Tri-fused ring compound as well as preparation method and application thereof

Abstract

The invention relates to a tricyclic compound as well as a preparation method and application thereof. The structural formula of the tri-fused ring compound is as shown in formula (I): # imgabs0 #, wherein R1, R2, R3, R4, R5, R6, R7, E, X and Y are as 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 technical field of medicine, and particularly relates to a tricyclic compound, a preparation method thereof, and uses thereof. Background Art

[0002] The phosphodiesterase (PDE) enzyme superfamily contains 11 gene families, specifically PDE1 - PDE11. PDE3 and PDE4 are the main cAMP - hydrolyzing enzymes in smooth muscle tissue and are highly expressed in the airway smooth muscle of the lungs. PDE3 can hydrolyze both cAMP and cGMP, and its ability to hydrolyze cAMP is about ten times that of cGMP. PDE3 is the main PDE in airway smooth muscle cells. Inhibiting PDE3 blocks the metabolism of intracellular cAMP, and the accumulation of cAMP can cause a large amount of Ca 2+ to be released, thereby enhancing the contractility of smooth muscle, dilating the surrounding blood vessels, and relaxing bronchial smooth muscle. PDE4 can specifically hydrolyze cAMP and plays a major regulatory role in the expression of pro - inflammatory and anti - inflammatory mediators. PDE4 inhibitors can inhibit the release of harmful mediators by inflammatory cells. Therefore, inhibiting the hydrolysis of cAMP and cGMP by PDE3 / 4 can increase the intracellular concentration of cAMP and cGMP in the smooth muscle tissue of the lungs, thereby activating the downstream phosphorylation cascade, relaxing airway smooth muscle, and inhibiting inflammation. Given the important role of PDE4 in inhibiting airway inflammation, and the potential synergistic effect on airway caliber by enhancing bronchodilation through PDE3 inhibition and regulating inflammation and mucus production through PDE4 inhibition. Therefore, the combined inhibition of PDE3 and PDE4 has additive and synergistic anti - inflammatory and bronchodilation effects.

[0003] WO0058308A1 discloses a PDE3 / 4 dual - target inhibitor RPL554, which has positive clinical results and has been approved for marketing.

[0004]

[0005] However, its enzyme activity data shows that the inhibitory activity against PDE4 needs to be improved, and there is still room for improvement in the inhibitory activity against PDE3. Summary of the Invention

[0006] In order to meet the huge clinical needs, the present invention aims to develop more efficient and safe PDE3 / 4 dual inhibitors. For this purpose, the present invention provides a tricyclic compound, a preparation method thereof, and uses thereof.

[0007] Therefore, an object of the present invention is to provide a tricyclic compound as a PDE3 / 4 dual inhibitor.

[0008] Another object of the present invention is to provide a method for preparing the above compound.

[0009] Still another object of the present invention is to provide a pharmaceutical composition comprising the above compound.

[0010] The technical solution of the present invention is achieved by the following scheme.

[0011] On the one hand, the present invention provides a compound represented by the general formula (I) or its stereoisomer, tautomer, deuterated compound, prodrug or pharmaceutically acceptable salt:

[0012]

[0013] Wherein,

[0014] R 1 is selected from -NR’R”; R’ and R” are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl and hydroxyl;

[0015] Y is selected from

[0016] R 2 is selected from H, hydroxyl and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with 0, 1, 2 or 3 halogens, hydroxyls, or amino groups;

[0017] X is selected from C1-C6 alkylene (such as -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH2CH2CH2CH2-, -CH(CH3)CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH(CH3)CH2CH2CH2CH2-, etc.), C 3- C6 cycloalkylene, C 3- C6 cycloalkylene-C1-C6 alkylene, C1-C6 alkylene-C 3- C6 cycloalkylene-C1-C6 alkylene;

[0018] R 3 is selected from 5-6 membered heteroaryl and aryl (such as phenyl) containing 1-3 (such as 1, 2 or 3) heteroatoms selected from N, O, S, and the 5-6 membered heteroaryl and aryl containing 1-3 heteroatoms selected from N, O, S are optionally substituted with 0-5 R 3a substituents;

[0019] Each R 3aSame or different, and each independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkynyl, C2-C6 alkenyl, C3-C6 epoxyalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), a 4-6 membered (e.g., 4, 5 or 6 membered) heterocycle containing 1 to 3 (e.g., 1, 2 or 3) heteroatoms selected from N, O, S, -O(C3-C6 epoxyalkyl), hydroxy, cyano, amino or mercapto, and the C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkynyl, C2-C6 alkenyl, C3-C6 epoxyalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), a 4-6 membered heterocycle containing 1 to 3 heteroatoms selected from N, O, S, -O(C3-C6 epoxyalkyl) is optionally substituted with 0, 1, 2 or 3 deuterium, halogen, hydroxy, cyano, amino, mercapto;

[0020] R 4 、R 5 、R 6 、R 7 Each independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), hydroxy, cyano, amino and mercapto, and the C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl) and -O(C3-C6 cycloalkyl) are optionally substituted with 0, 1, 2 or 3 deuterium, halogen, hydroxy, cyano, amino, mercapto;

[0021] E is -(CH2) v -;

[0022] v is 1, 2 or 3.

[0023] Preferably, the compound has the structure shown in formula (II):

[0024]

[0025] Preferably, R 1 is selected from -NR’R”, and R’, R” are independently selected from H, C1-C6 alkyl;

[0026] More preferably, R 1 is selected from -NR’R”, and R’, R” are independently selected from H, C1-C4 alkyl;

[0027] Most preferably, R 1 is selected from -NR’R”, and R’, R” are independently selected from H, C1-C3 alkyl, for example, R’, R” are independently H, methyl, ethyl, propyl, isopropyl, butyl, etc.

[0028] Preferably, R 2Selected from H, hydroxyl, and C1-C3 alkyl groups;

[0029] More preferably, R 2 Is selected from H and hydroxyl.

[0030] Most preferably, R 2 Is H.

[0031] Preferably, X is selected from C1-C6 alkylene groups (such as C1-C5 alkylene groups, C1-C4 alkylene groups, C1-C3 alkylene groups), C3-C6 cycloalkylene groups (such as cyclopropylene, cyclobutylene, cyclopentylene);

[0032] Even more preferably, X is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-;

[0033] Most preferably, X is selected from -CH2CH2- and

[0034] Preferably, R 3 Is selected from phenyl groups, and the phenyl groups are optionally substituted with 0-3 R 3a Substituents;

[0035] More preferably, R 3 Is selected from phenyl groups, and when substituted with 3 R 3a Substituents, they are substituted at the 2, 4, and 6 positions;

[0036] Preferably, R 3a Are each independently selected from H, deuterium, halogen, C1-C6 alkyl groups, C3-C6 cycloalkyl groups, C2-C6 alkynyl groups, C3-C6 epoxyalkyl groups, -O(C1-C6 alkyl groups), -O(C3-C6 cycloalkyl groups), -O(C3-C6 epoxyalkyl groups).

[0037] More preferably, R 3a Are each independently selected from H, C1-C4 alkyl groups, C3-C6 cycloalkyl groups, C2-C4 alkynyl groups, C3-C6 epoxyalkyl groups, -O(C1-C4 alkyl groups), -O(C3-C6 cycloalkyl groups), -O(C3-C6 epoxyalkyl groups). For example, R 3a Can be methyl, ethyl, propyl, butyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopropoxy, cyclobutoxy, epoxybutyloxy, ethynyl, propynyl, etc.

[0038] Further preferably, R at the 2,6 positions 3a Is methyl, and R at the 4 position 3aSelected from C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 epoxyalkyl, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 epoxyalkyl);

[0039] Preferably, R at the 2,6 positions 3a is methyl, and R at the 4 position 3a is selected from C1-C3 alkyl, C3-C6 cycloalkyl, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl).

[0040] Preferably, R 3 is selected from

[0041] Preferably, R 4 , R 5 , R 6 , R 7 are each independently selected from H, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), and the C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl) are optionally substituted with 0, 1, 2, or 3 deuteriums, halogens, or hydroxyl groups; more preferably, R 4 and R 7 are independently selected from H, halogen, and C1-C6 alkyl, preferably both are H;

[0042] Even more preferably, R 5 and R 6 are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), preferably selected from -O(C1-C6 alkyl), such as -O(C1-C4 alkyl), and are selected from methoxy, ethoxy, and propoxy. For another example, R 5 can be methoxy or ethoxy, and R 6 can be methoxy.

[0043] Preferably, E is -(CH2) v -, and v is 1 or 2;

[0044] More preferably, v is 1.

[0045] In one embodiment, in formula (I), R 1 is selected from -NR’R”; R’ and R” are independently selected from H, C1-C6 alkyl;

[0046] Y is

[0047] R 2 is selected from H, hydroxyl, and C1-C3 alkyl;

[0048] X is selected from C1-C6 alkylene (such as C1-C5 alkylene, C1-C4 alkylene, C1-C3 alkylene), C3-C6 cycloalkylene (such as cyclopropylidene, cyclobutylidene, cyclopentylidene);

[0049] R 3 is selected from phenyl, and the phenyl is optionally substituted by 0-3 R 3a substituents;

[0050] R 3a are each independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkynyl, C3-C6 epoxyalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 epoxyalkyl);

[0051] R 4 、R 5 、R 6 、R 7 are each independently selected from H, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), and the C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl) are optionally substituted by 0, 1, 2 or 3 deuterium, halogen, hydroxyl groups;

[0052] E is -(CH2) v -; v is 1, 2 or 3.

[0053] In another embodiment, in formula (I), R 1 is selected from -NR’R”; R’ and R” are independently selected from H, C1-C4 alkyl;

[0054] Y is

[0055] R 2 is selected from H, hydroxyl and C1-C3 alkyl;

[0056] X is selected from C1-C6 alkylene (such as C1-C5 alkylene, C1-C4 alkylene, C1-C3 alkylene), C3-C6 cycloalkylene (such as cyclopropylidene, cyclobutylidene, cyclopentylidene);

[0057] R 3 is selected from phenyl, and the phenyl is optionally substituted by 0-3 R 3a substituted at the 2, 4, 6 positions;

[0058] R 3aEach independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkynyl, C3-C6 epoxyalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 epoxyalkyl);

[0059] R 4 、R 5 、R 6 、R 7 Each independently selected from H, C1-C4 alkyl, C3-C5 cycloalkyl, -O(C1-C4 alkyl), -O(C3-C5 cycloalkyl);

[0060] E is -(CH2) v -;

[0061] v is 1 or 2.

[0062] In another embodiment, in formula (I), R 1 is selected from -NR’R”; R’ and R” are independently selected from H, C1-C3 alkyl;

[0063] Y is

[0064] R 2 is selected from H, hydroxyl and C1-C3 alkyl;

[0065] X is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-,

[0066] R 3 is selected from phenyl, and the phenyl is optionally substituted by 0-3 R 3a at the 2, 4, and 6 positions;

[0067] R 3a Each independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkynyl, C3-C6 epoxyalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 epoxyalkyl);

[0068] R 4 、R 5 、R 6 、R 7Each independently selected from H, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), wherein the C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl) are optionally substituted with 0, 1, 2 or 3 deuterium, halogen, hydroxyl groups;

[0069] E is -(CH2) v -;

[0070] v is 1 or 2.

[0071] In yet another embodiment, in formula (I), R 1 is selected from -NR’R”; R’ and R” are independently selected from H, C1-C3 alkyl;

[0072] Y is

[0073] R 2 is selected from H;

[0074] X is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-

[0075] R 3 is selected from phenyl, which is substituted at the 2, 4, 6 positions with 0-3 R 3a ;

[0076] R 3a are each independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkynyl, C3-C6 epoxyalkyl, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 epoxyalkyl);

[0077] R 4 and R 7 are independently selected from H, halogen and C1-C6 alkyl, preferably both are H;

[0078] R 5 and R 6 are independently selected from C1-C6 alkyl, C1-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), preferably selected from -O(C1-C6 alkyl), for example selected from methoxy, ethoxy and propoxy. Again, for example, R 5 can be methoxy or ethoxy, and R 6 can be methoxy;

[0079] E is -(CH2)v -; v is 1 or 2.

[0080] In yet another embodiment, in formula (I), R 1 is selected from -NR'R"; R' and R" are independently selected from H, C1-C3 alkyl;

[0081] Y is

[0082] R 2 is selected from H;

[0083] X is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-

[0084] R 3 is selected from phenyl, which is substituted at the 2, 4, and 6 positions by 3 Rs 3a wherein the Rs at the 2,6 positions 3a are methyl, and the R at the 4 position 3a is selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkynyl, C3-C6 epoxyalkyl, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 epoxyalkyl);

[0085] R 4 and R 7 are independently selected from H, halogen, and C1-C6 alkyl, preferably both are H;

[0086] R 5 and R 6 are independently selected from C1-C6 alkyl, C1-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), preferably selected from -O(C1-C6 alkyl), for example selected from methoxy, ethoxy, and propoxy. Again, for example, R 5 can be methoxy or ethoxy, and R 6 can be methoxy;

[0087] E is -(CH2) v -; v is 1 or 2.

[0088] In yet another embodiment, in formula (I), R 1 is selected from -NR'R"; R' and R" are independently selected from H, C1-C3 alkyl;

[0089] Y is

[0090] R 2 is selected from H;

[0091] X is selected from -CH2CH2- or

[0092] R 3 is selected from phenyl, which is substituted at the 2, 4, and 6 positions by three Rs 3a wherein the Rs at the 2,6 positions 3a are methyl, and the R at the 4 position 3a is selected from C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 epoxyalkyl, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl);

[0093] R 4 and R 7 are both H;

[0094] R 6 is methoxy, and R 5 is selected from -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl);

[0095] E is -(CH2) v -; v is 1.

[0096] In yet another embodiment, in formula (I), R 1 is selected from -NR’R”; R’ and R” are independently selected from H, C1-C3 alkyl;

[0097] Y is

[0098] R 2 is selected from H;

[0099] X is selected from -CH2CH2- and

[0100] R 3 is selected from

[0101] R 4 and R 7 are independently selected from H, halogen, and C1-C6 alkyl, preferably both are H;

[0102] R 5 and R 6 are independently selected from C1-C6 alkyl, C1-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), preferably selected from -O(C1-C6 alkyl), for example, selected from methoxy, ethoxy, and propoxy. Again, for example, R 5 can be methoxy or ethoxy, and R 6 can be methoxy;

[0103] E is -(CH2) v -; v is 1 or 2.

[0104] Preferably, the compound has the structure shown in the following formula (II-1) or (II-2):

[0105]

[0106]

[0107] Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , E are as described above;

[0108] Preferably, the compound has the structures of the following formula (II-1-1) and the following formula (II-2-1)

[0109] Wherein, R 1 , R 3a , R 5 are defined as above.

[0110] Preferably, the compound represented by the general formula (I) is selected from:

[0111]

[0112] On the other hand, the compound represented by the above general formula (I) provided by the present invention can be prepared by chemical synthesis methods known in the art. For example, it can be prepared by retro-synthesis using raw materials known in the market. Specific synthesis examples are provided in the examples of the present invention.

[0113] On yet another aspect, the present invention provides a pharmaceutical composition, which comprises the compound represented by the above general formula (I) or its stereoisomers, tautomers, deuterated compounds, prodrugs or pharmaceutically acceptable salts, as well as pharmaceutically acceptable excipients, carriers or diluents.

[0114] Definition

[0115] Unless otherwise indicated, the meanings and scopes of the terms of the present invention are illustrated by way of example below.

[0116] represents a connection site.

[0117] The minimum and maximum carbon atom contents in the hydrocarbon group are represented by prefixes. For example, the prefix (C a-b) "Alkyl" means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, (C 1-6 ) "alkyl" refers to an alkyl group containing from 1 to 6 carbon atoms. The alkyl group may be branched or straight-chain.

[0118] Atoms as described in this application include their isotopes. For example, hydrogen may be deuterium or tritium.

[0119] "Alkyl" refers to a monovalent straight-chain or branched saturated hydrocarbon group, including but not limited to groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and other similar groups. Preferably C 1-6 alkyl. More preferably C 1-3 alkyl.

[0120] "Alkylene", either by itself or as part of another term, generally refers to a substituted or unsubstituted branched or straight-chain saturated hydrocarbon group having the stated number of carbon atoms and having two monovalent group centers derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane, preferably 1-6 carbon atoms (-(C1-C6) alkylene-). When no number of carbon atoms is indicated, alkylene may have 1 to 6 carbon atoms. Typical alkylene groups include but are not limited to: methylene (-CH2-), 1,2-ethylene (-CH2CH2-), 1,3-n-propylene (-CH2CH2CH2-), and 1,4-n-butylene (-CH2CH2CH2CH2-). In some aspects, alkylene may be unsubstituted. Optionally, alkylene may be substituted, for example, by one or more groups.

[0121] "Cycloalkyl" refers to a saturated monocyclic, bicyclic, spirocyclic, fused-ring or bridged-ring alkyl group, which may be combined with other groups. Cycloalkyl includes but is not limited to groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. Preferably a 3-6 membered cycloalkyl group.

[0122] "Alkenyl" refers to a straight-chain, branched or cyclic hydrocarbon group containing one or more double bonds, including but not limited to vinyl, propenyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl. Preferably C 2-6 alkenyl. More preferably C 2-4 alkenyl.

[0123] "Alkynyl" refers to a straight-chain, branched or cyclic hydrocarbon group containing one or more triple bonds, including but not limited to ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl. Preferably C 2-6 alkynyl. More preferably C 2-4 alkynyl.

[0124] "Halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine.

[0125] "Haloalkyl" means an alkyl group as defined herein, wherein one or more hydrogens have been replaced by the same or different halogens. Including but not limited to, such as -CH2Cl, -CHF2, -CH2CF3, -CH2CCl3, perfluoroalkyl (e.g., -CF3), etc.

[0126] "Aryl" means a substituted or unsubstituted monocyclic or polycyclic aromatic group, including but not limited to, such as phenyl, naphthyl. Preferably a 6-10 membered monocyclic or bicyclic aromatic group. More preferably phenyl or naphthyl. Most preferably phenyl.

[0127] "Heteroaryl" means a substituted or unsubstituted 5-membered or 6-membered monocyclic heteroaromatic ring system, or a substituted or unsubstituted 9-membered or 10-membered fused or bicyclic heteroaromatic ring system, which contains 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, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, benzimidazolyl or benzothiazolyl.

[0128] "Pharmaceutically acceptable salts" refer to conventional acid addition salts or base addition salts that retain the biological effectiveness and properties of the compound of formula (I), which are formed by suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of acid addition salts include those salts derived from inorganic acids and those derived from organic acids. The inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid. The organic acids such as 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 salts derived from inorganic bases and those derived from organic bases. The inorganic bases such as ammonium salts, calcium salts, iron salts, aluminum salts, sodium salts, potassium salts, zinc salts, magnesium salts. The organic bases include salts of primary amines, secondary amines and tertiary amines, such as trimethylamine, triethylamine, tripropylamine, diethanolamine, ethylenediamine, ethanolamine, etc.

[0129] "Prodrug" means a prodrug that can be converted in vivo into the structure of the compound and its pharmaceutically acceptable salts involved in the present invention.

[0130] Compared with the prior art, the compounds of the present invention can simultaneously inhibit PDE3 and PDE4. And compared with the existing PDE3 and PDE4 dual inhibitors, the compounds of the present invention have stronger efficacy and lower toxicity. Detailed Description

[0131] The technical solution of the present invention will be further described below in conjunction with specific embodiments. The said embodiments are only for clarifying the present invention, rather than limiting the scope of the present invention, and the implementation schemes of the present invention are not limited thereto. Any other changes, substitutions, modifications, simplifications, etc. made without departing from the technical idea and method principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

[0132] Unless otherwise specified, the chemical drugs and devices used in the following examples are all commercially available.

[0133] Example 1: Preparation method of Compound 1

[0134]

[0135] (1) Synthesis of Compound 1-2

[0136] Compound 1-1 (30 g, 166.48 mmol) and ammonium acetate (32.1 g, 416.45 mmol) were added to acetic acid (200 mL). Nitromethane (30.5 g, 499.67 mmol) was added dropwise while maintaining the temperature not exceeding 10 °C. The temperature was raised to reflux and the reaction was carried out for 4 hours. After cooling to room temperature, the reaction solution was poured into ice water (500 mL). Crystallization was carried out at a temperature not exceeding 10 °C for 1 hour and then filtered. The filter cake was added to methanol (200 mL) and slurried at room temperature for 1 hour, and then filtered and dried to obtain Compound 1-2 (21 g, yellow solid), with a yield of 57%.

[0137] MS m / z (ESI): 224.0 [M+H] + .

[0138] (2) Synthesis of Compound 1-3

[0139] Compound 1-2 (21 g, 94.07 mmol) was added to a mixed solution of dimethyl sulfoxide (165 mL) and acetic acid (80 mL). Sodium borohydride (5.34 g, 141.16 mmol) was added while maintaining the temperature not exceeding 10 °C. Stirring was carried out at 10 °C for 1 hour. The reaction solution was slowly poured into water (500 mL), and extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain Compound 1-3 (21 g, yellow gum), with a yield of 99%.

[0140] MS m / z (ESI): 226.2 [M+H] + .

[0141] (3) Synthesis of Compound 1-4

[0142] Under a nitrogen atmosphere, compound 1-3 (20 g, 88.79 mmol) and 5% palladium on carbon (4.44 g) were added to methanol (100 mL). The mixture was purged with hydrogen three times and then heated to 40 °C under hydrogen (15 psi) and stirred for 16 hours. The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain compound 1-4 (17 g, colorless gum), with a yield of 98%.

[0143] MS m / z (ESI): 196.1 [M+H] + 。

[0144] (4) Synthesis of compound 1-5

[0145] Compound 1-4 (17 g, 87.06 mmol) was added to ethyl cyanoacetate (32 mL). The mixture was heated to 100 °C under a nitrogen atmosphere and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to dichloromethane / methanol = 10 / 1) to obtain 1-5 (18 g, light yellow solid), with a yield of 79%.

[0146] MS m / z (ESI): 263.1 [M+H] + 。

[0147] (5) Synthesis of compound 1-6

[0148] Compound 1-5 (18 g, 68.62 mmol) was added to phosphorus oxychloride (180 mL). The mixture was heated to 85 °C and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with dichloromethane (50 mL) and poured into ice water (200 mL). The pH was adjusted to 7 with saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (50 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1-6 (16 g, yellow solid), with a yield of 95%.

[0149] MS m / z (ESI): 245.2 [M+H] + 。

[0150] (6) Synthesis of compound 1-7

[0151] Compound 1-6 (16.0 g, 65.50 mmol) was added to concentrated sulfuric acid (160 mL). The mixture was stirred at 10 °C for 3 hours, and then the reaction mixture was slowly poured into ice water (800 mL). The pH was adjusted to 7 with 4 M aqueous sodium hydroxide. The mixture was extracted with dichloromethane (200 mL × 3). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1-7 (11.4 g, yellow solid), with a yield of 66%.

[0152] MS m / z (ESI): 263.2 [M+H] + 。

[0153] (7) Synthesis of Compound 1-8

[0154] Compound 1-7 (11.4 g, 43.46 mmol), sodium ethoxide (17.2 g, 252.72 mmol), and diethyl carbonate (16 mL) were added to anhydrous ethanol (200 mL). The mixture was heated to 80 °C and stirred for 8 hours. After cooling to room temperature, the reaction solution was slowly poured into ice water, and the pH was adjusted to 7 with 2 M hydrochloric acid. Stirring was continued for 1 hour for crystallization, and then filtration and drying gave Compound 1-8 (8.5 g, yellow solid), with a yield of 68%.

[0155] MS m / z (ESI): 289.1 [M+H] + 。

[0156] (8) Synthesis of Compound 1-9

[0157] Compound 1-8 (8.0 g, 27.75 mmol) was added to phosphorus oxychloride (120 mL). The mixture was heated to 100 °C and stirred for 3 hours. The filtrate was concentrated under reduced pressure, and the residue was diluted with dichloromethane (20 mL) and poured into ice water (100 mL). The pH was adjusted to 7 with saturated aqueous sodium bicarbonate solution, and extraction was carried out with dichloromethane (20 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Compound 1-9 (8.0 g, yellow solid), with a yield of 94%.

[0158] MS m / z (ESI): 307.1 [M+H] + 。

[0159] (9) Synthesis of Compound 1-10

[0160] Compound 1-9 (8.38 g, 27.33 mmol) and 2,4,6-trimethylaniline (5.55 g, 41.00 mmol) were added to isopropanol (160 mL). The mixture was heated to 90 °C and stirred for 16 hours. After cooling the reaction solution to room temperature, crystallization occurred for 1 hour, followed by filtration. The filter cake was rinsed with ethyl acetate (30 mL) and then dried to give Compound 1-10 (10.75 g, yellow solid), with a yield of 97%.

[0161] MS m / z (ESI): 406.3 [M+H] + 。

[0162] (10) Synthesis of Compound 1-11

[0163] Compound 1-10 (312 mg, 0.77 mmol), compound A (396 mg, 1.53 mmol), sodium iodide (581 mg, 3.83 mmol), and cesium carbonate (2.02 g, 6.13 mmol) were added to methyl ethyl ketone (5 mL), and the mixture was stirred at 110 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by flash silica gel column chromatography (dichloromethane / methanol = 1 / 0 - 10 / 1) to obtain compound 1-11 (160 mg, bright yellow colloid), yield: 36%.

[0164] MS m / z (ESI): 575.4 [M+H] + 。

[0165] (11) Synthesis of compound 1-12

[0166] Compound 1-11 (155 mg, 0.27 mmol) was dissolved in dichloromethane (1 mL), then trifluoroacetic acid (0.3 mL) was added, and the mixture was stirred at 10 °C for 16 h. The reaction mixture was concentrated under reduced pressure to obtain compound 1-12 (127 mg, brown solid), yield: 100%.

[0167] MS m / z (ESI): 475.3 [M+H] + 。

[0168] (12) Synthesis of compound 1

[0169] Compound 1-12 (10 mg, 0.022 mmol), potassium cyanate (3 mg, 0.033 mmol), and acetic acid (2 mg, 0.033 mmol) were added to water (1 mL), and the temperature was raised to 80 °C and stirred for 16 h. The reaction mixture was purified by a C18 reverse-phase column (acetonitrile / aqueous solution containing 10 mM ammonium bicarbonate = 30% - 60%) to obtain compound 1 (4.5 mg, off-white solid), yield: 41%.

[0170] MS m / z (ESI): 518.3 [M+H] + 。

[0171] 1 H NMR (400 MHz, CDCl3) δ 7.14 (1H), 6.80 - 6.77 (3H), 5.42 (1H), 4.15 - 4.01 (5H), 3.89 (3H), 3.75 - 3.69 (1H), 2.93 - 2.88 (2H), 2.26 (3H), 2.20 - 2.15 (8H), 2.06 - 2.01 (2H), 1.41 (3H).

[0172] Example 2: Preparation methods of Compounds 2-4, 9-15

[0173] The preparation methods of Compounds 2-4 and 9-15 refer to the synthesis of Compound 1. Among them, the raw materials 2,6-dimethyl-4-methoxyaniline, 2,6-dimethoxy-4-cyclopropylaniline, and 3,4-dimethoxybenzaldehyde were directly purchased. The preparation methods of 4-(cyclobutyloxy)-2,6-dimethylaniline and 4-(cyclopropyloxy)-2,6-dimethylaniline are as follows:

[0174] 1. Synthesis of 4-(cyclobutyloxy)-2,6-dimethylaniline:

[0175]

[0176] (1) Synthesis of 5-(cyclobutyloxy)-1,3-dimethyl-2-nitrobenzene

[0177] 3,5-Dimethyl-4-nitrophenol (0.878 g, 5.25 mmol), bromocyclobutane (1.134 g, 8.40 mmol), and cesium carbonate (4.600 g, 14.12 mmol) were added to DMF (16 mL). The temperature was raised to 90 °C and stirred for 16 hours. After the reaction solution was cooled to room temperature, it was filtered. Ethyl acetate (45 mL) and water (45 mL) were added to the filtrate, and it was left to stand for phase separation. The aqueous phase was extracted with ethyl acetate three times (10 mL * 3). The organic phases were combined, washed with saturated brine (45 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 5-(cyclobutyloxy)-1,3-dimethyl-2-nitrobenzene (crude product, 1.290 g, oil), with a yield of 111%.

[0178] MS m / z (ESI): 222.2 [M + H] + 。

[0179] (2) Synthesis of 4-(cyclobutyloxy)-2,6-dimethylaniline

[0180] 5-(Cyclobutyloxy)-1,3-dimethyl-2-nitrobenzene (1.290 g, 5.83 mmol), iron powder (1.902 g, 34.06 mmol), and methanol (15 mL) were added to saturated ammonium chloride solution (25 mL). The temperature was raised to 65 °C and stirred for 6 hours. After cooling to room temperature, it was filtered. Methanol was removed by reduced pressure concentration of the filtrate. Ethyl acetate (20 mL) was added to the residue and left to stand for phase separation. The aqueous phase was extracted with ethyl acetate (10 mL * 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 4-(cyclobutyloxy)-2,6-dimethylaniline (0.902 g, oil), with a yield of 81%.

[0181] MS m / z (ESI): 192.2 [M + H] + 。

[0182] Synthesis of 2,4-(cyclopropyloxy)-2,6-dimethylaniline:

[0183] The synthesis method of compound 4-(cyclopropyloxy)-2,6-dimethylaniline refers to the synthesis of compound 4-(cyclobutyloxy)-2,6-dimethylaniline.

[0184] MS m / z (ESI): 178.0 [M+H] + 。

[0185] Spectral data of compounds 2-4, 9-15:

[0186]

[0187]

[0188]

[0189] Example 3: Preparation method of Compound 5

[0190]

[0191] Compound 1-12 (19 mg, 0.04 mmol), dimethylamine (0.04 mL, 2 M in THF), CDI (16 mg, 0.10

[0192] mmol), DIPEA (26 mg, 0.20 mmol) were added to DMF (2 mL). After stirring at 25 °C for 2 h, it was purified by a C18 reverse-phase column (acetonitrile / aqueous solution containing 10 mM ammonium bicarbonate = 30% - 60%) to obtain compound 5 (9 mg, off-white solid), yield: 41%.

[0193] MS m / z (ESI) = 546.2 [M+H] + 。

[0194] 1 1H NMR (400 MHz, CDCl3) δ 6.91 (2H), 6.70 (1H), 6.58 (1H), 5.53 (1H), 4.15 - 4.00 (5H), 3.84 (3H), 3.73 - 3.69 (1H), 3.03 - 2.98 (2H), 2.88 (6H), 2.23 - 2.16 (5H), 2.10 (6H), 2.08 - 2.02 (2H), 1.39 (3H).

[0195] Example 4: Preparation methods of Compounds 6-8

[0196] The preparation methods of Compounds 6-8 refer to the synthesis of Compound 5, where the raw materials methylamine (2M in THF) and ethylamine (2M in THF) are directly purchased.

[0197] Spectral data of Compounds 6-8:

[0198]

[0199] Comparative Example 1: Synthesis of RPL554

[0200]

[0201] RPL554 was synthesized according to the preparation method provided in the invention patent WO 00 / 58308.

[0202] MS m / z (ESI): 478.2 [M+H] + 。

[0203] 1 1H NMR (400 MHz, CDCl3) 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).

[0204] Experimental Example 1: Inhibitory effects of representative compounds on PDE3A and PDE4B enzymes

[0205] 1) Reagent materials:

[0206] (1) PDE3A / 4B2 detection kit (BPS, catalog number: Cat.79736 / 60343)

[0207] PDE3A / 4B2 recombinant enzyme

[0208] FAM-cyclic-3′,5′-AMP

[0209] PDE test buffer

[0210] Binder binder diluent (cAMP)

[0211] (2) Black 96-well plate (PerkinElmer, catalog number: Cat#6005540)

[0212] 2) Instrument equipment:

[0213] EnVision-2104 Multichannel Microplate Reader (PerkinElmer)

[0214] 3) Experimental procedures:

[0215] (1) Compound dilution: First, prepare a 10 μM concentrated stock solution of the compound with DMSO. When testing the inhibitory activity of PDE4B2 enzyme, the concentrated stock solution of the compound is diluted from 10 μM in a 4-fold concentration gradient, resulting in a total of 10 concentration points; when testing the inhibitory activity of PDE3A enzyme, the concentrated stock solution of the compound is first diluted to 1 μM and then diluted in a 4-fold concentration gradient, resulting in a total of 10 concentration points.

[0216] (2) Incubation system:

[0217]

[0218]

[0219] (3) Add 5 μL of the compound to each well in the experimental group, and add the same volume of DMSO to the blank control group and the solvent control group. Subsequently, add the substrate FAM-cyclic-3′,5′-AMP and the enzyme successively according to the volumes in the table, mix gently, and incubate at room temperature for 1 hour.

[0220] (4) After the first round of incubation, add 100 μL of the binder reagent to each group to dilute the above system, mix well, and continue to incubate at room temperature for 1 hour.

[0221] (5) After incubation, detect the fluorescence signal using a microplate reader under the test conditions of an excitation wavelength of 490 nm and an emission wavelength of 520 nm, and read the data.

[0222] (6) % Inhibition rate = (FP B - FP S ) / (FP B - FP V ) × 100%

[0223] FP S = Sample fluorescence polarization value

[0224] FP B = Blank control fluorescence polarization value

[0225] FP V = Carrier control fluorescence polarization value.

[0226] Fit the inhibition rate-concentration curve and calculate the IC 50 value.

[0227] 4) Test results

[0228]

[0229]

[0230] It has been verified that the compounds provided by the present invention have good inhibitory activities against both PDE3A and PDE4B, and are significantly superior to RPL554.

[0231] Experimental Example 2: Agonist activity of representative compounds on cAMP

[0232] 1) Reagent materials:

[0233] (1) HTRF cAMP HiRange kit (Cisbio, Catalog number: Cat#62AM6PEB)

[0234] (2) Forskolin (MCE, Catalog number: HY-15371)

[0235] (3) Black 96-well plate (PerkinElmer, Catalog number: Cat#6005540)

[0236] 2) Instrumentation:

[0237] EnVision-2104 multi-channel microplate reader (PerkinElmer)

[0238] 3) Experimental procedures:

[0239] (1) Cell line: THP-1

[0240] Cell density: 6000 cells / well

[0241] Compound treatment time: 30 min before adding Forskolin

[0242] Final concentration of Forskolin: 6 μM

[0243] Forskolin treatment time: 30 min

[0244] Detection method: Refer to the instruction manual of the cAMP HTRF kit

[0245] Highest initial concentration of the compound: 100 μM

[0246] DMSO concentration in the system: 1%

[0247] (2) Incubation system:

[0248]

[0249] (3) Add 0.1 μL of the compound to each well in the experimental group, and add the same volume of DMSO to the blank control group and the solvent control group. Then, add each component successively according to the volumes in the table, gently mix, and incubate at room temperature for 1 hour.

[0250] (4) After the incubation is completed, the fluorescence signal is detected using a microplate reader under the test conditions of an excitation wavelength of 340 nm, an emission wavelength of 616 nm and 665 nm, and the data is read.

[0251] (5) Calculate the activation rate at different concentrations according to the fluorescence polarization value, fit the activation rate-concentration curve, and calculate the EC 50 value.

[0252] 4) Test results

[0253]

[0254]

[0255] It has been verified that the compound provided by the present invention has good agonist activity against cAMP and is superior to RPL554.

Claims

1. A compound of formula (I) or its stereoisomer, tautomer, deuterated compound, prodrug or pharmaceutically acceptable salt thereof: Wherein, R 1 selected from -NR’R”; R’ and R” are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl and hydroxy; Y is selected from R 2 selected from H, hydroxy, and C1-C6 alkyl, where the C1-C6 alkyl is optionally substituted with 0, 1, 2, or 3 halogens, hydroxy, or amino; X is selected from C1-C6 alkylene, C 3- C6 cycloalkylene, C 3- C6 cycloalkylene-C1-C6 alkylene, C1-C6 alkylene-C 3- C6 cycloalkylene-C1-C6 alkylene; R 3 selected from 5- to 6-membered heteroaryl and aryl containing 1 to 3 (e.g., 1, 2 or 3) heteroatoms selected from N, O, S, said 5- to 6-membered heteroaryl and aryl containing 1 to 3 heteroatoms selected from N, O, S being optionally substituted with 0 to 5 R 3a substituents; Each R 3a is the same or different and is independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkynyl, C2-C6 alkenyl, C3-C6 epoxyalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), a 4-6 membered (e.g., 4, 5 or 6 membered) heterocycle containing 1 to 3 (e.g., 1, 2 or 3) heteroatoms selected from N, O, S, -O(C3-C6 epoxyalkyl), hydroxy, cyano, amino or mercapto, and the C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkynyl, C2-C6 alkenyl, C3-C6 epoxyalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), a 4-6 membered heterocycle containing 1 to 3 heteroatoms selected from N, O, S, -O(C3-C6 epoxyalkyl) is optionally substituted with 0, 1, 2 or 3 deuterium, halogen, hydroxy, cyano, amino, mercapto; R 4 、R 5 、R 6 、R 7 are each independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), hydroxy, cyano, amino and mercapto, and the C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl) and -O(C3-C6 cycloalkyl) are optionally substituted with 0, 1, 2 or 3 deuteriums, halogens, hydroxy, cyano, amino, mercapto; E is -(CH2) v -; v is 1, 2 or 3.

2. The compound or its stereoisomer, tautomer, deuterated compound, prodrug or pharmaceutically acceptable salt according to claim 1, wherein, The compound has the structure shown in formula (II): wherein, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、X, E are as described in claim 1.

3. The compound or its stereoisomer, tautomer, deuterated compound, prodrug or pharmaceutically acceptable salt according to claim 1 or 2, wherein R 1 is selected from -NR’R”, wherein R’ and R” are independently selected from H, C1-C6 alkyl; Preferably, R 1 is selected from -NR'R", and R' and R" are independently selected from H, C1-C4 alkyl; Preferably, R 1 is selected from -NR'R", and R' and R" are independently selected from H, C1-C3 alkyl; Preferably, R 2 is selected from H, hydroxy, and C1-C3 alkyl; Preferably, R 2 is selected from H and hydroxyl; Preferably, R 2 is H.

4. A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, deuterated compound, prodrug or pharmaceutically acceptable salt thereof, wherein, X is selected from C1-C6 alkylene, C 3- C6 cycloalkylene; Preferably, X is independently selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2- Preferably, X is selected from -CH2CH2- and 5. A compound or a stereoisomer, tautomer, deuterated compound, prodrug or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein, R 3 selected from phenyl, said phenyl being optionally substituted with 0 - 3 R 3a substituents; Preferably, R 3 is selected from phenyl, which is substituted by three R 3a substituents at the 2, 4, and 6 positions when substituted; Preferably, R 3a is independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkynyl, C3-C6 epoxyalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 epoxyalkyl); Preferably, R 3a each independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkynyl, C3-C6 epoxyalkyl, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 epoxyalkyl); Preferably, R at the 2,6 positions 3a is methyl, and R at the 4 position 3a is selected from C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 epoxyalkyl, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 epoxyalkyl); Preferably, R at the 2,6 positions 3a is methyl, and R at the 4 position 3a is selected from C1-C3 alkyl, C3-C6 cycloalkyl, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl); Preferably, R 3 is selected from 6. The compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, deuterated compound, prodrug or pharmaceutically acceptable salt thereof, wherein, R 4 、R 5 、R 6 、R 7 are each independently selected from H, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), and the C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl) are optionally substituted by 0, 1, 2 or 3 deuteriums, halogens, hydroxyl groups; Preferably, R 4 and R 7 are independently selected from H, halogen, and C1-C6 alkyl, preferably both are H; Preferably, R 5 and R 6 are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), preferably selected from -O(C1-C6 alkyl), for example -O(C1-C4 alkyl); Preferably, E is -(CH2) v -, and v is 1 or 2; Preferably, v is 1.

7. A compound or a stereoisomer, tautomer, deuterated compound, prodrug or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein, In formula (I), R 1 is selected from -NR’R”; R’ and R” are independently selected from H, C1-C6 alkyl; Y is R 2 selected from H, a hydroxyl group, or a C1-C3 alkyl group; X is selected from C1-C6 alkylene, C 3- C6 cycloalkylene; R 3 selected from phenyl, said phenyl optionally being substituted with 0 - 3 R 3a substituents; R 3a each independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkynyl, C3-C6 epoxyalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 epoxyalkyl); R 4 、R 5 、R 6 、R 7 each independently selected from H, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), where the C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl) are optionally substituted by 0, 1, 2 or 3 deuteriums, halogens, or hydroxyl groups; E is -(CH2) v -, where v is 1, 2 or 3; Preferably, in formula (I), R 1 is selected from -NR'R"; R' and R" are independently selected from H, C1-C4 alkyl; Y is R 2 selected from H, hydroxy, and C1-C3 alkyl; X is selected from C1-C6 alkylene (such as C1-C5 alkylene, C1-C4 alkylene, C1-C3 alkylene), C3-C6 cycloalkylene (such as cyclopropylene, cyclobutylene, cyclopentylene); R 3 selected from phenyl, said phenyl being optionally substituted with 0 - 3 R 3a substituted at the 2, 4, and 6 positions; R 3a each independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkynyl, C3-C6 epoxyalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 epoxyalkyl); R 4 、R 5 、R 6 、R 7 each independently selected from H, C1-C4 alkyl, C3-C5 cycloalkyl, -O(C1-C4 alkyl), -O(C3-C5 cycloalkyl); E is -(CH2) v -; v is 1 or 2; Preferably, in formula (I), R 1 is selected from -NR'R"; R' and R" are independently selected from H, C1-C3 alkyl; Y is R 2 selected from H, a hydroxyl group, or a C1-C3 alkyl group; X is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2- R 3 selected from phenyl, wherein the phenyl is optionally substituted with 0-3 R 3a at the 2, 4, and 6 positions; R 3a each independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkynyl, C3-C6 epoxyalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 epoxyalkyl); R 4 、R 5 、R 6 、R 7 each independently selected from H, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), and the C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl) are optionally substituted with 0, 1, 2 or 3 deuteriums, halogens, or hydroxyl groups; E is -(CH2) v -; v is 1 or 2; Preferably, in formula (I), R 1 is selected from -NR'R"; R' and R" are independently selected from H, C1-C3 alkyl; Y is R 2 selected from H; X is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2- R 3 selected from phenyl, which is substituted at the 2, 4, and 6 positions by 0 - 3 R 3a groups; R 3a each independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkynyl, C3-C6 epoxyalkyl, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 epoxyalkyl); R 4 and R 7 are independently selected from H, halogen, and C1-C6 alkyl, preferably both are H; R 5 and R 6 are independently selected from C1-C6 alkyl, C1-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), preferably selected from -O(C1-C6 alkyl), for example selected from methoxy, ethoxy and propoxy; further for example, R 5 may be methoxy or ethoxy, and R 6 may be methoxy; E is -(CH2) v -; v is 1 or 2; Preferably, in formula (I), R 1 is selected from -NR'R"; R' and R" are independently selected from H, C1-C3 alkyl; Y is R 2 selected from H; X is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2- R 3 Selected from phenyl groups, which are substituted by three Rs 3a at the 2, 4, and 6 positions; wherein the Rs at the 2, 6 positions 3a are methyl groups, and the R at the 4 position 3a is selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkynyl, C3-C6 epoxyalkyl, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 epoxyalkyl); R 4 and R 7 are independently selected from H, halogen, and C1-C6 alkyl; R 5 and R 6 are independently selected from C1-C6 alkyl, C1-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl); E is -(CH2) v -; v is 1 or 2; Preferably, in formula (I), R 1 is selected from -NR'R"; R' and R" are independently selected from H, C1-C3 alkyl; Y is R 2 selected from H; X is selected from -CH2CH2- or R 3 Selected from phenyl groups, which are substituted by three Rs 3a at the 2, 4, and 6 positions; wherein the Rs at the 2, 6 positions 3a are methyl, and the R at the 4 position 3a is selected from C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 epoxyalkyl, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl); R 4 and R 7 are both H; R 6 is methoxy, R 5 is selected from -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl); E is -(CH2) v -; v is 1; Preferably, in formula (I), R 1 is selected from -NR'R"; R' and R" are independently selected from H, C1-C3 alkyl; Y is R 2 selected from H; X is selected from -CH2CH2- and R 3 selected from R 4 and R 7 are independently selected from H, halogen, and C1-C6 alkyl, preferably both are H; R 5 and R 6 are independently selected from C1-C6 alkyl, C1-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), preferably selected from -O(C1-C6 alkyl); E is -(CH2) v -; v is 1 or 2.

8. A compound or a stereoisomer, tautomer, deuterated compound, prodrug or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein, The compound has the structure shown in formula (II-1) or (II-2): Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , E as described in any one of claims 1 to 7; Preferably, the compound has the structure shown in formula (II-1-1) or (II-1-2): wherein, R 1 、R 3a 、R 5 are as described in any one of claims 1 to 7; Preferably, the compound of formula (I) is selected from:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or its stereoisomer, tautomer, deuterated compound, prodrug or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, carrier or diluent.

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