Pyrimido [6, 1-a] isoquinoline-4-ketone derivative and application thereof

Abstract

The invention relates to a pyrimido [6, 1-a] isoquinoline-4-ketone derivative and application thereof. The pyrimido [6, 1-a] isoquinoline-4-ketone derivative disclosed by the invention has a structural formula as shown in a formula (I): # imgabs0 #, wherein R1, R2, R3, X and Y are described in the specification. The compound can inhibit PDE3 and PDE4 at the same time, and compared with an existing PDE3 and PDE4 double-target inhibitor, the effect is better.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a pyrimido[6,1-a]isoquinoline-4-one derivative and a use thereof. Background Art

[0002] PDE3 and PDE4 belong to the PDE (Phosphodiesteras, phosphodiesterase) enzyme superfamily and are the main cAMP hydrolases in lung tissue cells. Among them, PDE3 can hydrolyze both cAMP and cGMP, and its ability to hydrolyze cAMP is about ten times that of cGMP. Inhibition of PDE3 blocks the hydrolysis of cAMP in cells, and the accumulated cAMP can cause Ca2+ to accumulate on the sarcoplasmic reticulum. 2+ A large amount of cAMP is released, thereby promoting the relaxation of bronchial smooth muscle. PDE4 specifically hydrolyzes cAMP and plays a major regulatory role in the expression of pro-inflammatory and anti-inflammatory mediators. When inhibited, it can significantly reduce the release of harmful mediators from inflammatory cells. The dual-target inhibition strategy can synergistically increase the intracellular cAMP / cGMP concentration, activate downstream signaling pathways, achieve dual enhancement of airway relaxation and anti-inflammatory effects, and promote airway clearance function.

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

[0004]

[0005] However, research data of RPL554 showed that its inhibitory activity against PDE4 was significantly insufficient, while its inhibitory activity against PDE3 still had room for improvement. Summary of the invention

[0006] In order to solve the unmet clinical needs, it is necessary to develop more efficient and safe PDE3 / 4 dual-target inhibitors. To this end, the present invention provides a pyrimido[6,1-a]isoquinolin-4-one derivative and its use.

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

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

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

[0010] In one aspect, the present invention provides a compound represented by the general formula (I) or a stereoisomer, tautomer, deuterated substance, prodrug or a pharmaceutically acceptable salt thereof:

[0011] in, R1 is selected from -NR4R5 or cycloCy; R4 and R5 are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl; Ring Cy is selected from 4-7 membered 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 membered heteroaryl and aryl groups containing 1-5 heteroatoms selected from N, O, and S are optionally substituted by 0, 1, 2, 3, 4 or 5 R 1a replace; Each R 1a are the same or different and are each independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, hydroxy, cyano, amino and thiol; R2 is selected from H, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy is optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, hydroxyl, cyano, amino and thiol; R3 is selected from H, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl is optionally substituted with 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.

[0012] Preferably, the compound has a structure shown in formula (II), formula (III) or formula (IV):

[0013] Preferably, R1 is -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, C3-C5 cycloalkyl; when it is cycloCy, cycloCy is selected from 4-6 membered heteroaryl and aryl groups containing 1-4 (e.g., 1, 2, 3 or 4) heteroatoms selected from N, O, and S, and the 4-6 membered heteroaryl and aryl groups containing 1-4 heteroatoms selected from N, O, and S are optionally replaced by 0, 1, 2, 3 or 4 R 1a replace; Preferably, R1 is -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, C3-C5 cycloalkyl; when it is cycloCy, cycloCy is selected from 4-6 membered heteroaryl and aryl containing 1-3 (e.g., 1, 2 or 3) heteroatoms selected from N, O, and S, and the 4-6 membered heteroaryl and aryl containing 1-3 heteroatoms selected from N, O, and S are optionally replaced by 0, 1, 2 or 3 R 1a replace; Preferably, R1 is -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, C3-C5 cycloalkyl; when it is cycloCy, cycloCy is selected from 4-6 membered heteroaryl and aryl containing 1-3 (e.g., 1, 2 or 3) heteroatoms selected from N, O, and S, and the 4-6 membered heteroaryl and aryl containing 1-3 heteroatoms selected from N, O, and S are optionally replaced by 0, 1 or 2 R 1a replace; Preferably, R1 is -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, C3-C5 cycloalkyl; when it is cycloCy, cycloCy is selected from 5-6 membered heteroaryl and aryl containing 1-3 (e.g., 1, 2 or 3) heteroatoms selected from N, O, and S, and the 5-6 membered heteroaryl and aryl containing 1-3 heteroatoms selected from N, O, and S are optionally replaced by 0, 1, 2 or 3 R 1a replace; Preferably, R1 is -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, C3-C5 cycloalkyl; when it is cycloCy, cycloCy is selected from 5-6 membered heteroaryl and aryl containing 1-3 (e.g., 1, 2 or 3) N heteroatoms, and the 5-6 membered heteroaryl and aryl containing 1-3 N heteroatoms are optionally replaced by 0, 1 or 2 R 1a replace.

[0014] Preferably, R1 is -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, C3-C5 cycloalkyl; when it is cycloCy, cycloCy is selected from

[0015] Where w is 0, 1 or 2, v is 0, 1, 2, 3, 4 or 5, and u is 0, 1, 2 or 3; 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 thiol; Preferably, R 1aEach is independently selected from H, deuterium, halogen, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, C3-C4 cycloalkoxy and hydroxy; Preferably, R 1a Each is independently selected from H, deuterium, halogen, C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C3-C4 cycloalkoxy and hydroxy; 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; 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 hydroxy; Preferably, R 1a Each is independently selected from H, deuterium, F, Cl, Br, methyl, ethyl, propyl, cyclopropyl, cyclobutyl and hydroxyl; Preferably, R1 is -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, C3-C5 cycloalkyl; when it is cycloCy, cycloCy is selected from:

[0016] Preferably, R2 is selected from H, hydroxyl, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy, wherein the C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy is optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, hydroxyl, cyano, amino and mercapto; Preferably, R2 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C3-C4 cycloalkoxy, and the C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C3-C4 cycloalkoxy are optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, hydroxyl, cyano, amino and mercapto.

[0017] Preferably, R2 is selected from methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, and the methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy are optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, hydroxyl, cyano, amino and thiol.

[0018] Preferably, R3 is selected from H, deuterium, C1-C4 alkyl, C3-C5 cycloalkyl, wherein the C1-C4 alkyl, C3-C5 cycloalkyl is optionally substituted with 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and thiol; Preferably, R3 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, and the C1-C3 alkyl, C3-C4 cycloalkyl is optionally substituted with 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and mercapto; Preferably, R3 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted with 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and thiol.

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

[0020] Preferably, X is -(CH2) m -, m is 1.

[0021] Preferably, Y is -(CH2) n -, n is 1, 2 or 3; Preferably, Y is -(CH2) n -, n is 1 or 2.

[0022] In a 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, C3-C5 cycloalkyl; cycloCy is selected from 5-6 membered heteroaryl and aryl containing 1-3 (e.g., 1, 2 or 3) N heteroatoms, wherein the 5-6 membered heteroaryl and aryl containing 1-3 N heteroatoms are optionally replaced by 0, 1 or 2 R 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 thiol; R2 is selected from H, hydroxyl, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy, wherein the C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy is optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, hydroxyl, cyano, amino and thiol; R3 is selected from H, deuterium, C1-C4 alkyl, C3-C5 cycloalkyl, wherein the C1-C4 alkyl, C3-C5 cycloalkyl is optionally substituted with 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and thiol; X is -(CH2) m -, m is 1, 2 or 3; Y is -(CH2) n -, 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, R4, R5 are independently selected from H, C1-C4 alkyl, C3-C5 cycloalkyl; Cy is selected from

[0023] 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 thiol; R2 is selected from H, hydroxyl, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy, wherein the C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy is optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, hydroxyl, cyano, amino and thiol; R3 is selected from H, deuterium, C1-C4 alkyl, C3-C5 cycloalkyl, wherein the C1-C4 alkyl, C3-C5 cycloalkyl is optionally substituted with 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and thiol; X is -(CH2) m -, m is 1, 2 or 3; Y is -(CH2) n -, n is 1, 2 or 3.

[0024] 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, C3-C5 cycloalkyl; Cy is selected from

[0025] 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 hydroxy; R2 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C3-C4 cycloalkoxy, and the C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C3-C4 cycloalkoxy is optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, hydroxy, cyano, amino and mercapto; R3 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, and the C1-C3 alkyl, C3-C4 cycloalkyl is optionally substituted with 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 -, n is 1, 2 or 3.

[0026] 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, C3-C5 cycloalkyl; cycloCy is selected from:

[0027] R2 is selected from H, hydroxyl, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy, wherein the C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy is optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, hydroxyl, cyano, amino and thiol; R3 is selected from H, deuterium, C1-C4 alkyl, C3-C5 cycloalkyl, wherein the C1-C4 alkyl, C3-C5 cycloalkyl is optionally substituted with 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and thiol; X is -(CH2) m -, m is 1, 2 or 3; Y is -(CH2) n -, n is 1, 2 or 3.

[0028] 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, C3-C5 cycloalkyl; Cy is selected from:

[0029] R2 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C3-C4 cycloalkoxy, and the C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C3-C4 cycloalkoxy is optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, hydroxy, cyano, amino and mercapto; R3 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, and the C1-C3 alkyl, C3-C4 cycloalkyl is optionally substituted with 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 -, n is 1, 2 or 3.

[0030] In another specific embodiment, the compound represented by general formula (I) is selected from:

[0031] The compound of formula (I) of the present invention can be prepared by chemical synthesis methods known in the art, for example, by reverse synthesis using raw materials known in the market. Specific synthesis examples are provided in the embodiments of the present invention.

[0032] On the other hand, the present invention provides a pharmaceutical composition comprising the above compound or its stereoisomers, tautomers, deuterated substances, prodrugs or pharmaceutically acceptable salts and pharmaceutically acceptable excipients, carriers or diluents.

[0033] Compared with the prior art, the compounds of the present invention or their stereoisomers, tautomers, deuterated substances, prodrugs or pharmaceutically acceptable salts or pharmaceutical compositions can inhibit PDE3 and PDE4 simultaneously. Compared with the existing PDE3 and PDE4 dual-target inhibitor RPL554, the compounds of the present invention or their stereoisomers, tautomers, deuterated substances, prodrugs or pharmaceutically acceptable salts or pharmaceutical compositions have the same or better inhibitory activity on PDE3, and have much higher inhibitory activity on PDE4 than RPL554, and have stronger activity on TNF-α and cAMP. definition

[0034] Unless otherwise specified, the meaning and scope of the terms of the present invention are explained below in an exemplary manner.

[0035] “ ” indicates the attachment site.

[0036] The minimum and maximum carbon content of a hydrocarbon group is indicated by a prefix, for example, the prefix (C a-b )alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, (C 1-6 ) Alkyl refers to an alkyl group containing 1 to 6 carbon atoms. The alkyl group is branched or linear.

[0037] Atoms described in the present application include isotopes thereof, for example, hydrogen may be deuterium or tritium.

[0038] "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. 1-6 Alkyl. More preferably C 1-4 Alkyl. More preferably C 1-3 alkyl.

[0039] "Cycloalkyl" refers to a saturated monocyclic, linked, spirocyclic, cyclic or bridged cycloalkyl group, which may be combined with other groups. Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Preferably, 3-6-membered cycloalkyl. Preferably, 3-5-membered cycloalkyl. Preferably, 3-4-membered cycloalkyl.

[0040] "Halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine.

[0041] "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.

[0042] "Heteroaryl" refers to a substituted or unsubstituted 5-membered or 6-membered monoheteroaromatic ring system, or a substituted or unsubstituted 9-membered or 10-membered fused or biheteroaromatic ring system, containing 1-4 heteroatoms independently selected from N, O, or S, and the remaining ring atoms are carbon atoms. Examples of heteroaryl moieties include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, quinolyl, isoquinolyl, benzimidazolyl or benzothiazolyl.

[0043] "Pharmaceutically acceptable salt" refers to conventional acid addition salts or base addition salts which retain the biological effectiveness and properties of the compound of formula (I) and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of acid addition salts include those derived from inorganic acids and those derived from 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, isethionic acid, benzenesulfonic acid, trifluoroacetic acid, mandelic acid, etc. Examples of base addition salts include those derived from inorganic acids and those derived from organic acids, such as ammonium salts, calcium salts, iron salts, aluminum salts, sodium salts, potassium salts, zinc salts, magnesium salts. The organic base includes salts of primary amines, secondary amines and tertiary amines, such as trimethylamine, triethylamine, tripropylamine, diethanolamine, ethylenediamine, ethanolamine and the like.

[0044] "Prodrug" refers to a prodrug that can be converted in vivo into a compound of the present invention and a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION

[0045] The technical solution of the present invention is further described below in conjunction with specific examples. The examples are only for illustrating the present invention, not for limiting the scope of the present invention, and the embodiments of the present invention are not limited thereto. Any other changes, substitutions, modifications, simplifications, etc. made without departing from the technical ideas and method principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

[0046] Unless otherwise specified, the chemicals and devices used in the following examples are commercially available.

[0047] Synthesis of intermediates

[0048]

[0049] 1. Synthesis of intermediate Int-A

[0050] (1) Synthesis of A-2 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. o C for 15 minutes. Nitromethane (30.5 g, 499.67 mmol) was added dropwise to the reaction mixture and stirred at 100 °C for 15 minutes. oC and stirred for 4 hours. After the reaction was completed, the reaction solution was slowly poured into 500 mL of water, and the precipitated solid was filtered and dried, and then slurried with 100 mL of methanol and dried to obtain A-2 (21 g, yellow solid), with a yield of 57%.

[0051] MS m / z(ESI): 224.0[M+H] + .

[0052] (2) Synthesis of A-3 A-2 (21 g, 94.07 mmol) was dissolved in dimethyl sulfoxide (165 mL) and acetic acid (80 mL) at 0 o Sodium borohydride (5.34 g, 141.16 mmol) was added portionwise at 10 °C. o C and stirred for 1 hour. After the reaction was completed, the reaction solution was slowly poured into 500 mL of water and extracted with ethyl acetate. The organic phases were combined and 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 obtain A-3 (21 g, yellow jelly), with a yield of 99%.

[0053] MS m / z(ESI): 226.2[M+H] + .

[0054] 1 H NMR (400 MHz, Chloroform- d ) δ 6.82 (d, J = 8.2 Hz, 1H), 6.77 -6.66 (m, 2H), 4.58 (t, J = 7.2 Hz, 2H), 4.08 (q, J = 7.2 Hz, 2H), 3.85 (s,3H), 3.25 (t, J = 7.6 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H).

[0055] (3) Synthesis of A-4 A-3 (20 g, 88.79 mmol) was dissolved in methanol (100 mL), and 5% palladium carbon (4.44 g) was added under nitrogen atmosphere. The hydrogen atmosphere was replaced three times, and then the mixture was heated at 40 °C under hydrogen atmosphere (15 psi). o C for 16 hours. After the reaction was completed, the palladium carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain A-4 (17 g, colorless colloid), with a yield of 98%.

[0056] MS m / z(ESI): 196.1 [M+H] + .

[0057] (4) Synthesis of A-5 A-4 (17 g, 87.06 mmol) was added to ethyl cyanoacetate (32 mL) and stirred at 100 °C in a nitrogen atmosphere. o C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 ~ dichloromethane / methanol = 10 / 1) to obtain A-5 (18 g, light yellow solid), with a yield of 79%.

[0058] MS m / z(ESI): 263.1 [M+H] + .

[0059] 1 H NMR (400 MHz, Chloroform- d ) δ 6.83 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 7.6 Hz, 2H), 6.10 (s, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.54 (q, J = 6.8 Hz, 2H), 3.33 (s, 2H), 2.79 (t, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H).

[0060] (5) Synthesis of A-6 A-5 (18 g, 68.62 mmol) was added in portions to 85 o C phosphorus oxychloride (180 mL) at 85 o C and stirred for 3 hours. After the reaction was completed, 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 a saturated sodium bicarbonate aqueous solution. The dichloromethane was extracted, and the organic phases were combined and 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 obtain the intermediate A-6 (16 g, crude product, yellow solid), with a yield of 95%.

[0061] MS m / z(ESI): 245.2 [M+H] +.

[0062] (6) Synthesis of A-7 At 0 o C, A-6 (16.0 g, 65.50 mmol) was added to concentrated sulfuric acid (160 mL) in portions, and the mixture was stirred at 10 °C. o C and stirred for 3 hours. After the reaction was completed, the reaction solution was slowly poured into ice water, the pH was adjusted to 7 with 4 M sodium hydroxide aqueous solution, extracted with dichloromethane, the organic phases were combined, 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 obtain A-7 (11.4 g, yellow solid), with a yield of 66%.

[0063] MS m / z(ESI): 263.2 [M+H] + .

[0064] 1 H NMR (400 MHz, DMSO- d 6) δ 9.44 (t, J = 3.2 Hz, 1H), 7.06 (s, 1H), 6.83 (s, 1H), 6.26 (s, 2H), 5.07 (s, 1H), 4.06 (t, J = 7.2 Hz, 2H), 3.78 (s,3H), 3.27 (td, J = 6.4, 2.8 Hz, 2H), 2.72 (t, J = 6.4 Hz, 2H), 1.34 (t, J =7.2 Hz, 3H).

[0065] (7) Synthesis of A-8 At 0 o Sodium metal (5.81 g, 252.72 mmol) was added to ethanol (200 mL) in batches at 80 °C and stirred until all the sodium metal reacted. A-7 (11.4 g, 43.46 mmol) was added to the freshly prepared sodium ethoxide solution and stirred at 80 °C. o C for 1 hour, then diethyl carbonate (15.80 mL) was added to the reaction mixture and the mixture was stirred at 80 o C and stirred for 8 hours. After the reaction was completed, the reaction solution 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) with a yield of 68%.

[0066] MS m / z(ESI): 289.1 [M+H]+ .

[0067] 1 H NMR (400 MHz, DMSO- d 6) δ 11.20 (s, 1H), 7.35 (s, 1H), 6.94 (s, 1H), 6.22 (d, J = 2.1 Hz, 1H), 4.08 (q, J = 6.9 Hz, 2H), 3.89 (t, J = 6.2 Hz, 2H),3.83 (s, 3H), 2.88 (t, J = 6.2 Hz, 2H), 1.35 (t, J = 6.9 Hz, 3H).

[0068] (8) Synthesis of A-9 A-8 (8.0 g, 27.75 mmol) was added to phosphorus oxychloride (120 mL) at 100 o C for 3 hours. After the reaction is completed, the filtrate is concentrated under reduced pressure to remove most of the phosphorus oxychloride. The crude product is diluted with dichloromethane, poured into ice water, and the pH is adjusted to 7 with a saturated sodium bicarbonate aqueous solution. The dichloromethane extraction is performed, and the organic phases are combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure to obtain A-9 (8.0 g, crude product, yellow solid), with a yield of 94%.

[0069] MS m / z(ESI): 307.1 [M+H] + .

[0070] (9) Synthesis of intermediate Int-A 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. o C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the solid precipitate was filtered, washed with ethyl acetate, and dried under reduced pressure to obtain the intermediate Int-A (2.0 g, yellow solid) with a yield of 97%.

[0071] MS m / z(ESI): 422.2 [M+H] + .

[0072] 2. Synthesis of intermediates Int-B~Int-D

[0073] Intermediates Int-B~Int-D were prepared by referring to the synthetic method of intermediate Int-A.

[0074]

[0075] Example 1: Synthesis of Compound 1

[0076] Synthesis of compound 1-1 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 butanone (10 mL) and heated at 110 °C under nitrogen protection. o C and stirred for 16 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 1) to obtain compound 1-1 (34.1 mg, yellow oil) with a yield of 24%.

[0077] MS m / z(ESI): 561.4[M+H] + .

[0078] Synthesis of Compound 1-2 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 30 min. o C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 1-2 (26.7 mg, yellow oil) with a yield of 95%.

[0079] MS m / z(ESI): 461.4[M+H] + .

[0080] Synthesis of compound 1 Compound b (2.3 mg, 0.02 mmol), HATU (15.2 mg, 0.04 mmol), DIPEA (10.3 mg, 0.08 mmol) and compound 1-2 (18.4 mg, 0.04 mmol) were added to DMF (1.5 mL) at 25 oC and stirred for 12 hours. After the reaction was completed, the reaction solution was purified by C18 reverse phase column (acetonitrile / water solution containing 10 mM ammonium bicarbonate = 20%~50%; purification method: RP4-25cm; flow rate: 40 mL / min; gradient time: 15 minutes) to obtain compound 1 (1.2 mg, yellow solid) with a yield of 5%.

[0081] MS m / z(ESI): 556.5[M+H] + .

[0082] 1 H NMR (400 MHz, Chloroform- d ) δ 8.22 (s, 1H), 7.00 (d, J = 7.6 Hz,2H), 6.69 (d, J = 20.8 Hz, 2H), 5.42 (s, 1H), 4.64 (dd, J = 13.6, 5.2 Hz,2H), 4.34 (dd, J = 10.8, 5.7 Hz, 1H), 4.29 - 4.05 (m, 3H), 3.91 (s, 3H), 3.87(s, 1H), 3.78 (dd, J = 10.4, 5.6 Hz, 1H), 3.74 (s, 3H), 3.04 (s, 1H), 2.94(t, J = 6.4 Hz, 2H), 2.34 (s, 3H), 2.14 (d, J = 9.6 Hz, 6H), 1.25 (s, 1H).

[0083] Example 2: Synthesis of Compound 2

[0084]

[0085] Synthesis of compound 2 Compound c (7.3 mg, 0.065 mmol), HATU (36.9 mg, 0.097 mmol), DIPEA (42.0 mg, 0.325 mmol) and compound 1-2 (29.9 mg, 0.065 mmol) were added to DMF (1.5 mL) and stirred at 25 °C for 30 min. oC and stirred for 12 hours. After the reaction was completed, the reaction solution was purified by C18 reverse phase column (acetonitrile / water solution containing 10 mM ammonium bicarbonate = 20%~50%; purification method: RP4-25cm; flow rate: 40 mL / min; gradient time: 15 minutes) to obtain compound 2 (2.2 mg, white solid) with a yield of 6%.

[0086] MS m / z(ESI) = 555.3 [M+H] + .

[0087] 1 H NMR (400 MHz, Chloroform- d ) δ 11.24 (s, 1H), 7.49 (s, 1H), 6.86 (s, 2H), 6.69 (d, J = 16.4 Hz, 2H), 6.61 (s, 1H), 5.46 (s, 1H), 4.59 (t, J =6.4 Hz, 4H), 4.32 (t, J = 9.6 Hz, 1H), 4.18 (dd, J = 10.4, 6.0 Hz, 1H), 4.08- 4.00 (m, 2H), 3.90 (s, 3H), 3.76 (s, 3H), 3.45 (p, J = 7.2 Hz, 1H), 2.91(t, J = 6.4 Hz, 2H), 2.27 (s, 3H), 2.03 (s, 6H).

[0088] Example 3: Synthesis of Compound 3

[0089]

[0090] Synthesis of compound 3-1 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 butanone (10 mL) and heated at 110 °C under nitrogen protection. oC and stirred for 16 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 1) to obtain compound 3-1 (427 mg, yellow solid), yield: 60%.

[0091] MS m / z(ESI) = 575.4 [M+H] + .

[0092] Synthesis of compound 3-2 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. o C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 3-2 (300 mg, brown solid), yield: 91%.

[0093] MS m / z(ESI) = 475.3 [M+H] + .

[0094] Synthesis of compound 3 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 stirred at 25 °C for 3 hours. o C and stirred for 12 hours. After the reaction was completed, the reaction solution was purified by C18 reverse phase column (acetonitrile / water solution containing 10 mM ammonium bicarbonate = 20%~50%; purification method: RP4-25cm; flow rate: 40 mL / min; gradient time: 15 minutes) to obtain compound 3 (2.0 mg, white solid) with a yield of 6%.

[0095] MS m / z(ESI): 570.4[M+H] + .

[0096] 1 H NMR (400 MHz, Methanol- d 4) δ 7.95 (s, 1H), 7.17 (d, J = 4.0 Hz,2H), 6.95 (s, 1H), 6.69 (s, 1H), 5.56 (s, 1H), 4.63 (dd, J = 13.6, 4.4 Hz,1H), 4.14 (q,J = 6.8 Hz, 4H), 3.83 - 3.60 (m, 9H), 3.03 (t, J = 6.4 Hz, 2H),2.37 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H).

[0097] Example 4: Synthesis of Compound 4

[0098]

[0099] Synthesis of compound 4 Compound d (8.3 mg, 0.065 mmol), HATU (36.9 mg, 0.097 mmol), DIPEA (42.0 mg, 0.325 mmol) and compound 1-2 (29.9 mg, 0.065 mmol) were added to DMF (1 mL) and stirred at 25 °C for 30 min. o C and stirred for 12 hours. After the reaction was completed, the reaction solution was purified by C18 reverse phase column (acetonitrile / water solution containing 10 mM ammonium bicarbonate = 20%~50%; purification method: RP4-25cm; flow rate: 40 mL / min; gradient time: 15 minutes) to obtain compound 4 (2.8 mg, white solid) with a yield of 8%.

[0100] MS m / z(ESI) = 570.3 [M+H] + .

[0101] 1 H NMR (400 MHz, Chloroform- d ) δ 13.13 (s, 1H), 6.85 (d, J = 3.2 Hz,2H), 6.69 (d, J = 14.4 Hz, 2H), 5.47 (s, 1H), 4.73 - 4.62 (m, 2H), 4.62 -4.53 (m, 2H), 4.29 (t, J = 9.6 Hz, 1H), 4.18 (dd, J = 10.4, 5.6 Hz, 1H), 4.05(t, J= 6.4 Hz, 2H), 3.90 (s, 3H), 3.76 (s, 3H), 3.49 - 3.39 (m, 1H), 2.92(t, J = 6.4 Hz, 2H), 2.52 (s, 3H), 2.26 (s, 3H), 2.04 (d, J = 7.2 Hz, 6H).

[0102] Example 5: Synthesis of Compound 5

[0103]

[0104] Synthesis of compound 5-1 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 heated at 110 °C under nitrogen. o C. and stirred for 16 hours. After the reaction was completed, the reaction solution was filtered, water and ethyl acetate were added to the filtrate for extraction, the organic phase was concentrated under reduced pressure, and the obtained crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 1) to obtain compound 5-1 (136 mg, yellow oil), yield: 19%.

[0105] MS m / z(ESI) = 575.4 [M+H] + .

[0106] Synthesis of compound 5-2 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 stirred at 25 o C. and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 5-2 (110 mg, yellow oil) with a yield of 98%.

[0107] MS m / z(ESI) = 475.3 [M+H] + .

[0108] Synthesis of compound 5 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 stirred at 25 °C for 1 h. o C and stirred for 12 hours. After the reaction was completed, the reaction solution was purified by C18 reverse phase column (acetonitrile / water solution containing 10 mM ammonium bicarbonate = 20%~50%; purification method: RP4-25cm; flow rate: 40 mL / min; gradient time: 15 minutes) to obtain compound 5 (26 mg, white solid) with a yield of 22%.

[0109] MS m / z(ESI) = 570.4 [M+H] + .

[0110] 1 H NMR (400 MHz, Chloroform- d ) δ 8.21 (d, J = 18.8 Hz, 1H), 6.85 (d, J = 3.2 Hz, 2H), 6.69 (dd, J = 18.8, 4.4 Hz, 2H), 5.48 (d, J = 1.6 Hz, 1H), 4.48 - 4.31 (m, 2H), 4.19 (dd, J = 11.2, 7.6 Hz, 1H), 4.14 - 3.86 (m, 7H), 3.76 (d, J = 3.2 Hz, 3H), 3.67 (dd, J = 9.6, 3.0 Hz, 1H), 3.16 - 3.02 (m,1H), 2.91 (d, J = 6.8 Hz, 2H), 2.25 (d, J = 2.4 Hz, 3H), 2.19 - 2.12 (m, 1H), 2.07 - 2.01 (m, 6H), 1.99 - 1.90 (m, 1H).

[0111] Example 6: Synthesis of Compound 6

[0112]

[0113] Synthesis of compound 6 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 stirred at 25 °C for 3 hours. o C and stirred for 12 hours. After the reaction was completed, the reaction solution was purified by C18 reverse phase column (acetonitrile / water solution containing 10 mM ammonium bicarbonate = 20%~50%; purification method: RP4-25cm; flow rate: 40 mL / min; gradient time: 15 minutes) to obtain compound 6 (2.2 mg, yellow solid) with a yield of 17%.

[0114] MS m / z(ESI) = 600.4 [M+H] + .

[0115] 1 H NMR (400 MHz, Chloroform- d ) δ 9.73 (s, 1H),7.03 (d, J = 2.8 Hz,2H), 6.73 (s, 1H), 6.56 (s, 1H), 5.45 (s, 1H), 4.65 (d, J = 14.0 Hz, 1H),4.15 (q, J = 6.8 Hz, 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 = 20.8 Hz, 6H), 1.48 (t, J = 6.8 Hz, 3H).

[0116] Example 7: Synthesis of Compound 7

[0117]

[0118] Synthesis of compound 7-1 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 butanone (10 mL) and heated at 110 °C under nitrogen protection. o C and stirred for 16 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 1) to obtain compound 7-1 (154 mg, yellow solid), yield: 55%.

[0119] MS m / z(ESI): 591.4[M+H] + .

[0120] Synthesis of compound 7-2 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 h. o C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 7-2 (120 mg, yellow oil) with a yield of 94%.

[0121] MS m / z(ESI): 491.3[M+H] + .

[0122] Synthesis of compound 7 Compound 7-2 (44.2 mg, 0.09 mmol) was added to water (1 mL), acetic acid (7.8 mg, 0.13 mmol), potassium cyanate (34.9 mg, 0.43 mmol), and the mixture was stirred at 80 °C under nitrogen protection. o C and stirred for 12 hours. After the reaction was completed, the reaction solution was purified by C18 reverse phase column (acetonitrile / water solution containing 10 mM ammonium bicarbonate = 20%~50%; purification method: RP4-25cm; flow rate: 40mL / min; gradient time: 15 minutes) to obtain compound 7 (12.4 mg, white solid) with a yield of 26%.

[0123] MS m / z(ESI): 534.4[M+H] + .

[0124] 1 H NMR (400 MHz, Methanol- d 4) 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, 4.0 Hz, 1H), 3.68 (s, 6H), 3.41 - 3.35 (m, 2H), 3.04 (t, J = 6.4 Hz, 2H), 2.28 (s, 4H), 2.25 (s, 4H), 1.43 (t, J = 7.2 Hz, 3H).

[0125] Example 8: Synthesis of Compound 8 and Compound 10

[0126]

[0127] 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 stirred at 25 °C for 30 min. o C and stirred for 12 hours. After the reaction was completed, the reaction solution was separated and purified by C18 reverse phase column (acetonitrile / water solution containing 10mM ammonium bicarbonate = 20%~50%; purification method: RP4-25cm; flow rate: 40 mL / min; gradient time: 15 minutes) to obtain compound 8 (10 mg, white solid, yield: 19%) and compound 10 (9 mg, white solid, yield: 17%). Compound 8: MS m / z(ESI): 586.4[M+H] + .

[0128] 1 H NMR (400 MHz, DMSO- d 6) δ 8.22 (t, J = 6.4 Hz, 1H), 7.62 (s, 1H), 7.05 (s, 1H), 6.89 (q, J= 2.8 Hz, 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 = 6.8 Hz, 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).

[0129] Compound 10: MS m / z(ESI): 586.3[M+H] + .

[0130] 1 H NMR (400 MHz, DMSO- d 6) δ 8.23 (t, J = 6.5 Hz, 1H), 7.63 (s, 1H), 7.05 (s, 1H), 6.90 (q, J = 2.8 Hz, 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 = 6.7 Hz, 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).

[0131] Example 9: Synthesis of Compound 9

[0132]

[0133] 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 stirred at 25 °C for 30 min. o C and stirred for 12 hours. After the reaction was completed, the reaction solution was purified by C18 reverse phase column (acetonitrile / water solution containing 10 mM ammonium bicarbonate = 20%~50%; purification method: RP4-25cm; flow rate: 40 mL / min; gradient time: 15 minutes) to obtain compound 9 (22 mg, white solid) with a yield of 42%.

[0134] MS m / z(ESI): 586.4[M+H] + .

[0135] 1 H NMR (400 MHz, Methanol- d 4) δ 7.94 (s, 1H), 6.95 (s, 1H), 6.89 (q, J = 3.2 Hz, 2H), 6.72 (s, 1H), 5.59 (s, 1H), 4.62 (dd, J = 14.0, 4.4 Hz, 1H),4.19 - 4.11 (m, 4H), 3.84 (s, 4H), 3.80 - 3.60 (m, 8H), 3.03 (t, J = 6.8 Hz,2H), 2.78 (d, J = 6.4 Hz, 1H), 2.28 (s, 3H), 2.25 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H).

[0136] Example 10: Synthesis of Compound 11 and Compound 13

[0137]

[0138] Synthesis of compound 11-1 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 butanone (10 mL) and stirred at 110 °C under nitrogen protection. oC and stirred for 16 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 1) to obtain compound 11-1 (90 mg, yellow solid) with a yield of 43%.

[0139] MS m / z(ESI): 601.4[M+H] + .

[0140] Synthesis of compound 11-2 Compound 11-1 (90 mg, 0.15 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added and the mixture was stirred at 25 °C. o C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 11-2 (70 mg, yellow oil) with a yield of 93%.

[0141] MS m / z(ESI): 501.3[M+H] + .

[0142] Synthesis of Compound 11 and Compound 13 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 stirred at 25 °C for 30 min. o C and stirred for 12 hours. After the reaction was completed, the reaction solution was separated and purified by C18 reverse phase column (acetonitrile / water solution containing 10 mM ammonium bicarbonate = 20%~50%; purification method: RP4-25cm; flow rate: 40 mL / min; gradient time: 15 minutes) to obtain compound 11 (5 mg, yellow solid, yield: 19%) and compound 13 (7 mg, white solid, yield: 27%), respectively.

[0143] Compound 11: MS m / z(ESI): 596.4[M+H] + .

[0144] 1 H NMR (400 MHz, Methanol- d 4) 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).

[0145] Compound 13: MS m / z(ESI): 596.4[M+H] + .

[0146] 1 H NMR (400 MHz, Methanol - d 4) 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).

[0147] Example 11: Synthesis of Compound 12

[0148]

[0149] 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 stirred at 25 °C for 30 min. o C and stirred for 12 hours. After the reaction was completed, the reaction solution was purified by C18 reverse phase column (acetonitrile / water solution containing 10 mM ammonium bicarbonate = 20%~50%; purification method: RP4-25cm; flow rate: 40mL / min; gradient time: 15 minutes) to obtain compound 12 (11 mg, white solid) with a yield of 42%.

[0150] MS m / z(ESI): 596.4[M+H] + .

[0151] 1 H NMR (400 MHz, Methanol- d 4) δ 7.94 (s, 1H), 7.05 (d, J = 3.6 Hz,2H), 6.95 (s, 1H), 6.67 (s, 1H), 5.53 (s, 1H), 4.63 (dd, J = 14.0, 4.4 Hz,1H), 4.22 - 4.10 (m, 4H), 3.88 - 3.62 (m, 8H), 3.03 (t, J = 6.8 Hz, 2H), 2.82- 2.73 (s, 1H), 2.25 (d, J = 15.6 Hz, 6H), 1.99 - 1.89 (m, 1H), 1.42 (t, J =7.2 Hz, 3H), 1.10 - 1.00 (m, 2H), 0.79 - 0.71 (m, 2H).

[0152] Example 12: Synthesis of Compound 14

[0153]

[0154] Synthesis of compound 14 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 stirred at 25 °C for 3 hours. o C and stirred for 12 hours. After the reaction was completed, the reaction solution was purified by C18 reverse phase column (acetonitrile / water solution containing 10 mM ammonium bicarbonate = 20%~50%; purification method: RP4-25cm; flow rate: 40 mL / min; gradient time: 15 minutes) to obtain compound 14 (2.2 mg, white solid) with a yield of 19%.

[0155] MS m / z(ESI): 584.4[M+H] + .

[0156] 1 H NMR (400 MHz, Chloroform- d ) δ 9.43 (s, 1H), 7.02 (d, J = 8.4 Hz,2H), 6.67 (d, J = 26.8 Hz, 2H), 5.47 (s, 1H), 4.39 (d, J = 14.0 Hz, 1H), 4.15(q, J = 6.8 Hz, 4H), 4.07 - 3.91 (m, 2H), 3.83 (d, J = 8.4 Hz, 1H), 3.73 (s,5H), 3.14 (s, 1H), 2.97 (d, J = 6.8 Hz, 2H), 2.44 (s, 3H), 2.33 (s, 3H), 2.30 (s, 3H), 2.13 (s, 3H), 1.48 (t, J = 7.2 Hz, 3H).

[0157] Example 13: Synthesis of Compound 15

[0158]

[0159] Synthesis of compound 15 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 stirred at 25 °C for 3 hours. o C and stirred for 12 hours. After the reaction was completed, the reaction solution was purified by C18 reverse phase column (acetonitrile / water solution containing 10 mM ammonium bicarbonate = 20%~50%; purification method: RP4-25cm; flow rate: 40 mL / min; gradient time: 15 minutes) to obtain compound 15 (1.8 mg, yellow solid) with a yield of 15%.

[0160] MS m / z(ESI): 569.3[M+H] + .

[0161] 1 H NMR (400 MHz, DMSO- d 6) δ 7.75 (d, J = 2.4 Hz, 1H), 6.94 (s, 1H), 6.85 (s, 2H), 6.66 (s, 1H), 6.59 (d, J = 2.4 Hz, 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 = 6.4 Hz, 2H), 2.21 (s, 3H), 1.96 (d, J = 5.2 Hz,6H), 1.33 (t, J = 6.8 Hz, 3H).

[0162] Example 14: Synthesis of Compound 16

[0163]

[0164] 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 stirred at 25 °C for 30 min. oC and stirred for 12 hours. After the reaction was completed, the reaction solution was purified by C18 reverse phase column (acetonitrile / water solution containing 10 mM ammonium bicarbonate = 20%~50%; purification method: RP4-25cm; flow rate: 40 mL / min; gradient time: 15 minutes) to obtain compound 16 (8 mg, white solid) with a yield of 30%.

[0165] MS m / z(ESI): 610.3 [M+H] + .

[0166] 1 H NMR (400 MHz, Methanol- d 4) δ 7.97 (s, 1H), 7.12 (d, J = 3.3 Hz,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 = 6.6 Hz, 2H), 2.80 - 2.73 (s, 1H), 2.55 (s, 3H), 2.28 (d, J = 15.2 Hz, 6H), 2.01 - 1.91 (m, 1H), 1.42 (t, J =7.0 Hz, 3H), 1.11 - 1.00 (m, 2H), 0.82 - 0.74 (m, 2H).

[0167] Example 15: Synthesis of Compound 17

[0168]

[0169] Synthesis of compound 17 Compound 1-2 (41.5 mg, 0.09 mmol) was added to water (1 mL), and acetic acid (7.8 mg, 0.13 mmol) and potassium cyanate (34.9 mg, 0.43 mmol) were added. o C and stirred for 12 hours. After the reaction was completed, the reaction solution was purified by C18 reverse phase column (acetonitrile / water solution containing 10 mM ammonium bicarbonate = 20%~50%; purification method: RP4-25cm; flow rate: 40mL / min; gradient time: 15 minutes) to obtain compound 17 (16.8 mg, white solid) with a yield of 37%.

[0170] MS m / z(ESI): 504.4[M+H] + .

[0171] 1 H NMR (400 MHz, Methanol- d 4) δ 7.02 (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).

[0172] Comparative Example 1: Synthesis of RPL554

[0173]

[0174] RPL554 was synthesized according to the preparation method provided in invention patent WO 00 / 58308A1.

[0175] MS m / z(ESI): 478.2[M+H] + .

[0176] 1 H NMR (400 MHz, CDCl 3 ) δ 6.89 (s, 2H), 6.70 (s, 1H), 6.67 (s, 1H), 5.45 (s, 1H), 4.41 (t, J = 6.99 Hz, 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 = 6.17 Hz, 2H), 2.28 (s, 3H), 2.06 (s, 6H).

[0177] Experimental Example 1: Enzyme Inhibition Activity Test of Representative Compounds on PDE3A and PDE4B 1) Materials and Equipment:

[0178]

[0179] 2) Experimental methods: (1) Compound dilution: First, prepare a 10 μM compound stock solution with DMSO. When testing the single-concentration inhibition rate, directly administer the compound according to the corresponding dilution ratio. When testing the enzyme activity IC 50 The compound concentrated stock solution was diluted 4-fold from 10 μM to obtain 10 concentration points.

[0180] (2) Prepare the incubation system according to the table below, mix well and incubate at room temperature for 1 h.

[0181]

[0182] (3) After the incubation, 100 μL of Binding Agent was added to each group to dilute the above system, mixed well, and incubated at room temperature for another 1 h.

[0183] (4) After the second round of incubation, the sample was placed in a microplate reader and the fluorescence signal was detected according to the test conditions of excitation wavelength 490 nm and emission wavelength 520 nm. The fluorescence signal was calculated according to %Inhibition rate = (FP B −FP S ) / (FP B −FP V ) × 100% to calculate the inhibition rate.

[0184] 3) Test results

[0185] It has been verified that the compound provided by the present invention has good inhibitory activity against both PDE3A and PDE4B, and is superior to RPL554.

[0186] Experimental Example 2: Agonist activity of representative compounds in increasing intracellular cAMP concentration

[0187] 1) Materials and Equipment:

[0188] 2) Experimental methods: (1) Add the compound 30 minutes before adding Forskolin, then add the remaining components except the compound in the table, mix gently, and incubate at room temperature for another 1 hour.

[0189] The incubation system is as follows:

[0190] (2) After the incubation, the fluorescence signal was detected using a microplate reader under the test conditions of an excitation wavelength of 340 nm and emission wavelengths of 616 nm and 665 nm, and the data was read.

[0191] 3) Test results

[0192] It has been verified that the compounds provided by the present invention have better and higher cAMP agonist activity.

[0193] Experimental Example 3: Inhibitory effect of representative compounds on the secretion of inflammatory factor TNF-α

[0194] 1) Materials and equipment:

[0195] 2) Experimental methods: (1) Mononuclear cells (concentration 10 6 / ml) in RPMI 1640 medium containing 1% fetal bovine serum and inoculated into 96-well plates (10 5 The cells were incubated at 37°C with 5% CO2 for 2 h to allow the cells to adhere.

[0196] (2) Adherent cells were cultured in fresh RPMI 1640 medium containing 1% fetal bovine serum (FBS) and LPS (10 ng / ml) and compounds (maximum final concentration 10 μM, 4-fold dilution) at 5% CO2 and 37°C.

[0197] (2) After 18 hours, collect the cell supernatant. According to the instructions of the TNF-α enzyme-linked immunosorbent assay (ELISA) kit, detect the TNF-α concentration in the supernatant and calculate the IC 50 .

[0198] 3) Test results

[0199] It has been verified that the compound provided by the present invention has a good effect of inhibiting the release of TNF-α.

Claims

1. A compound represented by the general formula (I) or its stereoisomers, tautomers, deuterated derivatives, prodrugs or pharmaceutically acceptable salts thereof: in, R1 is selected from -NR4R5 or cycloCy; R4 and R5 are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl; Ring Cy is selected from 4-7 membered heteroaryl and aryl groups containing 1-5 heteroatoms selected from N, O, and S, wherein the 4-7 membered heteroaryl and aryl groups containing 1-5 heteroatoms selected from N, O, and S are optionally substituted by 0, 1, 2, 3, 4, or 5 R 1a replace; Each R 1a are the same or different and are each independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, hydroxy, cyano, amino and thiol; R2 is selected from H, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy is optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, hydroxyl, cyano, amino and thiol; R3 is selected from H, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl is optionally substituted with 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 stereoisomer, tautomer, deuterated substance, prodrug or pharmaceutically acceptable salt thereof, wherein: The compound has a structure shown by formula (II), formula (III) or formula (IV):

3. The compound according to claim 1 or 2, or its stereoisomer, tautomer, deuterated substance, prodrug or a pharmaceutically acceptable salt thereof, wherein: R1 is -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, C3-C5 cycloalkyl; when it is cycloCy, cycloCy is selected from 5-6 membered heteroaryl and aryl containing 1-3 heteroatoms selected from N, O, and S, and the 5-6 membered heteroaryl and aryl containing 1-3 heteroatoms selected from N, O, and S are optionally replaced by 0, 1, 2 or 3 R 1a replace.

4. The compound according to claim 1 or 2, or its stereoisomer, tautomer, deuterated substance, prodrug or a pharmaceutically acceptable salt thereof, wherein: R1 is -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, 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 hydroxy.

5. The compound according to claim 1 or 2, or its stereoisomer, tautomer, deuterated substance, prodrug or a pharmaceutically acceptable salt thereof, wherein: R1 is -NR4R5 or cycloCy. When it is -NR4R5, R4 and R5 are independently selected from H, C1-C4 alkyl, C3-C5 cycloalkyl; when it is cycloCy, cycloCy is selected from:

6. The compound according to claim 1 or 2, or its stereoisomer, tautomer, deuterated substance, prodrug or a pharmaceutically acceptable salt thereof, wherein: R2 is selected from H, hydroxyl, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy, and the C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy are optionally substituted with 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 stereoisomer, tautomer, deuterated substance, prodrug or a pharmaceutically acceptable salt thereof, wherein: R3 is selected from H, deuterium, C1-C4 alkyl, C3-C5 cycloalkyl, and the C1-C4 alkyl, C3-C5 cycloalkyl is optionally substituted with 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 stereoisomer, tautomer, deuterated substance, prodrug or a pharmaceutically acceptable salt thereof, wherein: X is -(CH2) m -, m is 1, 2 or 3.

9. The compound according to claim 1 or 2, or its stereoisomer, tautomer, deuterated substance, prodrug or a pharmaceutically acceptable salt thereof, wherein: Y is -(CH2) n -, n is 1, 2 or 3.

10. The compound according to claim 1 or 2, or its stereoisomer, tautomer, deuterated substance, prodrug or a pharmaceutically acceptable salt thereof, wherein: 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, C3-C5 cycloalkyl; cycloCy is selected from 5-6 membered heteroaryl and aryl containing 1-3 N heteroatoms, and the 5-6 membered heteroaryl and aryl containing 1-3 N heteroatoms are optionally replaced by 0, 1 or 2 R 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 thiol; R2 is selected from H, hydroxyl, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy, wherein the C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy is optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, hydroxyl, cyano, amino and thiol; R3 is selected from H, deuterium, C1-C4 alkyl, C3-C5 cycloalkyl, wherein the C1-C4 alkyl, C3-C5 cycloalkyl is optionally substituted with 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and thiol; X is -(CH2) m -, m is 1, 2 or 3; Y is -(CH2) n -, n is 1, 2 or 3.

11. The compound according to claim 1 or 2, or its stereoisomer, tautomer, deuterated substance, prodrug or a pharmaceutically acceptable salt thereof, wherein: 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, C3-C5 cycloalkyl; Cy 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 thiol; R2 is selected from H, hydroxyl, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy, wherein the C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy is optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, hydroxyl, cyano, amino and thiol; R3 is selected from H, deuterium, C1-C4 alkyl, C3-C5 cycloalkyl, wherein the C1-C4 alkyl, C3-C5 cycloalkyl is optionally substituted with 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and thiol; X is -(CH2) m -, m is 1, 2 or 3; Y is -(CH2) n -, n is 1, 2 or 3.

12. The compound according to claim 1 or 2, or its stereoisomer, tautomer, deuterated substance, prodrug or a pharmaceutically acceptable salt thereof, wherein: 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, C3-C5 cycloalkyl; Cy 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 hydroxy; R2 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C3-C4 cycloalkoxy, and the C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C3-C4 cycloalkoxy is optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, hydroxy, cyano, amino and mercapto; R3 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, and the C1-C3 alkyl, C3-C4 cycloalkyl is optionally substituted with 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 -, n is 1, 2 or 3.

13. The compound according to claim 1 or 2, or its stereoisomer, tautomer, deuterated substance, prodrug or a pharmaceutically acceptable salt thereof, wherein: 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, C3-C5 cycloalkyl; cycloCy is selected from: R2 is selected from H, hydroxyl, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy, wherein the C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, C3-C5 cycloalkoxy is optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, hydroxyl, cyano, amino and thiol; R3 is selected from H, deuterium, C1-C4 alkyl, C3-C5 cycloalkyl, wherein the C1-C4 alkyl, C3-C5 cycloalkyl is optionally substituted with 0, 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, cyano, amino and thiol; X is -(CH2) m -, m is 1, 2 or 3; Y is -(CH2) n -, n is 1, 2 or 3.

14. The compound according to claim 1 or 2, or its stereoisomer, tautomer, deuterated substance, prodrug or a pharmaceutically acceptable salt thereof, wherein: 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, C3-C5 cycloalkyl; cycloCy is selected from: R2 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C3-C4 cycloalkoxy, and the C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C3-C4 cycloalkoxy is optionally substituted with 0, 1, 2 or 3 substituents selected from halogen, hydroxy, cyano, amino and mercapto; R3 is selected from C1-C3 alkyl, C3-C4 cycloalkyl, and the C1-C3 alkyl, C3-C4 cycloalkyl is optionally substituted with 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 -, n is 1, 2 or 3.

15. The compound according to claim 1 or its stereoisomer, tautomer, deuterated substance, prodrug or pharmaceutically acceptable salt thereof, wherein: The compound represented by general formula (I) is selected from:

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

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