Fused tricyclic compound, and preparation method therefor and use thereof

Abstract

The present invention relates to a fused tricyclic compound, and a preparation method therefor and the use thereof. The structural formula of the fused tricyclic compound of the present invention is as represented by formula (I), wherein R1, R2, R3, R4, R5, R6, R7, E, X and Y are as described in the description. The compound of the present invention can simultaneously inhibit PDE3 and PDE4. In addition, compared with the existing dual-target inhibitors of PDE3 and PDE4, the compound has a better effect.

Description

A tricyclic compound and a preparation method and use thereof TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a tricyclic compound and a preparation method and use thereof. BACKGROUND

[0002] The PDE (Phosphodiesterase) enzyme superfamily comprises 11 gene families, specifically PDE1-PDE11. PDE3 and PDE4 are the main cAMP hydrolytic enzymes in smooth muscle tissue and are highly expressed in the pulmonary airway smooth muscle. PDE3 can hydrolyze both cAMP and cGMP, and its cAMP hydrolysis capacity is about ten times that of cGMP. PDE3 is the main PDE in airway smooth muscle cells, and inhibition of PDE3 hinders the metabolism of intracellular cAMP. Accumulation of cAMP can cause Ca 2+ to be released from the sarcoplasmic reticulum, thereby enhancing the contractility of smooth muscle and dilating peripheral 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, and PDE4 inhibitors can inhibit the release of harmful mediators from inflammatory cells. Therefore, inhibition of the hydrolysis of cAMP and cGMP by PDE3 / 4 can increase the intracellular concentration of cAMP and cGMP in the pulmonary smooth muscle tissue, thereby activating the downstream phosphorylation cascade, relaxing the airway smooth muscle and inhibiting inflammation. Given the important role of PDE4 in inhibiting airway inflammation, inhibition of PDE3 can enhance bronchodilation, and modulation of inflammation and mucus production by PDE4 inhibition can have a potential synergistic effect on airway caliber. Therefore, combined inhibition of PDE3 and PDE4 has additive and synergistic anti-inflammatory and bronchodilatory effects.

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

[0004] However, its enzyme activity data show that the inhibitory activity on PDE4 needs to be improved, and the inhibitory activity on PDE3 also needs to be improved. SUMMARY

[0005] In order to meet the huge clinical needs, the present application aims to develop more efficient and safe PDE3 / 4 dual inhibitors. To this end, the present application provides a tricyclic compound and a preparation method and use thereof.

[0006] Therefore, an object of the present application is to provide a tricyclic compound as a PDE3 / 4 dual inhibitor.

[0007] Another object of the present application is to provide a method for preparing the above-mentioned compound.

[0008] Still another object of the present application is to provide a pharmaceutical composition comprising the above-mentioned compound.

[0009] Yet another object of the present application is to provide a pharmaceutical use of the above-mentioned compound or pharmaceutical composition.

[0010] Still yet another object of the present application is to provide a method for treating a condition associated with PDE3 and / or PDE4. The technical solution of the present application is achieved by using the following scheme.

[0011] In one aspect, the present application provides a compound represented by the general formula (I) or a stereoisomer, a tautomer, a deuterated analog, a prodrug, or a pharmaceutically acceptable salt thereof:

[0012] wherein,

[0013] R 1 is selected from -NR'R"; R', R" are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, and hydroxyl;

[0014] Y is selected from

[0015] R 2 is selected from H, hydroxyl, and C1-C6 alkyl optionally substituted with 0, 1, 2, or 3 halogen, hydroxyl, amino;

[0016] X is selected from C1-C6 alkylene (e.g., -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH2CH2CH2CH2-, -CH(CH3)CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH(CH3)CH2CH2CH2CH2-, and the like), C 3- C6 cycloalkylene, C 3- C6 cycloalkylene-C1-C6 alkylene, C1-C6 alkylene-C 3- C6 cycloalkylene-C1-C6 alkylene;

[0017] R 3 is selected from 5-6 membered heteroaryl containing 1-3 (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and aryl (e.g., phenyl), said 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S and aryl is optionally substituted with 0-5 R 3a ;

[0018] each R 3a are the same or different and each is independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkynyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, -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 cycloalkenyl), hydroxyl, cyano, amino, or mercapto, said C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkynyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), 4-6 membered heterocycle, -O(C3-C6 cycloalkenyl) being optionally substituted with 0, 1, 2, or 3 deuterium, halogen, hydroxyl, cyano, amino, mercapto;

[0019] 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), hydroxyl, cyano, amino, and mercapto, said C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), and -O(C3-C6 cycloalkyl) being optionally substituted with 0, 1, 2, or 3 deuterium, halogen, hydroxyl, cyano, amino, mercapto;

[0020] E is -(CH2) v -;

[0021] v is 1, 2, or 3.

[0022] Preferably, the compound has the structure shown in the following formula (II):

[0023] Preferably, R 1 is selected from -NR’R”, R’ and R” are independently selected from H, C1-C6 alkyl;

[0024] More preferably, R 1 is selected from -NR’R”, R’ and R” are independently selected from H, C1-C4 alkyl;

[0025] Most preferably, R 1 is selected from -NR’R”, R’ and R” are independently selected from H, C1-C3 alkyl, for example R’ and R” are independently H, methyl, ethyl, propyl, isopropyl, butyl, and the like.

[0026] Preferably, R 2 is selected from H, hydroxyl, and C1-C3 alkyl;

[0027] More preferably, R 2 is selected from H and hydroxyl.

[0028] Most preferably, R 2 is H.

[0029] Preferably, X is selected from C1-C6 alkylene (e.g., C1-C5 alkylene, C1-C4 alkylene, C1-C3 alkylene), C3-C6 cycloalkylene (e.g., cyclopropylene, cyclobutylene, cyclopentylene);

[0030] Further more preferably, X is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-,

[0031] Most preferably, X is selected from -CH2CH2- and

[0032] Preferably, R 3 is selected from phenyl, which is optionally substituted with 0-3 R 3a ;

[0033] More preferably, R 3 is selected from phenyl, which is substituted with 3 R 3a in the 2, 4, 6 positions;

[0034] Preferably, R 3a are each independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkynyl, C3-C6 cycloalkyloxy, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 cycloalkyloxy).

[0035] More preferably, R 3a are each independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkynyl, C3-C6 cycloalkyloxy, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 cycloalkyloxy). For example, R 3a may be methyl, ethyl, propyl, butyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, cycloalkyloxy, ethynyl, propynyl, etc.

[0036] Further preferably, R 3a in the 2, 6 positions are methyl and R 3aselected from the group consisting of C1-C4alkyl, C3-C6cycloalkyl, C3-C6cycloalkyloxy, -O(C1-C4alkyl), -O(C3-C6cycloalkyl), -O(C3-C6cycloalkyloxy);

[0037] Preferably, R 3a is methyl, R 3a is selected from the group consisting of C1-C3alkyl, C3-C6cycloalkyl, -O(C1-C4alkyl), -O(C3-C6cycloalkyl).

[0038] Preferably, R 3 is selected from the group consisting of

[0039] Preferably, R 4 , R 5 , R 6 , R 7 are each independently selected from the group consisting of H, halogen, C1-C6alkyl, C3-C6cycloalkyl, -O(C1-C6alkyl), -O(C3-C6cycloalkyl), said C1-C6alkyl, C3-C6cycloalkyl, -O(C1-C6alkyl), -O(C3-C6cycloalkyl) being optionally substituted with 0, 1, 2 or 3 deuterium, halogen, hydroxyl; more preferably, R 4 and R 7 are independently selected from the group consisting of H, halogen and C1-C6alkyl, preferably both are H;

[0040] Further preferably, R 5 and R 6 are independently selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, -O(C1-C6alkyl), -O(C3-C6cycloalkyl), preferably from -O(C1-C6alkyl), for example -O(C1-C4alkyl), selected from methoxy, ethoxy and propoxy. For example, R 5 may be methoxy or ethoxy, R 6 may be methoxy.

[0041] Preferably, E is -(CH2) v -, v is 1 or 2;

[0042] More preferably, v is 1.

[0043] In one embodiment, in formula (I), R 1 is selected from the group consisting of -NR’R”; R’, R” are independently selected from H, C1-C6alkyl;

[0044] Y is

[0045] R 2selected from H, hydroxyl, and C1-C3 alkyl;

[0046] X is selected from C1-C6 alkylene (e.g., C1-C5 alkylene, C1-C4 alkylene, C1-C3 alkylene), C3-C6 cycloalkylene (e.g., cyclopropylene, cyclobutylene, cyclopentylene);

[0047] R 3 is selected from phenyl, which phenyl is optionally substituted with 0-3 R 3a substituents;

[0048] R 3a are each independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkynyl, C3-C6 cycloalkynyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 cycloalkynyl);

[0049] 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), which C1-C6 alkyl, C3-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl) is optionally substituted with 0, 1, 2, or 3 deuterium, halogen, hydroxyl;

[0050] E is -(CH2) v ; v is 1, 2, or 3.

[0051] In another embodiment, in formula (I), R 1 is selected from -NR’R”; R’, R” are independently selected from H, C1-C4 alkyl;

[0052] Y is

[0053] R 2 is selected from H, hydroxyl, and C1-C3 alkyl;

[0054] X is selected from C1-C6 alkylene (e.g., C1-C5 alkylene, C1-C4 alkylene, C1-C3 alkylene), C3-C6 cycloalkylene (e.g., cyclopropylene, cyclobutylene, cyclopentylene);

[0055] R 3 is selected from phenyl, which phenyl is optionally substituted with 0-3 R 3a in the 2, 4, 6 positions;

[0056] R 3aeach independently selected from H, deuterium, halogen, C1-C6alkyl, C3-C6cycloalkyl, C2-C6alkynyl, C3-C6cycloalkyloxy, -0(C1-C6alkyl), -0(C3-C6cycloalkyl), -0(C3-C6cycloalkyloxy);

[0057] R 4 , R 5 , R 6 , R 7 each independently selected from H, C1-C4alkyl, C3-C5cycloalkyl, -0(C1-C4alkyl), -0(C3-C5cycloalkyl);

[0058] E is -(CH2) v -;

[0059] v is 1 or 2.

[0060] In another embodiment, in formula (I), R 1 is selected from -NR'R"; R', R" are independently selected from H, C1-C3alkyl;

[0061] Y is

[0062] R 2 is selected from H, hydroxyl and C1-C3alkyl;

[0063] X is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-,

[0064] R 3 is selected from phenyl, said phenyl being optionally substituted with 0-3 R 3a in 2, 4, 6 positions;

[0065] R 3a each independently selected from H, deuterium, halogen, C1-C6alkyl, C3-C6cycloalkyl, C2-C6alkynyl, C3-C6cycloalkyloxy, -0(C1-C6alkyl), -0(C3-C6cycloalkyl), -0(C3-C6cycloalkyloxy);

[0066] R 4 , R 5 , R 6 , R 7each independently selected from H, halogen, C1-C6alkyl, C3-C6cycloalkyl, -O(C1-C6alkyl), -O(C3-C6cycloalkyl), said C1-C6alkyl, C3-C6cycloalkyl, -O(C1-C6alkyl), -O(C3-C6cycloalkyl) optionally substituted with 0, 1, 2, or 3 deuterium, halogen, hydroxyl;

[0067] E is -(CH2) v -;

[0068] v is 1 or 2.

[0069] In yet another embodiment, in formula (I), R 1 is selected from -NR’R”; R’, R” are independently selected from H, C1-C3alkyl;

[0070] Y is

[0071] R 2 is selected from H;

[0072] X is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-,

[0073] R 3 is selected from phenyl, which is substituted with 0-3 R 3a in 2, 4, 6 positions;

[0074] R 3a each independently selected from H, C1-C4alkyl, C3-C6cycloalkyl, C2-C4alkynyl, C3-C6cycloalkyloxy, -O(C1-C4alkyl), -O(C3-C6cycloalkyl), -O(C3-C6cycloalkyloxy);

[0075] R 4 and R 7 are independently selected from H, halogen and C1-C6alkyl, preferably both are H;

[0076] R 5 and R 6 are independently selected from C1-C6alkyl, C1-C6cycloalkyl, -O(C1-C6alkyl), -O(C3-C6cycloalkyl), preferably from -O(C1-C6alkyl), for example from methoxy, ethoxy and propoxy. For example, R 5 may be methoxy or ethoxy, R 6 may be methoxy;

[0077] E is -(CH2)v v is 1 or 2.

[0078] In a further embodiment, in formula (I), R 1 is selected from -NR'R"; R', R" are independently selected from H, C1-C3 alkyl;

[0079] Y is

[0080] R 2 is selected from H;

[0081] X is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-,

[0082] R 3 is selected from phenyl, which is substituted in 2, 4, 6 positions with 3 R 3a ; wherein R 3a in 2, 6 positions is methyl and R 3a in 4 position is selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkynyl, C3-C6 cycloalkyloxy, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 cycloalkyloxy);

[0083] R 4 and R 7 are independently selected from H, halogen and C1-C6 alkyl, preferably both are H;

[0084] R 5 and R 6 are independently selected from C1-C6 alkyl, C1-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), preferably from -O(C1-C6 alkyl), for example from methoxy, ethoxy and propoxy. For example, R 5 may be methoxy or ethoxy and R 6 may be methoxy;

[0085] E is -(CH2) v v is 1 or 2.

[0086] In a further embodiment, in formula (I), R 1 is selected from -NR'R"; R', R" are independently selected from H, C1-C3 alkyl;

[0087] Y is

[0088] R 2 is selected from H;

[0089] X is selected from -CH2CH2- or

[0090] R 3 is selected from phenyl, which is substituted in 2, 4, 6 positions; wherein R 3a in 2, 6 positions is methyl and R 3a in 4 position is selected from C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl); 3a

[0091] R 4 and R 7 are both H;

[0092] R 6 is methoxy and R 5 is selected from -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl);

[0093] E is -(CH2) v -; v is 1.

[0094] In still another embodiment, in formula (I), R 1 is selected from -NR'R"; R', R" are independently selected from H, C1-C3 alkyl;

[0095] Y is

[0096] R 2 is selected from H;

[0097] X is selected from -CH2CH2- and

[0098] R 3 is selected from

[0099] R 4 and R 7 are independently selected from H, halogen and C1-C6 alkyl, preferably both are H;

[0100] R 5 and R 6 are independently selected from C1-C6 alkyl, C1-C6 cycloalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), preferably from -O(C1-C6 alkyl), for example from methoxy, ethoxy and propoxy. For example, R 5 may be methoxy or ethoxy and R6may be methoxy;

[0101] E is -(CH2)​v v is 1 or 2.

[0102] Preferably, the compound has the structure of the following formula (II-1) or (II-2):

[0103] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , E is as described above.

[0104] Preferably, the compound has the structure of the following formula (II-1-1), the following formula (II-2-1)

[0105] wherein R 1 , R 3a , R 5 are as described above.

[0106] Preferably, the compound of the general formula (I) is selected from:

[0107] In another aspect, the compound of the general formula (I) described above can be prepared by using the chemical synthesis method known in the art, for example, by using the raw materials known in the market through the retrosynthesis method. Specific synthesis examples are provided in the embodiments of the present application.

[0108] In still another aspect, the present application provides a pharmaceutical composition comprising the compound of the general formula (I) described above or a stereoisomer, tautomer, deuterated compound, prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier or diluent.

[0109] In yet another aspect, the present application provides the use of the compound of the general formula (I) described above, a stereoisomer, tautomer, deuterated compound, prodrug or pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above in the preparation of a medicament for preventing and / or treating a condition associated with PDE3 and / or PDE4.

[0110] In still another aspect, the present application provides a method for treating a condition associated with PDE3 and / or PDE4 in a mammal, which comprises administering to a mammal in need of treatment a therapeutically effective amount of the compound of the general formula (I) described above, a stereoisomer, tautomer, deuterated compound, prodrug or pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above.

[0111] Definitions

[0112] The following illustrates the meaning and scope of the terms of the present application by way of example, unless otherwise indicated.

[0113] denotes a point of attachment.

[0114] The minimum and maximum number of carbon atoms in a hydrocarbon group is indicated by a prefix, e.g., the prefix (C a-b )alkyl denotes any alkyl group having "a" to "b" carbon atoms. Thus, for example, (C 1-6 )alkyl means an alkyl group containing 1 to 6 carbon atoms. The alkyl group is branched or straight chain.

[0115] Atoms as described in the present application include isotopes thereof, e.g., hydrogen can be deuterium or tritium.

[0116] "Alkyl" means a monovalent straight chain or branched chain saturated hydrocarbon group including but not limited to, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl and other similar groups. Preferred is C 1-6 alkyl. More preferred is C 1-3 alkyl.

[0117] "Alkylene" by itself or as part of another term refers typically to a substituted or unsubstituted branched or straight chain saturated hydrocarbon group having the indicated number of carbon atoms and having two monovalent radical centers derived by removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane, preferably 1-6 carbon atoms (-(C1-C6)alkylene-). When the number of carbon atoms is not indicated, the alkylene group can have from 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, the alkylene group can be unsubstituted. Optionally, the alkylene group can be substituted, e.g., with one or more groups.

[0118] "Cycloalkyl" means a saturated monocyclic, bicyclic, spiro, fused or bridged ring alkyl group, possibly in combination with other groups. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. Preferred is a 3-6 membered cycloalkyl group.

[0119] "Alkenyl" means a straight chain, branched chain or cyclic hydrocarbon group containing one or more double bonds, including but not limited to, for example, ethenyl, propenyl, (E)-2-methylethenyl, (Z)-2-methylethenyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-l-enyl, (Z)-but-l-enyl. Preferred is C 2-6 alkenyl. More preferred is C 2-4Alkenyl.

[0120] "Alkynyl" means straight chained, branched or cyclic hydrocarbon groups 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. Preferred are C 2-6 Alkynyl. More preferred are C 2-4 Alkynyl.

[0121] "Halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine.

[0122] "Haloalkyl" means alkyl groups as defined herein, wherein one or more hydrogens have been replaced by the same or different halogen. Included are, but are not limited to, -CH2Cl, -CHF2, -CH2CF3, -CH2CCl3, perfluoroalkyl groups (e.g., -CF3), and the like.

[0123] "Aryl" means substituted or unsubstituted, mono- or polycyclic aromatic groups, including but not limited to, phenyl, naphthyl. Preferred are 6-10 membered monocyclic or bicyclic aromatic groups. More preferred are phenyl or naphthyl. Most preferred is phenyl.

[0124] "Heteroaryl" means a substituted or unsubstituted 5- or 6-membered single heteroaromatic ring system, or a substituted or unsubstituted 9- or 10-membered fused or bicyclic heteroaromatic ring system, containing 1-4 heteroatoms independently selected from N, O, or S, with the remaining ring atoms being carbon atoms. Examples of heteroaryl moieties include, but are not limited to: thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, or benzothiazolyl.

[0125] "Pharmaceutically acceptable salt" means a conventional acid addition salt or base addition salt that retains the biological effectiveness and properties of the compounds of formula (I) and is 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 such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric, and nitric acids, and organic acids such as acetic, propionic, glycolic, oxalic, stearic, ascorbic, p-toluene sulfonic, salicylic, mesyl, ethanesulfonic, oxalic, succinic, citric, maleic, hydroxymaleic, lactic, fumaric, tartaric, malic, isethionic, benzenesulfonic, trifluoroacetic, mandelic, and the like. Examples of base addition salts include those derived from inorganic bases such as ammonium, calcium, ferric, aluminum, sodium, potassium, zinc, magnesium. Organic bases include salts of primary, secondary and tertiary amines, such as methylamine, diethylamine, triethylamine, diethanolamine, ethanolamine, and the like.

[0126] "Prodrug" means a precursor of a compound of the present application, which can be converted in vivo into a structure of the compound of the present application and its pharmaceutically acceptable salts.

[0127] Compared with the prior art, the compound of the present application can simultaneously inhibit PDE3 and PDE4. And compared with the prior PDE3 and PDE4 dual inhibitors, the compound of the present application has stronger efficacy and lower toxicity. DETAILED DESCRIPTION

[0128] The technical solutions of the present application are further described below in combination with specific examples. The examples are only for illustrating the present application, and are not intended to limit the scope of the present application, and the embodiments of the present application are not limited thereto. Any changes, substitutions, modifications, simplifications, etc. made without departing from the technical ideas and principles of the present application shall be equivalent replacement manners, and are all included in the protection scope of the present application.

[0129] Unless otherwise specified, the chemicals and devices used in the following examples are commercially available.

[0130] Example 1: Preparation method of compound 1

[0131] (1) Synthesis of compound 1-2

[0132] Compound 1-1 (30 g, 166.48 mmol), ammonium acetate (32.1 g, 416.45 mmol) were added into acetic acid (200 mL), and nitromethane (30.5 g, 499.67 mmol) was added dropwise at not more than 10°C, and the reaction was heated to reflux for 4 hours. After cooling to room temperature, the reaction solution was poured into ice water (500 mL), and compound 1-2 (21 g, yellow solid) was obtained by crystallization at not more than 10°C for 1 hour, filtration, slurry in methanol (200 mL) at room temperature for 1 hour, filtration and drying. Yield: 57%.

[0133] MS m / z (ESI): 224.0 [M+H] + .

[0134] (2) Synthesis of compound 1-3

[0135] Compound 1-2 (21 g, 94.07 mmol) was added to a mixed solution of dimethyl sulfoxide (165 mL) and acetic acid (80 mL), and sodium borohydride (5.34 g, 141.16 mmol) was added at no more than 10°C, and stirred at 10°C for 1 hour. The reaction solution was slowly poured into water (500 mL), extracted with ethyl acetate (500 mL*2), and the organic phase was combined and washed with saturated brine (500 mL). After drying over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure to obtain compound 1-3 (21 g, yellow gum), yield: 99%.

[0136] MS m / z (ESI): 226.2 [M+H] + .

[0137] (3) Synthesis of compound 1-4

[0138] Compound 1-3 (20 g, 88.79 mmol) and 5% palladium-carbon (4.44 g) were added to methanol (100 mL) under a nitrogen atmosphere, and hydrogen was replaced three times, and stirred at 40°C under hydrogen (15 psi) for 16 hours. The palladium-carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain compound 1-4 (17 g, colorless gum), yield: 98%.

[0139] MS m / z (ESI): 196.1 [M+H] + .

[0140] (4) Synthesis of compound 1-5

[0141] Compound 1-4 (17 g, 87.06 mmol) was added to ethyl cyanoacetate (32 mL), and stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 ~ dichloromethane / methanol = 10 / 1) to obtain 1-5 (18 g, light yellow solid), yield: 79%.

[0142] MS m / z (ESI): 263.1 [M+H] + .

[0143] (5) Synthesis of compound 1-6

[0144] Compound 1-5 (18 g, 68.62 mmol) was added to phosphorus oxychloride (180 mL), warmed to 85 °C and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with dichloromethane (50 mL), poured into ice water (200 mL), and the pH was adjusted to 7 with saturated aqueous sodium bicarbonate solution. The organic phase was extracted with dichloromethane (50 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 1-6 (16 g, yellow solid) at a yield of 95%.

[0145] MS m / z (ESI): 245.2 [M+H] + .

[0146] (6) Synthesis of compound 1-7

[0147] Compound 1-6 (16.0 g, 65.50 mmol) was added to concentrated sulfuric acid (160 mL) and stirred at 10 °C for 3 hours. The reaction solution was slowly poured into ice water (800 mL), the pH was adjusted to 7 with 4 M aqueous sodium hydroxide solution, and the organic phase was extracted with dichloromethane (200 mL*3). The organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 1-7 (11.4 g, yellow solid) at a yield of 66%.

[0148] MS m / z (ESI): 263.2 [M+H] + .

[0149] (7) Synthesis of compound 1-8

[0150] 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) and stirred at 80 °C for 8 hours. The reaction solution was slowly poured into ice water after cooling to room temperature, the pH was adjusted to 7 with 2 M hydrochloric acid, and the product was crystallized by stirring for 1 hour. The product was filtered and dried to obtain compound 1-8 (8.5 g, yellow solid) at a yield of 68%.

[0151] MS m / z (ESI): 289.1 [M+H] + .

[0152] (8) Synthesis of compound 1-9

[0153] Compound 1-8 (8.0 g, 27.75 mmol) was added to phosphorus oxychloride (120 mL) and stirred at 100°C for 3 hours. The filtrate was concentrated under reduced pressure, the residue was diluted with dichloromethane (20 mL), poured into ice water (100 mL), the pH was adjusted to 7 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (20 mL*2), the organic phase was combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1-9 (8.0 g, yellow solid), yield: 94%.

[0154] MS m / z (ESI): 307.1 [M+H] + .

[0155] (9) Synthesis of compound 1-10

[0156] Compound 1-9 (8.38 g, 27.33 mmol), 2,4,6-trimethylaniline (5.55 g, 41.00 mmol) were added to isopropanol (160 mL) and stirred at 90°C for 16 hours. The reaction solution was cooled to room temperature and crystallized for 1 hour, then filtered. The filter cake was rinsed with ethyl acetate (30 mL) and dried to obtain compound 1-10 (10.75 g, yellow solid), yield: 97%.

[0157] MS m / z (ESI): 406.3 [M+H] + .

[0158] (10) Synthesis of compound 1-11

[0159] Compound 1-10 (312 mg, 0.77 mmol), compound A (396 mg, 1.53 mmol), sodium iodide (581 mg, 3.83 mol), and cesium carbonate (2.02 g, 6.13 mmol) were added to butanone (5 mL) and stirred at 110°C for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by flash silica gel plate chromatography (dichloromethane / methanol = 1 / 0 ~ 10 / 1) to obtain compound 1-11 (160 mg, bright yellow gel), yield: 36%.

[0160] MS m / z (ESI): 575.4 [M+H] + .

[0161] (11) Synthesis of compound 1-12

[0162] Compound 1-11 (155 mg, 0.27 mmol) was dissolved in dichloromethane (1 mL), then trifluoroacetic acid (0.3 mL) was added, and stirred at 10 °C for 16 hours, the reaction was concentrated under reduced pressure to obtain compound 1-12 (127 mg, brown solid), yield: 100%.

[0163] MS m / z (ESI): 475.3 [M+H] + .

[0164] Synthesis of compound 1

[0165] Compound 1-12 (10 mg, 0.022 mmol), potassium cyanate (3 mg, 0.033 mmol), acetic acid (2 mg, 0.033 mmol) were added to water (1 mL), and stirred at 80 °C for 16 hours, the reaction mixture was purified by C18 reverse phase column (acetonitrile / water containing 10 mM ammonium bicarbonate = 30%~60%) to obtain compound 1 (4.5 mg, white solid), yield: 41%.

[0166] MS m / z (ESI): 518.3 [M+H] + .

[0167] 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).

[0168] Example 2: Preparation method of compounds 2~4, 9~15

[0169] The preparation method of compounds 2~4, 9~15 refers to the synthesis of compound 1, wherein the raw materials 2,6-dimethyl-4-methoxyaniline, 2,6-dimethoxy-4-cyclopropyl aniline, 3,4-dimethoxybenzaldehyde are directly purchased, and the preparation methods of 4-(cyclobutyloxy)-2,6-dimethyl aniline and 4-(cyclopropyloxy)-2,6-dimethyl aniline are as follows:

[0170] 1. Synthesis of 4-(cyclobutyloxy)-2,6-dimethyl aniline:

[0171] (1) Synthesis of compound 5-(cyclobutyloxy)-1,3-dimethyl-2-nitrobenzene

[0172] Into a 100 mL round bottom flask, 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 into DMF (16 mL), and the mixture was stirred at 90 °C for 16 h. After the reaction was cooled to room temperature, the mixture was filtered. Ethyl acetate (45 mL) and water (45 mL) were added to the filtrate, and the mixture was allowed to stand to separate into two layers. The aqueous layer was extracted with ethyl acetate (10 mL x 3), and the combined organic phase was washed with saturated brine (45 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give 5-(cyclobutyloxy)-1,3-dimethyl-2-nitrobenzene (crude, 1.290 g, oil) in 111% yield.

[0173] MS m / z (ESI): 222.2 [M+H] + .

[0174] (2) Synthesis of compound 4-(cyclobutyloxy)-2,6-dimethylaniline

[0175] Into a 100 mL round bottom flask, 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 into saturated ammonium chloride solution (25 mL), and the mixture was stirred at 65 °C for 6 h. After the mixture was cooled to room temperature, the mixture was filtered. The filtrate was concentrated under reduced pressure to remove methanol. Ethyl acetate (20 mL) was added to the residue, and the mixture was allowed to stand to separate into two layers. The aqueous layer was extracted with ethyl acetate (10 mL x 3), and the combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give 4-(cyclobutyloxy)-2,6-dimethylaniline (0.902 g, oil) in 81% yield.

[0176] MS m / z (ESI): 192.2 [M+H] + .

[0177] 2. Synthesis of compound 4-(cyclopropyloxy)-2,6-dimethylaniline:

[0178] The synthesis of compound 4-(cyclopropyloxy)-2,6-dimethylaniline was performed by referring to the synthesis of compound 4-(cyclobutyloxy)-2,6-dimethylaniline.

[0179] MS m / z (ESI): 178.0 [M+H] + .

[0180] Spectroscopic data of compounds 2-4, 9-15:

[0181] Example 3: Preparation method of compound 5

[0182] Compound 1-12 (19 mg, 0.04 mmol), dimethylamine (0.04 mL, 2M in THF), CDI (16 mg, 0.10 mmol), DIPEA (26 mg, 0.20 mmol) were added into DMF (2 mL), after stirring at 25℃ for 2h, purified by C18 reverse phase column (acetonitrile / 10 mM ammonium bicarbonate aqueous solution = 30% ~ 60%), to obtain compound 5 (9 mg, white solid), yield: 41%.

[0183] MS m / z (ESI) = 546.2 [M+H] + .

[0184] 1 H 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).

[0185] Example 4: Preparation method of compounds 6-8

[0186] The preparation method of compounds 6-8 refers to the synthesis of compound 5, wherein the raw materials methylamine (2M in THF), ethylamine (2M in THF) are directly purchased.

[0187] Spectra data of compounds 6-8:

[0188] Comparative example 1: Synthesis of RPL554

[0189] RPL554 was synthesized according to the preparation method provided in the invention patent WO 00 / 58308.

[0190] MS m / z (ESI): 478.2 [M+H] + .

[0191] 1H NMR (400 MHz, CDC13) 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).

[0192] Experimental Example 1: Inhibition of PDE3A and PDE4B enzymes by representative compounds

[0193] 1) Reagent materials:

[0194] (1) PDE3A / 4B2 Assay Kit (BPS, Cat. No.: 79736 / 60343)

[0195] PDE3A / 4B2 recombinant enzymes

[0196] FAM-cyclo-3',5'-AMP

[0197] PDE test buffer

[0198] Binding agent Binding agent diluent (cAMP)

[0199] (2) Black 96-well plate (PerkinElmer, Cat# 6005540)

[0200] 2) Instrumentation:

[0201] EnVision-2104 Multilabel Plate Reader (PerkinElmer)

[0202] 3) Experimental procedure:

[0203] (1) Compound dilution: First, prepare a 10 mM compound stock solution with DMSO for testing PDE4B2 enzyme activity inhibition. Dilute the compound stock solution from 10 mM to 10 concentration points with a 4-fold concentration gradient. For testing PDE3A enzyme activity inhibition, first dilute the compound stock solution to 1 mM, and then dilute it to 10 concentration points with a 4-fold concentration gradient.

[0204] (2) Incubation system:

[0205] (3) Add 5 pL of compound to each well of the experimental group, and add the same volume of DMSO to the blank control group and the solvent control group. Then add the substrate FAM-cyclo-3',5'-AMP and the enzyme to each well according to the table, mix gently, and incubate at room temperature for 1 hour.

[0206] (4) After the first round of incubation, 100 μL of binding agent reagent was added to each group to dilute the above system, and after mixing, it was incubated at room temperature for 1 hour.

[0207] (5) After incubation, the fluorescence signal was detected under the test conditions of excitation wavelength 490 nm and emission wavelength 520 nm using an enzyme label instrument to read the data.

[0208] (6) % Inhibition = (FP B -FP S ) / (FP B -FP V )×100%

[0209] FP S = sample fluorescence polarization value

[0210] FP B = blank control fluorescence polarization value

[0211] FP V = carrier control fluorescence polarization value.

[0212] Fitting the inhibition rate-concentration curve, calculating the IC 50 value.

[0213] 4) Test results

[0214] It has been verified that the compound provided by the present application has good inhibitory activity on PDE3A and PDE4B, which is significantly better than RPL554.

[0215] Experimental Example 2: Agonistic activity of representative compounds on cAMP

[0216] 1) Reagent materials:

[0217] (1) HTRF cAMP HiRange kit (Cisbio, Cat# 62AM6PEB)

[0218] (2) Forskolin (MCE, Cat# HY-15371)

[0219] (3) Black 96-well plate (PerkinElmer, Cat# 6005540)

[0220] 2) Instrument equipment:

[0221] EnVision-2104 multichannel enzyme label instrument (PerkinElmer)

[0222] 3) Experimental steps:

[0223] (1) Cell line: THP-1

[0224] Cell density: 6000 cells / well

[0225] Compound treatment time: 30 min before the addition of Forskolin

[0226] Forskolin final concentration: 6 μM

[0227] Forskolin treatment time: 30 min

[0228] Detection method: refer to the cAMP HTRF kit instruction

[0229] Maximum initial concentration of compound: 100 μM

[0230] DMSO concentration in the system: 1%

[0231] (2) Incubation system:

[0232] (3) 0.1 μL of compound was added to each well of the experimental group, and the same volume of DMSO was added to the blank control group and the solvent control group, then the components were added in the order shown in the table, and the mixture was gently mixed and incubated at room temperature for 1 hour.

[0233] (4) After the incubation was completed, the fluorescence signal was detected by using an enzyme marker under the test conditions of an excitation wavelength of 340 nm and an emission wavelength of 616 nm and 665 nm, and the data was read.

[0234] (5) The activation rate at different concentrations was calculated according to the fluorescence polarization value, the activation rate-concentration curve was fitted, and the EC 50 value was calculated.

[0235] 4) Test results

[0236] It has been verified that the compound provided in the application has better agonistic activity on cAMP and is superior to RPL554.

Claims

1. A compound represented by Formula (I) or a stereoisomer, tautomer, deuterated isomer, pro-drug, or pharmaceutically acceptable salt thereof: wherein R 1 selected from -NR'R"; R', R" are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl and hydroxyl; Y is selected from R 2 selected from H, hydroxyl, and C1-C6 alkyl, said C1-C6 alkyl optionally substituted with 0, 1, 2, or 3 halo, hydroxyl, amino; X is selected from the group consisting of 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 5-6 membered heteroaryl containing 1-3 (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and aryl, said 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S and aryl is optionally substituted with 0-5 R 3a substituents; Each R 3a The same or different, and each independently selected from H, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 ynyl, C2-C6 alkenyl, C3-C6 epoxyalkyl, -O (C1-C6 alkyl), -O (C3-C6 cycloalkyl), 4-6 membered (e.g., 4, 5, or 6 membered) heterocycles containing 1 to 3 (e.g., 1, 2, or 3) heteroatoms selected from N, O, and S, -O (C3-C6 epoxyalkyl), hydroxyl The C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkynyl, C2-C6 alkenyl, C3-C6 epoxyalkyl, -O(C1-C6 alkyl), -O(C3-C6 cycloalkyl), containing 1 to 3 4-6 membered heterocycles selected from N, O, S heteroatoms, -O(C3-C6 epoxyalkyl) is optionally substituted with 0, 1, 2 or 3 deuterium, halogen, hydroxyl, cyano, amino or mercapto groups; R 4 , R 5 , R 6 , R 7 are each independently selected from H, deuterium, halogen, C1-C6alkyl, C3-C6cycloalkyl, -O(C1-C6alkyl), -O(C3-C6cycloalkyl), hydroxyl, cyano, amino, and mercapto, said C1-C6alkyl, C3-C6cycloalkyl, -O(C1-C6alkyl), and -O(C3-C6cycloalkyl) optionally substituted with 0, 1, 2, or 3 deuterium, halogen, hydroxyl, cyano, amino, mercapto; E is -(CH2) v -; v is 1, 2 or 3.

2. The compound of claim 1 or a stereoisomer, tautomer, deuterated isomer, prodrug, or pharmaceutically acceptable salt thereof, wherein, The compound has a structure shown in the following 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 of claim 1 or 2, or a stereoisomer, tautomer, deuterated isomer, prodrug, or pharmaceutically acceptable salt thereof, wherein R 1 is selected from -NR’R”, wherein R’, R” are independently selected from H, C1-C6 alkyl; Preferably, R 1 is selected from -NR'R", R', R" are independently selected from H, C1-C4 alkyl; Preferably, R 1 selected from -NR'R", R', R" are independently selected from H, C1-C3 alkyl; Preferably, R 2 is selected from H, hydroxyl and C1-C3 alkyl; Preferably, R 2 is selected from H and hydroxyl; Preferably, R 2 is H.

4. The compound of any one of claims 1 to 3, or a stereoisomer, tautomer, deuterated isotope, prodrug, or pharmaceutically acceptable salt thereof, wherein, X is selected from C1-C6alkylene, C 3- C6cycloalkylene; Preferably, X is independently selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, Preferably, X is selected from -CH2CH2- and 5. The compound of any one of claims 1 to 4 or a stereoisomer, tautomer, deuterated isotope, prodrug, or pharmaceutically acceptable salt thereof, 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 in 2, 4, 6 positions by 3 R 3a substituted in 2, 4, 6 positions by 3 R R is preferably selected from the group consisting of H, deuterium, halogen, C1-C6alkyl, C3-C6cycloalkyl, C2-C6alkynyl, C3-C6cycloalkyloxy, -O(C1-C6alkyl), -O(C3-C6cycloalkyl), -O(C3-C6cycloalkyloxy); and 3a each independently is selected from the group consisting of H, deuterium, halogen, C1-C6alkyl, C3-C6cycloalkyl, C2-C6alkynyl, C3-C6cycloalkyloxy, -O(C1-C6alkyl), -O(C3-C6cycloalkyl), -O(C3-C6cycloalkyloxy); and R is preferably selected from the group consisting of H, C1-C4alkyl, C3-C6cycloalkyl, C2-C4alkynyl, C3-C6cycloalkyloxy, -0(C1-C4alkyl), -0(C3-C6cycloalkyl), -0(C3-C6cycloalkyloxy); and 3a each independently selected from the group consisting of H, C1-C4alkyl, C3-C6cycloalkyl, C2-C4alkynyl, C3-C6cycloalkyloxy, -0(C1-C4alkyl), -0(C3-C6cycloalkyl), -0(C3-C6cycloalkyloxy); and Preferably, 2-bit or 6-bit R 3a It is a methyl group, with R at the 4-position. 3a Selected from C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 epoxyalkyl, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 epoxyalkyl); Preferably, 2-bit or 6-bit R 3a It is a methyl group, with R at the 4-position. 3a Selected from C1-C3 alkyl, C3-C6 cycloalkyl, -O (C1-C4 alkyl), -O (C3-C6 cycloalkyl); Preferably, R 3 selected from 6. The compound of any one of claims 1 to 5, or a stereoisomer, tautomer, deuterated isotope, prodrug, or pharmaceutically acceptable salt thereof, wherein, R 4 , R 5 , R 6 , R 7 are each independently selected from H, halogen, C1-C6alkyl, C3-C6cycloalkyl, -O(C1-C6alkyl), -O(C3-C6cycloalkyl), said C1-C6alkyl, C3-C6cycloalkyl, -O(C1-C6alkyl), -O(C3-C6cycloalkyl) optionally substituted with 0, 1, 2, or 3 deuterium, halogen, hydroxyl; Preferably, R 4 and R 7 are independently selected from H, halogen and Ci-C6alkyl, preferably both are H; Preferably, R 5 and R 6 It is 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. The compound of any one of claims 1 to 6 or a stereoisomer, tautomer, deuterated isotope, prodrug, or pharmaceutically acceptable salt thereof, wherein, In formula (I), R 1 is selected from -NR'R"; R', R" are independently selected from H, C1-C6 alkyl; Y is R 2 selected from H, hydroxyl, or C1-C3alkyl; X is selected from C1-C6alkylene, C 3- C6cycloalkylene; R 3 selected from phenyl, said phenyl being optionally substituted with 0-3 R 3a substituents; R 3a each independently selected from H, deuterium, halogen, C1-C6alkyl, C3-C6cycloalkyl, C2-C6alkynyl, C3-C6cycloalkyloxy, -0(C1-C6alkyl), -0(C3-C6cycloalkyl), -0(C3-C6cycloalkyloxy); R 4 , R 5 , R 6 , R 7 are each independently selected from H, halogen, C1-C6alkyl, C3-C6cycloalkyl, -O(C1-C6alkyl), -O(C3-C6cycloalkyl), said C1-C6alkyl, C3-C6cycloalkyl, -O(C1-C6alkyl), -O(C3-C6cycloalkyl) optionally substituted with 0, 1, 2, or 3 deuterium, halogen, hydroxyl; E is -(CH2) v - and v is 1, 2 or 3; Preferably, in formula (I), R 1 is selected from -NR'R"; R', R" are independently selected from H, C1-C4 alkyl; Y is R 2 selected from H, hydroxyl, and C1-C3alkyl; X is selected from C1-C6 alkylene (e.g. C1-C5 alkylene, C1-C4 alkylene, C1-C3 alkylene), C3-C6 cycloalkylene (e.g. cyclopropylene, cyclobutylene, cyclopentylene); R 3 selected from phenyl, said phenyl being optionally substituted with 0-3 R 3a in 2, 4, 6 positions; R 3a each independently is selected from the group consisting of H, deuterium, halogen, C1-C6alkyl, C3-C6cycloalkyl, C2-C6alkynyl, C3-C6cycloalkyloxy, -O(C1-C6alkyl), -O(C3-C6cycloalkyl), -O(C3-C6cycloalkyloxy); R 4 , R 5 , R 6 , R 7 are each independently selected from the group consisting of 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', R" are independently selected from H, C1-C3 alkyl; Y is R 2 selected from H, hydroxyl, or C1-C3alkyl; X is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, R 3 selected from phenyl, said phenyl being optionally substituted with 0-3 R 3a in 2, 4, 6 positions; R 3a each independently is selected from the group consisting of H, deuterium, halogen, C1-C6alkyl, C3-C6cycloalkyl, C2-C6alkynyl, C3-C6cycloalkyloxy, -O(C1-C6alkyl), -O(C3-C6cycloalkyl), -O(C3-C6cycloalkyloxy); R 4 , R 5 , R 6 , R 7 each independently is selected from H, halogen, C1-C6alkyl, C3-C6cycloalkyl, -O(C1-C6alkyl), -O(C3-C6cycloalkyl), said C1-C6alkyl, C3-C6cycloalkyl, -O(C1-C6alkyl), -O(C3-C6cycloalkyl) optionally substituted with 0, 1, 2, or 3 deuterium, halogen, hydroxyl; E is -(CH2) v -; v is 1 or 2; Preferably, in formula (I), R 1 is selected from -NR'R"; R', 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 with 0-3 R 3a in the 2, 4, 6 positions; R 3a each independently is selected from the group consisting of H, C1-C4alkyl, C3-C6cycloalkyl, C2-C4alkynyl, C3-C6cycloalkyloxy, -0(C1-C4alkyl), -0(C3-C6cycloalkyl), -0(C3-C6cycloalkyloxy); R 4 and R 7 are independently selected from H, halogen and Ci-C6alkyl, preferably both are H; R 5 and R 6 are independently selected from the group consisting of Ci-C6-alkyl, C3-C6-cycloalkyl, -0(Ci-C6-alkyl), -0(C3-C6-cycloalkyl), preferably from -0(Ci-C6-alkyl), for example from methoxy, ethoxy and propoxy. For example, R 5 may be methoxy or ethoxy, 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', 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 is selected from phenyl, which is substituted in 2, 4, 6 positions by R 3a is selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkynyl, C3-C6 cycloalkyloxy, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 cycloalkyloxy); and R 3a is selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkynyl, C3-C6 cycloalkyloxy, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 cycloalkyloxy); and R 3a is selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkynyl, C3-C6 cycloalkyloxy, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl), -O(C3-C6 cycloalkyloxy R 4 and R 7 is independently selected from H, halogen and Ci-C6alkyl; R 5 and R 6 are independently selected from the group consisting of Ci-C6-alkyl, C3-C6-cycloalkyl, -0(Ci-C6-alkyl), -0(C3-C6-cycloalkyl); E is -(CH2) v -; v is 1 or 2; Preferably, in formula (I), R 1 is selected from -NR'R"; R', R" are independently selected from H, C1-C3 alkyl; Y is R 2 selected from H; X is selected from -CH2CH2- or R 3 is selected from phenyl, which is substituted in 2, 4, 6 positions; wherein R 3a in 2, 6 positions is methyl and R 3a in 4 position is selected from C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl); and 3a R1is selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -O(C1-C4 alkyl), -O(C3-C6 cycloalkyl); R 4 and R 7 are each H; R 6 is methoxy, R 5 is selected from -0(Ci-C6alkyl), -0(C3-C6cycloalkyl); E is -(CH2) v -; v is 1; Preferably, in formula (I), R 1 is selected from -NR'R"; R', 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 Ci-C6alkyl, preferably both are H; R 5 and R 6 are independently selected from the group consisting of Ci-C6-alkyl, C3-C6-cycloalkyl, -0(Ci-C6-alkyl), -0(C3-C6-cycloalkyl), preferably from -0(Ci-C6-alkyl); E is -(CH2) v -; v is 1 or 2.

8. The compound of any one of claims 1 to 7, or a stereoisomer, tautomer, deuterated isotope, prodrug, or pharmaceutically acceptable salt thereof, wherein, The compounds have the structure shown in the following formula (II-1) or (II-2): wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , E is 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 as in any one of claims 1 to 7; Preferably, the compound of general formula (I) is selected from the group consisting of:

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

10. Use of a compound, stereoisomer, tautomer, deuterated analog, prodrug of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 9, for the manufacture of a medicament for the prevention and / or treatment of a condition associated with PDE3 and / or PDE4.

11. A method of treating a condition associated with PDE3 and / or PDE4 in a mammal, comprising administering to a mammal in need of treatment a therapeutically effective amount of a compound of Formula (I), stereoisomer, tautomer, deuterated analog, prodrug of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 9.

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