 4

[0175]

[0176] Synthesis of Compound 4

[0177] Compound d (8.3 mg, 0.065 mmol), HATU (36.9 mg, 0.097 mmol), DIPEA (42.0 mg, 0.325 mmol), and compounds 1-2 (29.9 mg, 0.065 mmol) were added to DMF (1 mL) and stirred at 25 °C for 12 hours. After the reaction was completed, the reaction solution was purified by a C18 reverse-phase column (acetonitrile / aqueous solution containing 10 mM ammonium bicarbonate = 20%–50%; purification method: RP4-25 cm; flow rate: 40 mL / min; gradient time: 15 min) to give compound 4 (2.8 mg, white solid), yield: 8%.

[0178] MSm / z(ESI) = 570.3 [M+H] + .

[0179] 1 H NMR(400MHz,Chloroform-d)δ13.13(s,1H),6.85(d,J=3.2Hz,2H),6.69(d,J=14.4H z,2H),5.47(s,1H),4.73-4.62(m,2H),4.62-4.53(m,2H),4.29(t,J=9.6Hz,1H),4. 18(dd,J=10.4,5.6Hz,1H),4.05(t,J=6.4Hz,2H),3.90(s,3H),3.76(s,3H),3.49-3 .39(m,1H),2.92(t,J=6.4Hz,2H),2.52(s,3H),2.26(s,3H),2.04(d,J=7.2Hz,6H).

[0180] Example 5: Synthesis of Compound 5

[0181]

[0182] Synthesis of Compound 5-1

[0183] Compound Int-D (493 mg, 1.26 mmol), compound e (1.00 g, 3.79 mmol), cesium carbonate (3.58 g, 10.99 mmol), and sodium iodide (1.08 g, 7.21 mmol) were added to DMF (10 mL) and stirred at 110 °C for 16 hours under nitrogen protection. After the reaction was complete, the reaction solution was filtered, and the filtrate was extracted with water and ethyl acetate. The organic phase was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give compound 5-1 (136 mg, yellow oil), yield: 19%.

[0184] MSm / z(ESI) = 575.4 [M+H] + .

[0185] Synthesis of compound 5-2

[0186] Compound 5-1 (136 mg, 0.237 mmol) was dissolved in dichloromethane (3 mL), followed by the addition of trifluoroacetic acid (0.5 mL), and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give compound 5-2 (110 mg, yellow oil), yield: 98%.

[0187] MSm / z(ESI) = 475.3 [M+H] + .

[0188] Synthesis of Compound 5

[0189] Compound b (19.0 mg, 0.168 mmol), HATU (120.2 mg, 0.316 mmol), DIPEA (135.7 mg, 1.050 mmol), and compound 5-2 (99.7 mg, 0.210 mmol) were added to DMF (3 mL), and the mixture was stirred at 25 °C for 12 hours. After the reaction was complete, the reaction solution was purified by a C18 reverse-phase column (acetonitrile / aqueous solution containing 10 mM ammonium bicarbonate = 20%–50%; purification method: RP4-25 cm; flow rate: 40 mL / min; gradient time: 15 min) to give compound 5 (26 mg, white solid), yield: 22%.

[0190] MSm / z(ESI) = 570.4 [M+H] + .

[0191] 1 H NMR (400MHz, Chloroform-d) δ8.21 (d, J=18.8Hz, 1H), 6.85 (d, J=3.2Hz, 2H), 6.69 (dd, J=18. 8,4.4Hz,2H),5.48(d,J=1.6Hz,1H),4.48-4.31(m,2H),4.19(dd,J=11.2,7.6Hz,1H),4.14-3 .86(m,7H),3.76(d,J=3.2Hz,3H),3.67(dd,J=9.6,3.0Hz,1H),3.16-3.02(m,1H),2.91(d,J =6.8Hz,2H),2.25(d,J=2.4Hz,3H),2.19-2.12(m,1H),2.07-2.01(m,6H),1.99-1.90(m,1H).

[0192] Example 6: Synthesis of Compound 6

[0193]

[0194] Synthesis of Compound 6

[0195] Compound f (3.0 mg, 0.021 mmol), HATU (12.2 mg, 0.032 mmol), DIPEA (8.1 mg, 0.063 mmol), and compound 3-2 (10.0 mg, 0.021 mmol) were added to DMF (1 mL), and the mixture was stirred at 25 °C for 12 hours. After the reaction was complete, the reaction solution was purified by a C18 reversed-phase column (acetonitrile / aqueous solution containing 10 mM ammonium bicarbonate = 20%–50%; purification method: RP 4-25 cm; flow rate: 40 mL / min; gradient time: 15 min) to give compound 6 (2.2 mg, yellow solid), yield: 17%.

[0196] MSm / z(ESI) = 600.4[M+H] + .

[0197] 1 H NMR(400MHz,Chloroform-d)δ9.73(s,1H),7.03(d,J=2.8Hz,2H),6.73(s,1H),6.56(s,1H),5.45(s,1H),4.65(d,J=14.0Hz,1H),4. 15(q,J=6.8Hz,4H),4.01(s,3H),3.70(s,8H),3.00(s,2H),2.81(s,1H),2.34(s,3H),2.22(d,J=20.8Hz,6H),1.48(t,J=6.8Hz,3H).

[0198] Example 7: Synthesis of Compound 7

[0199]

[0200] Synthesis of Compound 7-1

[0201] Compound Int-A (198.1 mg, 0.47 mmol), compound a (354.7 mg, 1.42 mmol), cesium carbonate (462.7 mg, 1.42 mmol), and sodium iodide (212.8 mg, 1.42 mmol) were added to 10 mL of butanone and stirred at 110 °C for 16 hours under nitrogen protection. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give compound 7-1 (154 mg, yellow solid), yield: 55%.

[0202] MSm / z(ESI): 591.4 [M+H] + .

[0203] Synthesis of Compound 7-2

[0204] Compound 7-1 (154 mg, 0.26 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of trifluoroacetic acid (1.5 mL), and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give compound 7-2 (120 mg, yellow oil), yield: 94%.

[0205] MSm / z(ESI): 491.3 [M+H] + .

[0206] Synthesis of Compound 7

[0207] Compound 7-2 (44.2 mg, 0.09 mmol) was added to water (1 mL), followed by acetic acid (7.8 mg, 0.13 mmol) and potassium cyanate (34.9 mg, 0.43 mmol). The mixture was stirred at 80 °C for 12 hours under nitrogen protection. After the reaction was complete, the reaction solution was purified by a C18 reverse-phase column (acetonitrile / aqueous solution containing 10 mM ammonium bicarbonate = 20%–50%; purification method: RP 4-25 cm; flow rate: 40 mL / min; gradient time: 15 min) to give compound 7 (12.4 mg, white solid), yield: 26%.

[0208] MSm / z(ESI): 534.4 [M+H] + .

[0209] 1 H NMR(400MHz, Methanol-d4)δ6.96(s,1H),6.94-6.87(m,2H),6.72(s,1H),5.59(s,1H),4.63-4.54(m,1H),4.23-4.12(m,4H),3.85(s,3H) ), 3.75(dd,J=14.4,4.0Hz,1H),3.68(s,6H),3.41-3.35(m,2H),3.04(t,J=6.4Hz,2H),2.28(s,4H),2.25(s,4H),1.43(t,J=7.2Hz,3H).

[0210] Example 8: Synthesis of Compound 8 and Compound 10

[0211]

[0212] Compound b (10.2 mg, 0.09 mmol), HATU (49.4 mg, 0.13 mmol), DIPEA (33.6 mg, 0.26 mmol), and compound 7-2 (44.2 mg, 0.09 mol) were added to DMF (2 mL), and the mixture was stirred at 25 °C for 12 hours. After the reaction was complete, the reaction solution was purified by separation using a C18 reverse-phase column (acetonitrile / aqueous solution containing 10 mM ammonium bicarbonate = 20%–50%; purification method: RP4-25 cm; flow rate: 40 mL / min; gradient time: 15 min) to obtain compound 8 (10 mg, white solid, yield: 19%) and compound 10 (9 mg, white solid, yield: 17%).

[0213] Compound 8: MS m / z (ESI): 586.4 [M+H] + .

[0214] 1 H NMR (400MHz, DMSO-d6) δ8.22(t,J=6.4Hz,1H),7.62(s,1H),7.05(s,1H),6.89(q,J =2.8Hz,2H),6.65(s,1H),5.46(s,1H),4.50-4.40(m,1H),4.16-4.00(m,4H),3.78 (s,3H),3.72-3.65(m,2H),3.61(s,3H),3.59-3.48(m,2H),3.45(d,J=6.8Hz,1H), 2.98 (t, J = 5.6 Hz, 2H), 2.68 (s, 1H), 2.20 (d, J = 18.4 Hz, 6H), 1.34 (t, J = 6.8 Hz, 3H).

[0215] Compound 10:

[0216] MSm / z(ESI): 586.3 [M+H] + .

[0217] 1H NMR (400MHz, DMSO-d6) δ8.23(t,J=6.5Hz,1H),7.63(s,1H),7.05(s,1H),6.90(q,J =2.8Hz,2H),6.66(s,1H),5.46(s,1H),4.51-4.40(m,1H),4.16-4.00(m,4H),3.79 (s,3H),3.72-3.66(m,2H),3.61(s,3H),3.59-3.49(m,2H),3.46(d,J=6.7Hz,1H), 2.99 (t, J = 5.5 Hz, 2H), 2.69 (s, 1H), 2.22 (d, J = 18.3 Hz, 6H), 1.35 (t, J = 6.8 Hz, 3H).

[0218] Example 9: Synthesis of Compound 9

[0219]

[0220] Compound g (10.2 mg, 0.09 mmol), HATU (49.4 mg, 0.13 mmol), DIPEA (33.6 mg, 0.26 mmol), and compound 7-2 (44.2 mg, 0.09 mol) were added to DMF (2 mL), and the mixture was stirred at 25 °C for 12 hours. After the reaction was completed, the reaction solution was purified by a C18 reverse-phase column (acetonitrile / aqueous solution containing 10 mM ammonium bicarbonate = 20%–50%; purification method: RP4-25 cm; flow rate: 40 mL / min; gradient time: 15 min) to give compound 9 (22 mg, white solid), yield: 42%.

[0221] MSm / z(ESI): 586.4 [M+H] + .

[0222] 1 H NMR (400MHz, Methanol-d4) δ7.94(s,1H),6.95(s,1H),6.89(q,J=3.2Hz,2H),6.72(s,1H),5.59(s,1H),4.62(dd,J=14.0,4.4Hz,1H),4.19- 4.11(m,4H),3.84(s,4H),3.80-3.60(m,8H),3.03(t,J=6.8Hz,2H),2.78(d,J=6.4Hz,1H),2.28(s,3H),2.25(s,3H),1.42(t,J=7.2Hz,3H).

[0223] Example 10: Synthesis of Compound 11 and Compound 13

[0224]

[0225] Synthesis of Compound 11-1

[0226] Compound Int-B (151 mg, 0.35 mmol), compound a (260 mg, 1.04 mmol), cesium carbonate (339 mg, 1.04 mmol), and sodium iodide (156 mg, 1.04 mmol) were added to 10 mL of butanone and stirred at 110 °C for 16 hours under nitrogen protection. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give compound 11-1 (90 mg, yellow solid), yield: 43%.

[0227] MSm / z(ESI): 601.4 [M+H] + .

[0228] Synthesis of compound 11-2

[0229] Compound 11-1 (90 mg, 0.15 mmol) was dissolved in dichloromethane (6 mL), then trifluoroacetic acid (2 mL) was added, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give compound 11-2 (70 mg, yellow oil), yield: 93%.

[0230] MSm / z(ESI): 501.3 [M+H] + .

[0231] Synthesis of Compounds 11 and 13

[0232] Compound b (5.0 mg, 0.044 mmol), HATU (25.1 mg, 0.066 mmol), DIPEA (16.8 mg, 0.130 mmol), and compound 11-2 (22.0 mg, 0.044 mmol) were added to DMF (2 mL), and the mixture was stirred at 25 °C for 12 hours. After the reaction was completed, the reaction solution was purified by separation using a C18 reverse-phase column (acetonitrile / aqueous solution containing 10 mM ammonium bicarbonate = 20%–50%; purification method: RP4-25 cm; flow rate: 40 mL / min; gradient time: 15 min) to obtain compound 11 (5 mg, yellow solid, yield: 19%) and compound 13 (7 mg, white solid, yield: 27%).

[0233] Compound 11:

[0234] MSm / z(ESI): 596.4 [M+H] + .

[0235] 1 ¹H NMR (400 MHz, Methanol-d4) δ 8.14(s, 1H), 6.99(s, 2H), 6.88(s, 1H), 6.67(s, 1H), 5.45(s, 1H), 4.68(t, J=9.1 Hz, 1H), 4.45-4.29(m, 2H), 4.25-4.04(m, 6H), 3.90-3.80(m, 1H), 3.66(s, 3H), 3.16-3.10(m, 1H), 2.93(t, J=6.6 Hz, 2H), 2.15(s, 6H), 1.98-1.91(m, 1H), 1.40(t, J=7.0 Hz, 3H), 1.06-0.96(m, 2H), 0.79-0.70(m, 2H).

[0236] Compound 13:

[0237] MS m / z (ESI): 596.4 [M+H] + .

[0238] 1 ¹H NMR (400 MHz, Methanol-d4) δ 8.15(s, 1H), 7.00(s, 2H), 6.88(s, 1H), 6.68(s, 1H), 5.46(s, 1H), 4.69(t, J=9.2 Hz, 1H), 4.45-4.29(m, 2H), 4.25-4.03(m, 6H), 3.90-3.81(m, 1H), 3.67(s, 3H), 3.17-3.10(m, 1H), 2.93(t, J=6.4 Hz, 2H), 2.17(s, 6H), 1.97-1.89(m, 1H), 1.41(t, J=7.2 Hz, 3H), 1.06-0.95(m, 2H), 0.79-0.69(m, 2H).

[0239] Example 11: Synthesis of Compound 12

[0240]

[0241] Compound g (5.0 mg, 0.044 mmol), HATU (25.1 mg, 0.066 mmol), DIPEA (16.8 mg, 0.130 mmol), and compound 11-2 (22.0 mg, 0.044 mmol) were added to DMF (2 mL), and the mixture was stirred at 25 °C for 12 hours. After the reaction was complete, the reaction solution was purified by a C18 reverse-phase column (acetonitrile / aqueous solution containing 10 mM ammonium bicarbonate = 20%–50%; purification method: RP4-25 cm; flow rate: 40 mL / min; gradient time: 15 min) to give compound 12 (11 mg, white solid), yield: 42%.

[0242] MSm / z(ESI):596.4[M+H]+.

[0243] 1 H NMR (400MHz, Methanol-d4) δ7.94 (s, 1H), 7.05 (d, J = 3.6Hz, 2H), 6.95 (s, 1H), 6 .67(s,1H),5.53(s,1H),4.63(dd,J=14.0,4.4Hz,1H),4.22-4.10(m,4H),3.88- 3.62(m,8H),3.03(t,J=6.8Hz,2H),2.82-2.73(s,1H),2.25(d,J=15.6Hz,6H), 1.99-1.89(m,1H),1.42(t,J=7.2Hz,3H),1.10-1.00(m,2H),0.79-0.71(m,2H).

[0244] Example 12: Synthesis of Compound 14

[0245]

[0246] Synthesis of Compound 14

[0247] Compound d (2.5 mg, 0.02 mmol), HATU (11.4 mg, 0.03 mmol), DIPEA (7.8 mg, 0.06 mmol), and compound 3-2 (9.5 mg, 0.02 mmol) were added to DMF (1 mL), and the mixture was stirred at 25 °C for 12 hours. After the reaction was complete, the reaction solution was purified by a C18 reversed-phase column (acetonitrile / aqueous solution containing 10 mM ammonium bicarbonate = 20%–50%; purification method: RP4-25 cm; flow rate: 40 mL / min; gradient time: 15 min) to give compound 14 (2.2 mg, white solid), yield: 19%.

[0248] MSm / z(ESI): 584.4 [M+H]+ .

[0249] 1 H NMR(400MHz,Chloroform-d)δ9.43(s,1H),7.02(d,J=8.4Hz,2H),6.67(d,J=26 .8Hz,2H),5.47(s,1H),4.39(d,J=14.0Hz,1H),4.15(q,J=6.8Hz,4H),4.07-3. 91(m,2H),3.83(d,J=8.4Hz,1H),3.73(s,5H),3.14(s,1H),2.97(d,J=6.8Hz,2 H), 2.44 (s, 3H), 2.33 (s, 3H), 2.30 (s, 3H), 2.13 (s, 3H), 1.48 (t, J = 7.2Hz, 3H).

[0250] Example 13: Synthesis of Compound 15

[0251]

[0252] Synthesis of Compound 15

[0253] Compound c (2.4 mg, 0.021 mmol), HATU (12.2 mg, 0.032 mmol), DIPEA (8.1 mg, 0.063 mmol), and compound 3-2 (10.0 mg, 0.021 mmol) were added to DMF (1 mL), and the mixture was stirred at 25 °C for 12 hours. After the reaction was complete, the reaction solution was purified by a C18 reverse-phase column (acetonitrile / aqueous solution containing 10 mM ammonium bicarbonate = 20%–50%; purification method: RP4-25 cm; flow rate: 40 mL / min; gradient time: 15 min) to give compound 15 (1.8 mg, yellow solid), yield: 15%.

[0254] MSm / z(ESI):569.3[M+H]+.

[0255] 1H NMR (400MHz, DMSO-d6) δ7.75(d,J=2.4Hz,1H),6.94(s,1H),6.85(s,2H),6.66(s,1H),6.59(d,J=2.4Hz,1H),5.32(s,1H),4.68-4.42(m,4H),4.15 -4.02(m,3H),4.00-3.89(m,3H),3.61(s,3H),3.25-3.22(m,1H),2.89(t ,J=6.4Hz,2H),2.21(s,3H),1.96(d,J=5.2Hz,6H),1.33(t,J=6.8Hz,3H).

[0256] Example 14: Synthesis of Compound 16

[0257]

[0258] Compound h (5.6 mg, 0.044 mmol), HATU (25.1 mg, 0.066 mmol), DIPEA (16.8 mg, 0.130 mmol), and compound 11-2 (22.0 mg, 0.044 mmol) were added to DMF (2 mL), and the mixture was stirred at 25 °C for 12 hours. After the reaction was completed, the reaction solution was purified by a C18 reverse-phase column (acetonitrile / aqueous solution containing 10 mM ammonium bicarbonate = 20%–50%; purification method: RP4-25 cm; flow rate: 40 mL / min; gradient time: 15 min) to give compound 16 (8 mg, white solid), yield: 30%.

[0259] MSm / z(ESI): 610.3 [M+H] + .

[0260] 1 H NMR (400MHz, Methanol-d4) δ7.97 (s, 1H), 7.12 (d, J = 3.3Hz, 2H), 6.98 (s, 1H), 6. 69(s,1H),5.55(s,1H),4.66-4.61(m,1H),4.20-4.10(m,4H),3.89-3.64(m,8H) ,3.03(t,J=6.6Hz,2H),2.80-2.73(s,1H),2.55(s,3H),2.28(d,J=15.2Hz,6H), 2.01-1.91(m,1H),1.42(t,J=7.0Hz,3H),1.11-1.00(m,2H),0.82-0.74(m,2H).

[0261] Example 15: Synthesis of Compound 17

[0262]

[0263] Synthesis of Compound 17

[0264] Compounds 1-2 (41.5 mg, 0.09 mmol) were added to water (1 mL), followed by acetic acid (7.8 mg, 0.13 mmol) and potassium cyanate (34.9 mg, 0.43 mmol). The mixture was stirred at 80 °C for 12 hours under nitrogen protection. After the reaction was complete, the reaction solution was purified by a C18 reverse-phase column (acetonitrile / aqueous solution containing 10 mM ammonium bicarbonate = 20%–50%; purification method: RP 4-25 cm; flow rate: 40 mL / min; gradient time: 15 min) to give compound 17 (16.8 mg, white solid), yield: 37%.

[0265] MSm / z(ESI): 504.4 [M+H] + .

[0266] 1 H NMR(400MHz, Methanol-d4)δ7.02(s,1H),6.98-6.92(m,2H),6.76(s,1H),5.59(s,1H),4.63-4.54(m,1H),4.23-4. 12(m,4H),3.85(s,3H),3.78-3.72(m,1H),3.68(s,6H),3.41-3.35(m,2H),3.04(s,3H),2.28(s,4H),2.25(s,4H).

[0267] Comparative Example 1: Synthesis of RPL554

[0268]

[0269] RPL554 was synthesized according to the preparation method provided in invention patent WO 00 / 58308A1.

[0270] MSm / z(ESI): 478.2 [M+H] + .

[0271] 1 H NMR (400MHz, CDCl3) δ6.89 (s, 2H), 6.70 (s, 1H), 6.67 (s, 1H), 5.45 (s, 1H), 4.41 (t, J = 6.99Hz, 2H), 4.07-4. 02(m,2H),3.90(s,3H),3.76(s,3H),3.58-3.49(m,2H),2.91(t,J=6.17Hz,2H),2.28(s,3H),2.06(s,6H).

[0272] Experimental Example 1: Test of the inhibitory activity of representative compounds against PDE3A and PDE4B enzymes

[0273] 1) Materials and equipment:

[0274] name factory PDE3A Assay Kit BPS PDE4B2 Assay Kit BPS PDE4B1 Assay Kit BPS Black 96-well Plate PerkinElmer EnVision-2104 Multichannel Microplate Reader PerkinElmer

[0275] 2) Experimental methods:

[0276] (1) Compound dilution: First, prepare a 10 μM concentrated stock solution of the compound using DMSO. When testing the single-concentration inhibition rate, administer the compound directly according to the corresponding dilution ratio; when testing the enzyme activity IC50... 50 At that time, the concentrated stock solution of the compound was diluted at a concentration gradient of 4 times starting from 10 μM to obtain a total of 10 concentration points.

[0277] (2) Prepare the incubation system according to the table below, mix well and incubate at room temperature for 1 hour.

[0278]

[0279] (3) After incubation, add 100 μL of Binding Agent to each group to dilute the above system, mix well and continue incubation at room temperature for 1 h.

[0280] (4) After the second round of incubation, place the sample in a microplate reader and detect the fluorescence signal according to the test conditions of excitation wavelength 490nm and emission wavelength 520nm, and calculate the fluorescence signal according to %Inhibition rate = (FP B -FP S ) / (FP B -FP V The inhibition rate is calculated using the formula 100% × 100%.

[0281] 3) Test Results

[0282]

[0283]

[0284] Verification has shown that the compounds provided by this invention have good inhibitory activity against both PDE3A and PDE4B, which is superior to RPL554.

[0285] Experimental Example 2: Representative Compounds' Agonistaltic Activity in Enhancing Intracellular cAMP Concentration

[0286] 1) Materials and equipment:

[0287] name factory Item number HTRF cAMP HiRange kit Cisbio 62AM6PEB Forskolin MCE HY-15371 Black 96-well Plate PerkinElmer 6005540 EnVision-2104 Multichannel Microplate Reader PerkinElmer - Countstar BioMed Automated Cell Counter Shanghai Ruiyu Biotechnology -

[0288] 2) Experimental methods:

[0289] (1) Add the compound 30 minutes before adding Forskolin, then add the remaining components in the table other than the compound, mix gently, and incubate at room temperature for 1 hour.

[0290] The incubation system is as follows:

[0291]

[0292]

[0293] (2) After incubation, the fluorescence signal was detected and the data was read using an enzyme-linked immunosorbent assay (ELISA) reader under the test conditions of excitation wavelength 340 nm and emission wavelengths 616 nm and 665 nm.

[0294] 3) Test Results

[0295]

[0296]

[0297] Verification has shown that the compounds provided by this invention have good and high cAMP agonist activity.

[0298] Experimental Example 3: Inhibitory effect of representative compounds on the secretion of the inflammatory factor TNF-α

[0299] 1) Materials and equipment:

[0300]

[0301] 2) Experimental methods:

[0302] (1) Mononuclear cells (concentration of 10) 6 ( / ml) was suspended in RPMI 1640 medium containing 1% fetal bovine serum and inoculated into 96-well plates (10 ml per well). 5 Incubate the cells in 5% CO2 at 37°C for 2 hours to allow them to adhere.

[0303] (2) Adherent cells were cultured in fresh RPMI 1640 medium containing 1% fetal bovine serum at 37°C under 5% CO2 conditions. The medium contained LPS (10 ng / ml) and a compound (maximum final concentration 10 μM, 4-fold dilution).

[0304] (2) After 18 hours, the cell supernatant was collected. Following the instructions of the TNF-α enzyme-linked immunosorbent assay (ELISA) kit, the concentration of TNF-α in the supernatant was measured, and the IC50 was determined. 50 .

[0305] 3) Test Results

[0306]

[0307]

[0308] Verification has shown that the compounds provided by this invention have a good effect in inhibiting the release of TNF-α.

Claims

1. A compound of general formula (I) or its stereoisomers, tautomers, deuterated derivatives, prodrugs or their chemically acceptable salts: in, R1 is selected from -NR4R5 or cyclone Cy; R4 and R5 are independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl; Cy is selected from 4-7 heteroaryl and aryl groups containing 1-5 heteroatoms selected from N, O, and S, wherein the 4-7 heteroaryl and aryl groups containing 1-5 heteroatoms selected from N, O, and S are optionally surrounded by 0, 1, 2, 3, 4, or 5 R groups. 1a replace; Each R 1a They may be the same or different, and each is independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, hydroxyl, cyano, amino and mercapto; R2 is selected from H, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy are optionally substituted by 0, 1, 2, or 3 substituents selected from halogen, hydroxyl, cyano, amino, and mercapto. R3 is selected from H, deuterium, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted by 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and mercapto. X is -(CH2) m -; m is 1, 2, 3, or 4; Y is -(CH2). n -; n is 1, 2, 3 or 4.

2. The compound according to claim 1, or its stereoisomers, tautomers, deuterated derivatives, prodrugs, or chemically acceptable salts thereof, wherein, The compound has the structure shown in formula (II), formula (III) or formula (IV):

3. The compound according to claim 1 or 2, or its stereoisomers, tautomers, deuterated derivatives, prodrugs, or chemically acceptable salts thereof, wherein, R1 is -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl. When it is cycloCy, cycloCy is selected from 5-6-membered heteroaryl and aryl groups containing 1-3 heteroatoms selected from N, O, and S. The 5-6-membered heteroaryl and aryl groups containing 1-3 heteroatoms selected from N, O, and S are optionally surrounded by 0, 1, 2, or 3 R groups. 1a replace.

4. The compound according to claim 1 or 2, or its stereoisomers, tautomers, deuterated derivatives, prodrugs, or chemically acceptable salts thereof, wherein, R1 is either -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl. When it is cycloCy, cycloCy is selected from... Where w is 0, 1 or 2, v is 0, 1, 2, 3, 4 or 5, and u is 0, 1, 2 or 3; R 1a Each is independently selected from H, deuterium, halogen, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C3-C4 cycloalkoxy, and hydroxyl.

5. The compound according to claim 1 or 2, or its stereoisomers, tautomers, deuterated derivatives, prodrugs, or chemically acceptable salts thereof, wherein, R1 is -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl. When it is cycloCy, cycloCy is selected from:

6. The compound according to claim 1 or 2, or its stereoisomers, tautomers, deuterated derivatives, prodrugs, or chemically acceptable salts thereof, wherein, R2 is selected from H, hydroxyl, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, and C3-C5 cycloalkoxy, wherein the C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, and C3-C5 cycloalkoxy are optionally substituted by 0, 1, 2, or 3 substituents selected from halogen, hydroxyl, cyano, amino, and mercapto.

7. The compound according to claim 1 or 2, or its stereoisomers, tautomers, deuterated derivatives, prodrugs, or chemically acceptable salts thereof, wherein, R3 is selected from H, deuterium, C1-C4 alkyl, and C3-C5 cycloalkyl, wherein the C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted by 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and mercapto.

8. The compound according to claim 1 or 2, or its stereoisomers, tautomers, deuterated derivatives, prodrugs, or chemically acceptable salts thereof, wherein, X is -(CH2) m -, m is 1, 2 or 3.

9. The compound according to claim 1 or 2, or its stereoisomers, tautomers, deuterated derivatives, prodrugs, or chemically acceptable salts thereof, wherein, Y is -(CH2) n - where n is 1, 2, or 3.

10. The compound according to claim 1 or 2, or a stereoisomer, tautomer, deuterated product, prodrug, or a chemically acceptable salt thereof, wherein, In formula (I), (II), (III), or (IV), R1 is -NR4R5 or cycloCy, R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl; cycloCy is selected from 5-6-membered heteroaryl and aryl groups containing 1-3 N heteroatoms, wherein the 5-6-membered heteroaryl and aryl groups containing 1-3 N heteroatoms are optionally surrounded by 0, 1, or 2 R groups. 1a replace; R 1a Each is independently selected from H, deuterium, halogen, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy, hydroxyl, cyano, amino and mercapto; R2 is selected from H, hydroxyl, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, and C3-C5 cycloalkoxy, wherein the C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, and C3-C5 cycloalkoxy are optionally substituted by 0, 1, 2, or 3 substituents selected from halogen, hydroxyl, cyano, amino, and mercapto. R3 is selected from H, deuterium, C1-C4 alkyl, and C3-C5 cycloalkyl, wherein the C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted by 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and mercapto. X is -(CH2) m -, m is 1, 2 or 3; Y is -(CH2) n - where n is 1, 2, or 3.

11. The compound or its stereoisomers, tautomers, deuterated derivatives, prodrugs or chemically acceptable salts according to claim 1 or 2, wherein, In formula (I), formula (II), formula (III), or formula (IV), R1 is -NR4R5 or cycloCy, and R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl; cycloCy is selected from... Where w is 0, 1 or 2, v is 0, 1, 2, 3, 4 or 5, and u is 0, 1, 2 or 3; R 1a Each is independently selected from H, deuterium, halogen, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy, hydroxyl, cyano, amino and mercapto; R2 is selected from H, hydroxyl, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, and C3-C5 cycloalkoxy, wherein the C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, and C3-C5 cycloalkoxy are optionally substituted by 0, 1, 2, or 3 substituents selected from halogen, hydroxyl, cyano, amino, and mercapto. R3 is selected from H, deuterium, C1-C4 alkyl, and C3-C5 cycloalkyl, wherein the C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted by 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and mercapto. X is -(CH2) m -, m is 1, 2 or 3; Y is -(CH2) n - where n is 1, 2, or 3.

12. The compound or its stereoisomers, tautomers, deuterated derivatives, prodrugs or chemically acceptable salts according to claim 1 or 2, wherein, In formula (I), formula (II), formula (III), or formula (IV), R1 is -NR4R5 or cycloCy, and R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl; cycloCy is selected from... Where w is 0, 1 or 2, v is 0, 1, 2, 3, 4 or 5, and u is 0, 1, 2 or 3; R 1a Each is independently selected from H, deuterium, halogen, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C3-C4 cycloalkoxy, and hydroxyl; R2 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, and C3-C4 cycloalkoxy, wherein the C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, and C3-C4 cycloalkoxy are optionally substituted by 0, 1, 2, or 3 substituents selected from halogen, hydroxyl, cyano, amino, and mercapto. R3 is selected from C1-C3 alkyl and C3-C4 cycloalkyl, wherein the C1-C3 alkyl and C3-C4 cycloalkyl are optionally substituted by 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and mercapto. X is -(CH2) m -, m is 1, 2 or 3; Y is -(CH2) n - where n is 1, 2, or 3.

13. The compound or its stereoisomers, tautomers, deuterated derivatives, prodrugs or chemically acceptable salts according to claim 1 or 2, wherein, In formula (I), formula (II), formula (III), or formula (IV), R1 is -NR4R5 or cycloCy, and R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl; cycloCy is selected from: R2 is selected from H, hydroxyl, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, and C3-C5 cycloalkoxy, wherein the C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, and C3-C5 cycloalkoxy are optionally substituted by 0, 1, 2, or 3 substituents selected from halogen, hydroxyl, cyano, amino, and mercapto. R3 is selected from H, deuterium, C1-C4 alkyl, and C3-C5 cycloalkyl, wherein the C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted by 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and mercapto. X is -(CH2) m -, m is 1, 2 or 3; Y is -(CH2) n - where n is 1, 2, or 3.

14. The compound or its stereoisomers, tautomers, deuterated derivatives, prodrugs or chemically acceptable salts according to claim 1 or 2, wherein, In formula (I), formula (II), formula (III), or formula (IV), R1 is -NR4R5 or cycloCy, and R4 and R5 are independently selected from H, C1-C4 alkyl, and C3-C5 cycloalkyl; cycloCy is selected from: R2 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, and C3-C4 cycloalkoxy, wherein the C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, and C3-C4 cycloalkoxy are optionally substituted by 0, 1, 2, or 3 substituents selected from halogen, hydroxyl, cyano, amino, and mercapto. R3 is selected from C1-C3 alkyl and C3-C4 cycloalkyl, wherein the C1-C3 alkyl and C3-C4 cycloalkyl are optionally substituted by 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and mercapto. X is -(CH2) m -, m is 1, 2 or 3; Y is -(CH2) n - where n is 1, 2, or 3.

15. The compound according to claim 1, or a stereoisomer, tautomer, deuterated product, prodrug, or a chemically acceptable salt thereof, wherein, The compounds represented by general formula (I) are selected from:

16. A pharmaceutical composition comprising the compound of any one of claims 1 to 15 or a stereoisomer, tautomer, deuterated form, prodrug, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

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