ISOQUINOLONE COMPOUND AND ITS APPLICATIONS

Abstract

The present invention relates to an isoquinolone compound and a use thereof. Specifically, the present invention provides a 4-H pyrimido[6,1-a]isoquinolin-4-one compound represented by formula I or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer thereof, wherein R1, R2, E1, E2, ring Cy, m, and n are defined as the present text.

Description

Isoquinolinone compounds and uses thereof Technical Field

[0001] The present invention relates to the field of medicine and isoquinolinone compounds and uses thereof. Background Art

[0002] Phosphodiesterases (PDEs) belong to a superfamily of enzymes encompassing 11 families, each involved in distinct signaling pathways and regulating distinct physiological processes. PDE3 hydrolyzes both cAMP and cGMP, but its cAMP hydrolysis capacity is approximately ten times greater than that of cGMP. PDE3 has two genetic isoforms: PDE3A and PDE3B, located on chromosomes 11 and 12, respectively. PDE3A is further divided into three isoforms, PDE3A1, PDE3A2, and PDE3A3, depending on their start codons. These isoforms are primarily distributed in the heart, platelets, vascular smooth muscle, and oocytes, regulating cardiac contractility, platelet aggregation, vascular smooth muscle contraction, oocyte maturation, and renin release. PDE3B has only one isoform, PDE3B1, primarily distributed in adipocytes, hepatocytes, spermatocytes, and pancreas. It regulates the signaling of insulin, insulin-like growth factor, and leptin, playing a crucial role in metabolic diseases such as obesity and diabetes. The main PDE3 selective inhibitors include cilostazol, cilostazolamide, milrinone, amrinone, enoximone and cyanguanzodone.

[0003] For example, amrinone can inhibit PDE3 activity, increase the concentration of cAMP in myocardial cells, and increase intracellular Ca 2+ Concentration, thereby fully exerting its positive inotropic effect. Amrinone also acts directly on vascular smooth muscle cells, exerting a potent vasodilator effect, increasing myocardial contractility, reducing pulmonary artery pressure, and restoring cardiopulmonary function. It is of great value in the treatment of chronic cor pulmonale combined with heart failure. Furthermore, cilostazol is clinically used to treat platelet aggregation, pulmonary hypertension (PAH), chronic obstructive pulmonary disease (COPD), intermittent claudication, and cerebral microvascular disease.

[0004] On the other hand, PDE4 is highly specific for cAMP and has four isoforms: PDE4A, PDE4B, PDE4C, and PDE4D. PDE4 is involved in promoting physiological and pathological processes such as monocyte and macrophage activation, neutrophil infiltration, vascular smooth muscle proliferation, vasodilation, and myocardial contraction, affecting central nervous system function, cardiovascular function, inflammation / immune system, and cell adhesion. PDE4 plays a major role in regulating the expression of pro- and anti-inflammatory mediators. PDE4 inhibitors can inhibit the release of harmful mediators from inflammatory cells.

[0005] Developing new molecules with both PDE3 and PDE4 inhibitory activity will have the bronchodilation effect of β-adrenergic receptor agonists and the anti-inflammatory effect of inhaled corticosteroids. The complementary dual targeting functions have better efficacy than single targets.

[0006] For example, RPL554 (9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1a]isoquinolin-4-one) is a dual-target PDE3 / PDE4 inhibitor disclosed in WO00 / 58308A1. Recent Phase II clinical data show that the drug significantly improves bronchodilation and symptoms in patients with COPD. The drug is also well tolerated, with no significant adverse events, such as mild cardiac events, nausea, and diarrhea. The drug's safety profile and limited systemic exposure are encouraging.

[0007]

[0008] In addition, other companies are also actively involved in the development of PDE3 / 4 molecules, such as the published related patent applications WO2016040083, WO2020011254, WO2018020249, WO2014140647, WO2020011254, etc. However, in order to better meet market demand, it is still necessary to develop new, highly efficient, low-toxic, selective PDE inhibitors.

[0009] Summary of the Invention

[0010] The present disclosure provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof,

[0011]

[0012] Among them, R 1 is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally substituted by one or more RA1 replaced by;

[0013] R A1 are independently selected from deuterium, halogen, hydroxy, nitro, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Cycloalkoxy, 3 to 7 membered heterocycloalkyl, 3 to 7 membered heterocycloalkoxy, C 6-10 Aryl and 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloepoxy, aryl and heteroaryl groups are each independently optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro, cyano and amino;

[0014] R 2 are independently selected from deuterium, halogen, hydroxy, nitro, amino, cyano, C 1-6 Alkyl, C 2-7 Alkenyl, C 3-7 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C 1-6 Alkoxy, C 2-7 Alkenyloxy, C 3-7 Cycloalkoxy, 3 to 7 membered heterocycloalkoxy, C 6-10 Aryl and 5 to 10 membered heteroaryl, said hydroxy, amino, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, alkoxy, alkenyloxy, cycloalkoxy, heterocycloalkoxy, aryl and heteroaryl being optionally substituted by one or more R A2 replaced by;

[0015] R A2 are independently selected from deuterium, halogen, hydroxy, nitro, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C 3-7 Cycloalkoxy, 3 to 7 membered heterocycloalkoxy, C 6-10 Aryl and 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, aryl and heteroaryl groups are each independently optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro, cyano and amino;

[0016] E 1 -(CH2) q -;

[0017] q is selected from 1, 2, 3 and 4;

[0018] E 2 is selected from -O-, -NH-, -S- and a single bond;

[0019] m is selected from 0, 1, 2, 3 and 4;

[0020] n is selected from 0, 1, 2, 3 and 4;

[0021] L is selected from -N(R 6 )-、-N(R 6 )C(O)-、-C(O)N(R 6 )-, -S-, -OC(O)-, -C(O)O-, -C(O)N(R 6 )CH2-、-N(R 6 )C(O)CH2-, -NHS(O)2-, -S(O)2NH- and single bonds;

[0022] R 6 Selected from hydrogen, hydroxyl and C 1-3 an alkyl group optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro, amino, and cyano;

[0023] Ring Cy is heterocycloalkyl or heteroaryl, said heterocycloalkyl or heteroaryl being optionally substituted by one or more R A3 replaced by;

[0024] R A3 are independently selected from deuterium, halogen, hydroxyl, nitro, cyano, C 1-6 Alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, SR′, SOR′, SO2R′, SO2NR′(R″), NR′(R″), COOR′, and CONR′(R″), each of said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl being independently optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro, cyano, and amino; and

[0025] R' and R" are each independently selected from hydrogen, deuterium, hydroxyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are each independently optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro, cyano and amino.

[0026] In some embodiments, in the compound of Formula I, E 1 It is -(CH2)q-, where q is 1 or 2.

[0027] In some embodiments, in the compound of Formula I, E 2 For a single bond.

[0028] In some embodiments, in the compound of Formula I, E 1 is -(CH2)q-, q is 1 or 2; and E 2 For a single bond.

[0029] In some embodiments, in the compound of Formula I, E 2 It is -NH-.

[0030] In some embodiments, in the compound of Formula I, E 1 is -(CH2)q-, q is 1 or 2; and E 2 It is -NH-.

[0031] In other embodiments, in the compound of Formula I, m is 1 or 2.

[0032] In some embodiments, in the compound of Formula I, E 1 -(CH2)q-, q is 1 or 2; E 2 is -NH-; and m is 1 or 2.

[0033] In some embodiments, in the compound of Formula I, E 1 -(CH2)q-, q is 1 or 2; E 2 is a single bond; and m is 1 or 2.

[0034] In some embodiments, in the compound of formula I, ring Cy is a 5- to 6-membered heterocycloalkyl group, which is optionally substituted by one or more R A3 Replaced by R A3 As defined above.

[0035] Further, in some embodiments, in the compound represented by Formula I, ring Cy is selected from

[0036] Furthermore, the ring Cy is optionally replaced by one or more R A3 Replaced by R A3 As defined above.

[0037] On the other hand, some embodiments provide compounds of formula I in which ring Cy is a 5- to 10-membered heteroaryl group, which is optionally replaced by one or more R A3 Replaced by R A3 As defined above. In some embodiments, in the compound of formula I, ring Cy is selected from

[0038] Further, the ring Cy is optionally replaced by one or more R A3 Replaced by R A3As defined above.

[0039] In other embodiments, in the compound of formula I, ring Cy is a 9-10 heteroaryl group, which is optionally replaced by one or more R A3 Replaced by R A3 As defined above. The ring Cy is selected from Further, the ring Cy is optionally replaced by one or more R A3 Replaced by R A3 As defined above.

[0040] In some embodiments, in the compound of Formula I, R A3 are each independently selected from deuterium, halogen, hydroxyl, amino and C 1-6 Alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro, cyano and amino.

[0041] In other embodiments, in the compound of Formula I, R A3 Each independently selected from deuterium, halogen, hydroxyl, amino, C 3-7 Cycloalkyl and 3 to 7 membered heterocycloalkyl, said cycloalkyl or heterocycloalkyl being optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro, cyano and amino.

[0042] On the other hand, some embodiments provide compounds of Formula I, wherein R 1 C 6-10 Aryl, said aryl being optionally substituted with one or more R A1 Replaced by R A1 As defined above. Further, the compound represented by formula I is the compound represented by formula II,

[0043]

[0044] In some embodiments, the compound of formula II is provided, R 3 Each independently selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the alkyl group is optionally substituted by one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro, cyano and amino. In some other embodiments, the compound of formula II is provided, R 3 Each independently selected from C 3-7 Cycloalkyl, C 3-7Cycloalkyloxy, 3 to 7 membered heterocycloalkyl and 3 to 7 membered heterocycloalkoxy, wherein the cycloalkyl, cycloalkoxy, heterocycloalkyl and heterocyclic epoxy are each independently optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano and amino. In other embodiments, the compound of formula II is provided, R 3 Each independently is C 6-10 Aryl or 5- to 10-membered heteroaryl, said aryl or heteroaryl being optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, oxo, nitro, cyano and amino.

[0045] Furthermore, in some embodiments, in the compound of Formula I or Formula II, R 2 Each is independently selected from deuterium, halogen, hydroxy, amino and cyano.

[0046] In other embodiments, in the compound of Formula I or Formula II, R 2 Each independently selected from C 1-6 Alkoxy, C 2-7 Alkenyloxy, C 3-7 Cycloalkoxy and 3 to 7 membered heterocycloalkoxy, said alkoxy, alkenyloxy, cycloalkoxy and heterocycloalkoxy being optionally substituted by one or more R A2 Replaced by R A2 As defined above.

[0047] In other embodiments, in the compound of Formula I or Formula II, n is selected from 0, 1, and 3. In other embodiments, in the compound of Formula I or Formula II, n is 2.

[0048] In some embodiments, in the compound of Formula II, R 3 C 1-6 Alkyl groups such as methyl, ethyl or propyl.

[0049] In some embodiments, in the compound of Formula II, R 3 C 1-6 Alkoxy, for example methoxy, ethoxy or propoxy.

[0050] In some embodiments, in the compound of Formula I, R 1 It is 2,4,6-trimethylphenyl or 2,4,6-trimethoxyphenyl.

[0051] On the other hand, in the compound represented by Formula I or Formula II, L is selected from -N(R 6 )-、-N(R 6 )C(O)-、-C(O)N(R 6 )-, -NHS(O)2- and a single bond.

[0052] In some embodiments, in the compound of Formula I or Formula II, L is -N(R 6 In some embodiments, in the compound represented by Formula I or Formula II, L is -N(R 6 )C(O)-. In some embodiments, in the compound represented by Formula I or Formula II, L is -C(O)N(R 6 )-. Further, in certain embodiments, in the compound represented by Formula I or Formula II, R 6 is hydrogen or C 1-3 Alkyl (e.g., methyl, ethyl, or propyl), the alkyl group is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro, amino, and cyano. In certain embodiments, in the compound of Formula I or Formula II, R 6 In certain embodiments, in the compound represented by Formula I or Formula II, R 6 It is a methyl group.

[0053] In other embodiments, in the compound of Formula I or Formula II, L is -NHS(O)2-. In some embodiments, in the compound of Formula I or Formula II, L is a single bond.

[0054] On the other hand, the compound represented by formula I or formula II is the compound represented by III,

[0055] Among them, the ring Cy, R 2 ,m,n,R 3 and o are as defined above.

[0056] In some embodiments, in the compound represented by Formula I, Formula II, or Formula III, ring Cy is

[0057] Furthermore, the ring Cy is optionally replaced by one or more R A3 Replaced by R A3 As defined above.

[0058] In certain embodiments, the compound of formula I is a compound of formula IV,

[0059]

[0060] Among them, R 4 Selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, said alkyl and cycloalkyl being each independently optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro, cyano and amino;

[0061] R 5are independently selected from deuterium, halogen, hydroxyl, nitro, cyano, C 1-6 Alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro, cyano, and amino;

[0062] p is selected from 0, 1, 2, 3 and 4;

[0063] R 2 , m and n are as defined in the compound of formula I, and

[0064] R 3 and o are as defined in the compound represented by Formula II.

[0065] In some embodiments, in the compound of formula IV, R 4 is hydrogen or C 1-6 Alkyl (e.g., C 1-3 alkyl, methyl, ethyl and propyl), said alkyl being optionally substituted by one or more substituents selected from halogen, hydroxy and amino.

[0066] In other embodiments, in the compound of formula IV, R 5 Each is independently selected from deuterium, halogen, hydroxy, nitro and cyano.

[0067] In other embodiments, in the compound of formula IV, R 5 Each independently selected from C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7 membered heterocycloalkyl, said alkyl, cycloalkyl and heterocycloalkyl being each independently optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro, cyano and amino.

[0068] In other embodiments, in the compound of formula IV, R 5 Each is independently a 6- to 10-membered aryl group (such as phenyl) or a 5- to 10-membered heteroaryl group (such as a 5- to 6-membered heteroaryl group, pyridine; a 9- to 10-membered heteroaryl group), wherein the aryl or heteroaryl group is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyl, oxo, nitro, cyano, and amino. Further, the compound represented by formula I is a compound represented by formula V,

[0069]

[0070] Among them, R 7 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 2-7 Alkenyl, C3-7 Cycloalkyl and 3 to 7 membered heterocycloalkyl, said alkyl, alkenyl, cycloalkyl and heterocycloalkyl being each independently optionally substituted with one or more R A4 replaced by;

[0071] R A4 Selected from deuterium, halogen, hydroxy, oxo, nitro, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl and heterocycloalkyl groups are each independently optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro, cyano and amino;

[0072] R 8 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 2-7 Alkenyl, C 3-7 Cycloalkyl and 3 to 7 membered heterocycloalkyl, said alkyl, alkenyl, cycloalkyl and heterocycloalkyl being each independently optionally substituted with one or more R A5 replaced by;

[0073] R A5 Selected from deuterium, halogen, hydroxy, oxo, nitro, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl and heterocycloalkyl groups are each independently optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, oxo, nitro, cyano and amino;

[0074] m is as defined in the compound of formula I;

[0075] R 3 , o is defined as in the compound of formula II; and

[0076] R 4 、R 5 and p are as defined in the compound of formula V.

[0077] In some embodiments, in the compound of Formula V, R 8 is hydrogen or C 1-6 Alkyl, the alkyl group is optionally substituted by one or more R A5 Replaced by R A5 As defined above.

[0078] In some embodiments, in the compound of Formula V, R 8C 2-7 Alkenyl (e.g. C 2-4 alkenyl, propenyl or allyl) or 3 to 7 membered heterocycloalkyl (e.g. 3 to 5 membered heterocycloalkyl), the alkenyl or heterocycloalkyl being optionally substituted by one or more R A5 Replaced by R A5 As defined above.

[0079] In some embodiments, in the compound of Formula V, R 8 C 3-7 Cycloalkyl, the cycloalkyl is optionally substituted by one or more R A5 Replaced by R A5 As defined above.

[0080] In some embodiments, in the compound of Formula V, R A5 is selected from the group consisting of deuterium, halogen, hydroxy, oxo, nitro, amino and cyano.

[0081] In some embodiments, in the compound of Formula V, R A5 Selected from C 3-7 Cycloalkyl, 3 to 7 membered heterocycloalkyl and C 6-10 The aryl, cycloalkyl or heterocycloalkyl groups are optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro and cyano.

[0082] In some embodiments, in the compound of Formula V, R A5 Selected from C 1-6 Alkyl, C 1-6 Alkoxy and 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy and heteroaryl groups are each independently optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro and cyano.

[0083] On the other hand, in some embodiments, in the compound represented by Formula V, R 7 Selected from hydrogen, C 1-6 Alkyl and C 3-7 Cycloalkyl, the alkyl and cycloalkyl groups are each independently optionally substituted with one or more R A4 Replaced by R A4 As defined above.

[0084] In some embodiments, in the compound of Formula V, R 7 C 2-7 alkenyl or 3 to 7 membered heterocycloalkyl, the alkenyl or heterocycloalkyl being optionally substituted by one or more R A4 Replaced by R A4 As defined above.

[0085] In other embodiments, in the compound represented by Formula V, RA4 is selected from the group consisting of deuterium, halogen, hydroxy, oxo, nitro, amino and cyano.

[0086] In other embodiments, in the compound represented by Formula V, R A4 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl, the alkyl, alkoxy, cycloalkyl and heterocycloalkyl groups are each independently optionally substituted with one or more substituents of deuterium, halogen, hydroxy, oxo, nitro and cyano.

[0087] On the other hand, some embodiments provide compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 1 Selected from

[0088] Further R 1 Optionally one or more R A1 replaced.

[0089] In some embodiments, in the compound of Formula I or a pharmaceutically acceptable salt thereof, R 1 Selected from Further R 1 Optionally one or more R A1 replaced.

[0090] In some embodiments, in the compound of Formula I or a pharmaceutically acceptable salt thereof, R 1 Selected from Further R 1 Optionally one or more R A1 replaced.

[0091] In some embodiments, in the compound of Formula I or a pharmaceutically acceptable salt thereof, R 1 Selected from Further R 1 Optionally one or more R A1 replaced.

[0092] On the other hand, in some embodiments, in the compound of Formula I or a pharmaceutically acceptable salt thereof, ring Cy is a 7- to 9-membered heterocycloalkyl group, which is optionally replaced by one or more R A3 In certain embodiments, in the compound of Formula I or a pharmaceutically acceptable salt thereof, ring Cy is selected from

[0093] Furthermore, the ring Cy is optionally replaced by one or more R A3 replaced.

[0094] Typical compounds of formula I include, but are not limited to:

[0095]

[0096]

[0097] The present disclosure also provides a pharmaceutical composition comprising at least one therapeutically effective amount of a compound represented by the aforementioned formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0098] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0099] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the compound shown in the aforementioned formula I, II, III, IV or V, or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the compound shown in the aforementioned formula I, II, III, IV or V, or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the compound shown in the aforementioned formula I, II, III, IV or V, or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the compound shown in the aforementioned formula I, II or III, or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2%-98% of the compound shown in the aforementioned formula I, II, III, IV or V, or a pharmaceutically acceptable salt thereof.

[0100] The present disclosure also provides a method for preventing and / or treating PDE-related disorders, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by the aforementioned formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition.

[0101] In some embodiments, the PDE-related disorder is preferably asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism.

[0102] The present disclosure also provides a method for preventing and / or treating asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by the aforementioned Formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0103] The present disclosure also provides the use of a compound as shown in the aforementioned Formula I, II, III, IV or V or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating a PDE-related disorder. In some embodiments, the PDE-related disorder is preferably asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis or rheumatism.

[0104] The present disclosure also provides the use of the compounds represented by the aforementioned Formulas I, II, III, IV or V, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions in the preparation of medicaments for preventing and / or treating asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis, or rheumatism.

[0105] In another aspect, the pharmaceutically acceptable salts of the compounds described in the present disclosure are inorganic salts or organic salts.

[0106] On the other hand, the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0107] In addition, the compounds and intermediates of the present disclosure can also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. The lactam-lactim equilibrium example is between A and B as shown below.

[0108]

[0109] All compounds of the present invention can be drawn as either Type A or Type B. All tautomeric forms are within the scope of the present invention. The naming of the compounds does not exclude any tautomers.

[0110] The compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0111] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0112] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0113] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have at least 1000 times the abundance of deuterium greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). In the example, the natural abundance of the compound greater than deuterium can be at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times the abundance of deuterium, at least 6000 times the abundance of deuterium or more abundant deuterium. The disclosure also includes various deuterated forms of formula (I) compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of formula (I) compounds with reference to relevant literature. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds of formula (I), or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0114] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or or include both and Although all the above structural formulas are drawn as certain isomers for the sake of simplicity, the present invention can include all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates and enantiomers. In the chemical structure of the compounds disclosed in this disclosure, the bond The configuration is not specified, that is, it can be Z configuration or E configuration, or contain both configurations.

[0115] Explanation of terms:

[0116] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0117] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or domestic animals.

[0118] As used herein, an "effective amount" or "therapeutically effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also refers to an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0119] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched chain isomers thereof. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from deuterium, halogen, hydroxyl, nitro, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C 3-7 Cycloalkoxy, 3 to 7 membered heterocycloalkoxy, C 6-10 Aryl and 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are each independently optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro, cyano and amino.

[0120] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0121] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, halogen, hydroxyl, nitro, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C 3-7 Cycloalkoxy, 3 to 7 membered heterocycloalkoxy, C 6-10Aryl and 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are each independently optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro, cyano and amino.

[0122] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocycloalkyl groups include spirocyclic, fused ring and bridged heterocycloalkyl groups. Non-limiting examples of "heterocycloalkyl" include:

[0123]

[0124] The heterocycloalkyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocycloalkyl, non-limiting examples of which include:

[0125]

[0126] Heterocycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, halogen, hydroxy, nitro, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C 3-7 Cycloalkoxy, 3 to 7 membered heterocycloalkoxy, C 6-10 Aryl and 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are each independently optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro, cyano or amino.

[0127] "Alkenyl" refers to an unsaturated aliphatic straight or branched hydrocarbon group, and contains one or more carbon-carbon double bonds. Exemplary alkenyls include C2-C8, C2-C7, C2-C6, C2-C4, C3-C12 and C3-C6 alkenyls. Including but not limited to, vinyl (i.e., vinyl (vinyl)), 1-propenyl, 2-propenyl (i.e., allyl), 2-methyl-1-propenyl, 1-butenyl, 2-butenyl (i.e., crotyl) etc. The alkenyl used in any context herein is optionally substituted in the same manner as alkyl. The alkenyl used in any context herein may also be substituted by aryl.

[0128] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, more preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0129]

[0130] Aryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, halogen, hydroxy, nitro, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C 3-7 Cycloalkoxy, 3 to 7 membered heterocycloalkoxy, C 6-10 Aryl and 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are each independently optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro, cyano and amino.

[0131] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably 5-membered or 6-membered. For example, non-limiting examples include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine, etc.

[0132] The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0133]

[0134] Heteroaryl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, halogen, hydroxy, nitro, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C 3-7 Cycloalkoxy, 3 to 7 membered heterocycloalkoxy, C 6-10 Aryl and 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are each independently optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro, cyano and amino.

[0135] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, halogen, hydroxy, nitro, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C 3-7 Cycloalkoxy, 3 to 7 membered heterocycloalkoxy, C 6-10 Aryl and 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are each independently optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, nitro, cyano and amino.

[0136] The term "alkenyloxy" refers to an -O-alkenyl group, wherein alkenyl is as defined above.

[0137] The term "hydroxy" refers to an -OH group.

[0138] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0139] The term "amino" refers to -NH2.

[0140] The term "cyano" refers to -CN.

[0141] The term "nitro" refers to -NO2.

[0142] The term "oxo" refers to a =0 substituent.

[0143] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not. For example, "a heterocycloalkyl group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocycloalkyl group is substituted with an alkyl group and instances where the heterocycloalkyl group is not substituted with an alkyl group.

[0144] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond. BRIEF DESCRIPTION OF THE DRAWINGS

[0145] Figure 1: Projection diagram of the molecular structure of compound 1;

[0146] Figure 2: Single crystal unit cell stacking diagram of compound 1;

[0147] Figure 3: Projection diagram of the molecular structure of compound 2;

[0148] Figure 4: Single crystal unit cell stacking diagram of compound 2. DETAILED DESCRIPTION

[0149] The present disclosure is further described below with reference to examples, but these examples are not intended to limit the scope of the present disclosure.

[0150] Experimental methods in the examples of this disclosure that do not specify specific conditions are generally based on conventional conditions or the conditions recommended by the raw material or product manufacturers. Reagents without specific sources are conventional reagents purchased from the market.

[0151] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (Methanol-d4). The internal standard was tetramethylsilane (TMS).

[0152] HPLC determination used a Waters 2795 AllianceHT LC high pressure liquid chromatograph, a Waters 2996 Photodiode Array Detector UV detector, and a Thermo Accucore Polar Premium C18 50*4.6mm 2.6um chromatographic column.

[0153] MS was measured using a Waters Micromass Quattro micro API triple quadrupole mass spectrometer in positive / negative ion mode with a mass scan range of 120-1300.

[0154] X-ray single crystal diffraction was performed using a D8 Venture single crystal X-ray diffractometer with a light source (Mo target), X-ray (Mo-Ka ), detector (CMOS area detector), resolution Current and voltage (50 kV, 1.4 mA), exposure time (10 s), distance from the surface detector to the sample (40 mm), and test temperature (170 K).

[0155] The thin layer chromatography silica gel plate used was Yantai Huanghai HSGF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) was 0.2 mm ± 0.03 mm. The specification used for thin layer chromatography separation and purification products was 0.4 mm - 0.5 mm.

[0156] The flash column purification system used was Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

[0157] Forward column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh or 300-400 mesh silica gel as the carrier, or uses Changzhou Santai pre-packed ultra-pure normal phase silica gel column (40-63μm, 60g, 24g, 40g, 120g or other specifications).

[0158] The known starting materials in the present disclosure can be synthesized by methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Bid Pharmaceuticals, etc.

[0159] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0160] Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a capacity of about 1L.

[0161] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0162] Hydrogen was produced by a QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instrument Co., Ltd.

[0163] The nitrogen atmosphere or hydrogen atmosphere is usually evacuated and filled with nitrogen or hydrogen, and the operation is repeated three times.

[0164] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0165] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C-30°C.

[0166] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the column chromatography eluent system used to purify the compound, and the developing solvent system for thin layer chromatography, the volume ratio of the solvent were adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could be added for adjustment.

[0167] Example 1

[0168] Preparation of 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]isoquinolin-4-one (Compound 1)

[0169]

[0170]

[0171] Intermediate 1a: Preparation of 1-(2-chloroethyl)-imidazolin-2-one

[0172] To 1-(2-hydroxyethyl)imidazolidinone (3.5 g, 26.9 mmol) was slowly added thionyl chloride (5 ml) at 0°C, and the temperature was raised to 45°C and stirred until the reaction was complete. The reaction was quenched by adding saturated sodium chloride solution, and the pH was adjusted to 7 with 10% NaOH solution. The product was extracted with dichloromethane, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give intermediate 1a (3.5 g, yield 88.4%). MS (ESI) m / z 149.1 [M+H] + .

[0173] Intermediate 1b: Preparation of 1-(3,4-dimethoxyphenethyl)urea

[0174] At room temperature, 2-(3,4-dimethoxyphenyl)ethylamine hydrochloride (4.3 g, 19.8 mmol) was dissolved in water (25 ml), and the temperature was raised to 50°C. Potassium cyanate (1.8 g, 21.8 mmol) was added portionwise and stirred until the reaction was complete. The mixture was cooled to 0°C and filtered. The filter cake was washed with ice water and dried to obtain intermediate 1b (4.1 g, yield 93.8%). MS (ESI) m / z 225.1 [M+H] + .

[0175] Intermediate 1c: Preparation of 1-[2-(3,4-dimethoxy-phenyl)-ethyl]-pyrimidine-2,4,6-trione

[0176] Under ice-bath conditions, sodium ethoxide (3.8 g, 55.8 mmol) was added portionwise to anhydrous ethanol (50 ml). After the addition, the temperature was raised to reflux, and diethyl malonate (5.9 g, 36.6 mmol) was added dropwise. After the addition, stirring was continued for 0.25 h-0.5 h. A solution of intermediate 1b (4.1 g, 18.3 mmol) in ethanol (30 ml) was added dropwise. The reaction was stirred until the reaction was complete, and the temperature was lowered to 0°C. 5% HCl solution was added dropwise to pH = 6. 300 ml of water was added, and the mixture was filtered. The filter cake was washed with ice water and dried to give intermediate 1c (3.9 g, yield 77.1%). MS (ESI) m / z 293.1 [M+H] + .

[0177] Intermediate 1d: Preparation of 2-chloro-9,10-dimethoxy-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one

[0178] At room temperature, intermediate 1c (3.9 g, 13.4 mmol) was added to phosphorus oxychloride (120 ml), and the temperature was raised to 110°C and stirred until the reaction was completed. The temperature was then lowered and concentrated. The solid was poured into ice water, and saturated NaOH solution was added dropwise until the pH was 10. The mixture was filtered, and the filter cake was washed with ice water and dried to give intermediate 1d (2.4 g, yield 62.4%). MS (ESI) m / z 293.1 [M+H] + .

[0179] Intermediate 1e: Preparation of 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-2,3,6,7-tetrahydropyrimido[6,1-a]isoquinolin-4-one

[0180] At room temperature, intermediate 1d (2.4 g, 8.2 mmol) was suspended in isopropanol (30 ml), and 2,4,6-trimethylaniline (4.5 g, 24.6 mmol) was added. The system was heated to 90°C and stirred until the reaction was complete. The temperature was then lowered and the mixture was filtered. The filter cake was washed with ice water and dried to obtain intermediate 1e (3.0 g, yield 92.1%). MS (ESI) m / z 392.2 [M+H] + .

[0181] Compound 1: Preparation of 9,10-dimethoxy-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]isoquinolin-4-one

[0182] At room temperature, intermediate 1e (0.72 g, 1.8 mmol) was dissolved in tetrahydrofuran (20 ml), and potassium tert-butoxide (0.42 g, 3.6 mmol) was added under nitrogen atmosphere. After the addition, the temperature was raised to 65°C and stirring was continued for 48 h. The temperature was then lowered to 25°C and intermediate 1a (0.82 g, 5.5 mmol) was added. After the addition, the temperature was raised to 80°C and stirring was continued until the reaction was completed. A saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with dichloromethane, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The target compound 1 (0.21 g, yield 46.5%) was obtained by chromatography on a silica gel column (n-heptane / ethyl acetate).

[0183] 1 H NMR (400MHz, CDCl3) δ6.99(s,2H),6.69(s,1H),6.64(s,1H),5.39(s,1H),4.61(s,1H),4.22-4.15(m,2H),4.08-3.99(m,2H),3.93 (s,3H),3.77-3.69(m,5H),3.55-3.46(m,2H),3.38-3.42(t,J=6.8Hz,2H),2.88-2.92(t,J=6.4Hz,2H),2.34(s,3H),2.18(s,6H).

[0184] MS (ESI) m / z 504.4 [M+H] + .

[0185] Compound 1 was dissolved in 1 ml of 7% water / ethanol, filtered, and the filtrate was slowly evaporated at room temperature to obtain rod-shaped crystals. Diffraction intensity data were collected using a D8 Venture single crystal X-ray diffractometer.

[0186] Figure 1 shows the projection diagram of the molecular three-dimensional structure, and Figure 2 shows the molecular single crystal unit cell stacking diagram.

[0187] Example 2

[0188] 10-Methoxy-9-(methoxy-d3)-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]isoquinolin-4-one (Compound 2)

[0189]

[0190]

[0191] Intermediate 2a: Preparation of tert-butyl (3-hydroxy-4-methoxyphenethyl)carbamate

[0192] 5-(2-Aminoethyl)-2-methoxyphenol hydrochloride (10.0 g, 49.2 mmol) was suspended in dichloromethane (120 ml). Triethylamine (13.4 g, 132.2 mmol) and (Boc)2O (13.85 g, 63.5 mmol) were slowly added dropwise under ice-cooling conditions. The temperature was slowly raised to room temperature and stirred until the reaction was complete. Saturated sodium chloride solution was added to quench the reaction. The mixture was extracted with dichloromethane, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain the target compound 2a (10.6 g, yield 80.9%). MS (ESI) m / z 268.1 [M+H] + .

[0193] Intermediate 2b: Preparation of tert-butyl (4-methoxy-3-(methoxy-d3)phenethyl)carbamate

[0194] At room temperature, intermediate 2a (10.6 g, 39.7 mmol) and potassium carbonate (27.4 g, 198.0 mmol) were added to DMF (200 ml). Deuterated iodomethane (17.3 g, 119.1 mmol) was slowly added dropwise in an ice bath. The temperature was slowly raised to room temperature and stirred until the reaction was complete. Saturated sodium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give the target compound 2b (11.1 g, yield 99%). MS (ESI) m / z 285.2 [M+H] + .

[0195] Intermediate 2c: Preparation of 2-(4-methoxy-3-(methoxy-d3)phenyl)ethane-1-amine hydrochloride

[0196] To a solution of intermediate 2b (11.1 g, 39.1 mmol) in ethyl acetate (20 ml) was added dropwise 4 M HCl / EA solution (150 ml) under ice-bath conditions. The mixture was slowly warmed to room temperature and stirred until the reaction was complete. The mixture was filtered, and the filter cake was washed with ethyl acetate and dried to give intermediate 2c (7.1 g, yield 82.5%). MS (ESI) m / z 185.1 [M+H] + .

[0197] Intermediate 2d: Preparation of 1-((4-methoxy-3-(methoxy-d3))phenethyl)urea

[0198] At room temperature, intermediate 2c (7.1 g, 32.3 mmol) was dissolved in water (60 ml), heated to 50°C, and potassium cyanate (4.7 g, 58.1 mmol) was added portionwise. Stirring was continued until the reaction was complete, and the temperature was lowered to 0°C. The mixture was filtered, and the filter cake was washed with ice water and dried to obtain intermediate 2d (4.5 g, yield 61.6%). MS (ESI) m / z 228.2 [M+H] + .

[0199] Intermediate 2e: Preparation of 1-((4-methoxy-3-(methoxy-d3))phenethyl)pyrimidine-2,4,6-trione

[0200] Under ice bath conditions, sodium ethoxide (4.1 g, 59.4 mmol) was added portionwise to anhydrous ethanol (60 ml). After the addition, the temperature was raised to reflux, and diethyl malonate (5.7 g, 35.6 mmol) was added dropwise. After the addition, stirring was continued for 0.25 h-0.5 h. A solution of intermediate 2d (4.5 g, 19.8 mmol) in ethanol (20 ml) was added dropwise and stirred until the reaction was complete. The temperature was lowered to 0°C, and 5% HCl solution was added dropwise to pH = 6. 300 ml of water was added, and the mixture was filtered. The filter cake was washed with ice water and dried to give intermediate 2e (4.3 g, yield 74.1%). MS (ESI) m / z 296.1 [M+H] + .

[0201] Intermediate 2f: Preparation of 2-chloro-10-methoxy-9-(methoxy-d3)-6,7-dihydro-4H-pyrimidin[6,1-a]isoquinolin-4-one

[0202] At room temperature, intermediate 2e (4.3 g, 14.6 mmol) was added to phosphorus oxychloride (63 ml), and the temperature was raised to 110°C and stirred until the reaction was completed. The reaction mixture was cooled and concentrated. The solid was poured into ice water, and saturated NaOH solution was added dropwise until the pH was 10. The mixture was filtered, and the filter cake was washed with ice water and dried to give intermediate 2f (4.2 g, yield 97.7%). MS (ESI) m / z 296.1 [M+H] + .

[0203] Intermediate 2g: Preparation of 10-methoxy-9-(methoxy-d3)-2-((2,4,6-trimethyl-phenyl)-amino)-2,3,6,7-tetrahydro-4H-pyrimidinyl[6,1-a]isoquinolin-4-one

[0204] At room temperature, intermediate 2f (4.2 g, 14.2 mmol) was suspended in isopropanol (40 ml), 2,4,6-trimethylaniline (7.8 g, 42.6 mmol) was added, and the temperature was raised to 90°C. Stirring was continued until the reaction was complete, and the temperature was lowered. The mixture was filtered, and the filter cake was washed with isopropanol and dried to obtain intermediate 2g (5.1 g, yield 92.7%). MS (ESI) m / z 395.2 [M+H] + .

[0205] Compound 2: Preparation of 10-methoxy-9-(methoxy-d3)-2-[[2-(2-oxo-imidazolin-1-yl)-ethyl]-(2,4,6-trimethyl-phenyl)-amino]-6,7-dihydro-pyrimidinyl[6,1-a]isoquinolin-4-one

[0206] At room temperature, 2 g (0.5 g, 1.3 mmol) of the intermediate was dissolved in tetrahydrofuran (10 ml), and potassium tert-butoxide (0.31 g, 2.6 mmol) was added under a nitrogen atmosphere. After the addition, the temperature was raised to 65° C. and stirring was continued for 48 h until the reaction was completed. A saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with dichloromethane, washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (n-heptane / ethyl acetate) to obtain the target compound 2 (0.07 g, yield 10.9%).

[0207] 1 H NMR (400MHz, CDCl3) δ6.96(s,2H),6.68(s,1H),6.64(s,1H),5.36(s,1H),4.31(s,1H),4.15(t,J=6.4Hz,2H),4.01(t,J=7.4 Hz, 2H), 3.70 (d, J = 7.6Hz, 5H), 3.47 (t, J = 6.3Hz, 2H), 3.39 (t, J = 7.9Hz, 2H), 2.89 (t, J = 6.4Hz, 2H), 2.31 (s, 3H), 2.15 (s, 6H).

[0208] MS (ESI) m / z 507.5 [M+H] + .

[0209] Compound 2 was dissolved in 1 ml of ethanol, filtered, and the filtrate was allowed to evaporate slowly at room temperature to obtain needle-shaped crystals. Diffraction intensity data were collected using a D8 Venture single crystal X-ray diffractometer.

[0210] FIG3 shows a projection diagram of the molecular three-dimensional structure, and FIG4 shows a stacking diagram of the molecular single crystal unit cell.

[0211] Comparative Example 1

[0212]

[0213]

[0214] Intermediate 3d was prepared by referring to the method of Example 1 using 2-(3-ethoxy-4-methoxyphenyl)ethylamine hydrochloride as the starting material.

[0215] At room temperature, intermediate 3d (1 g) was dissolved in 1,2-dichloroethane (20 ml), and 4-methylbenzenesulfonic acid 2-(2-oxazolidinone-3-yl)ethyl ester (844 mg), potassium carbonate (612 mg), and sodium iodide (443 mg) were added sequentially. The mixture was heated to 80°C and stirred until the reaction was complete. The mixture was cooled, filtered, concentrated, diluted with water, and extracted with ethyl acetate. The organic phases were combined, dried, filtered, concentrated, and purified by column chromatography to obtain compound WX001. MS (ESI) m / z 519.0 [M+H] + .

[0216] Biological evaluation

[0217] The present disclosure is further described and explained below in conjunction with test examples, but these test examples are not intended to limit the scope of the present disclosure.

[0218] Test Example 1 In vitro PDE4B enzyme activity detection experiment: IMAP FP-based analysis method detection

[0219] 1. Experimental Materials

[0220] Material Brand No. / Model PDE4B1BPS60041 Trequinsin Sigma T205738 4-well plate Perkin Elmer 6007279 IMAP FP IPP Assay Kit MOLECULAR DEVICESR8124

[0221] 2. Experimental steps

[0222] The compound was serially diluted 5-fold with DMSO to obtain different concentrations (10000 nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, 0.0256 nM, 0.005 nM). 200 μL of compound at different concentrations was added to a 384-well plate (n=2), and two 200 μL DMSOs were added to the 384-well plate (n=2) as blank controls. 10 μL of 0.025 μg / mL PDE4B1 enzyme solution (prepared with 1 mM 5*IMAP reaction buffer and 1 mM DTT) was then added to the 384-well plate, and 10 μL of blank buffer without PDE4B1 enzyme was added to one of the blank controls. The plates were incubated with shaking at room temperature for 15 minutes. 10 μL of 0.1 μM FAM-cAMP solution (prepared with 1 mM 5*IMAP reaction buffer and 1 mM DTT) was then added. The plates were incubated with shaking at room temperature for 30 minutes, and then 60 μL of detection solution (prepared with 0.5625 mM 5*IMAP progressive binding buffer A) was added. A), 0.1875mM 5*IMAP binding buffer B and 0.75mM binding beads (beads), incubated at room temperature with shaking for 60 minutes and data collected. The inhibition rate is calculated as follows: Inhibition rate = M / (MM 对照 )*100; IC was calculated based on the concentration and inhibition rate fitting curve 50 In this experiment, RPL554 was used as a positive control.

[0223] The examples disclosed herein inhibit PDE4B1 enzyme activity in vitro by the above test, and the measured inhibition rate and IC 50 The values ​​are shown in Tables 1 and 2.

[0224] Test Example 2 In vitro PDE3A enzyme activity detection experiment: IMAP FP-based analysis method detection

[0225] 1. Experimental Materials

[0226] Material Brand Part Number / Model PDE3A, BPS60030, Quercetin, Sigma, T205738, 4-well plate, Perkin Elmer, 6007279, IMAP FP IPP Assay Kit, MOLECULAR DEVICE, SR8124

[0227] 2. Experimental steps

[0228] Compounds were serially diluted 5-fold with DMSO to obtain different concentrations (10000 nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, 0.0256 nM, 0.005 nM). 200 μL of compound at different concentrations was added to a 384-well plate (n=2), and 2 200 μL DMSO was added to the 384-well plate (n=2) as a blank control. 10 μL of 0.025 μg / mL PDE4B1 enzyme solution (prepared with 1 mM 5*IMAP reaction buffer and 1 mM DTT) was then added to the 384-well plate, and 10 μL of blank buffer without PDE3A enzyme was added to one of the blank controls. The plates were incubated with shaking at room temperature for 15 minutes, followed by the addition of 10 μL of 0.1 μM FAM-cAMP solution (prepared with 1mM 5*IMAP reaction buffer and 1mM DTT) was incubated at room temperature with shaking for 30 minutes, after which 60μL of detection solution (prepared with 0.5625mM 5*IMAP progress binding buffer A, 0.1875mM 5*IMAP progress binding buffer B, and 0.75mM binding beads) was added and incubated at room temperature with shaking for 60 minutes before data collection. The inhibition rate was calculated as follows: Inhibition rate = M / (MM 对照 )*100; IC was calculated based on the concentration and inhibition rate fitting curve 50 In this experiment, RPL554 was used as a positive control.

[0229] The examples disclosed herein inhibit PDE3A enzyme activity in vitro by the above test, and the measured inhibition rate and IC 50 The values ​​are shown in Tables 1 and 2.

[0230] Table 1

[0231]

[0232] Table 2

[0233]

[0234] Note: N / A not tested

[0235] Conclusion: Compared with the positive compound RPL554, compounds 1 and 2 showed good biological activity in in vitro enzyme experiments, and compared with compound WX001, compound 1 had a 7-fold increase in inhibitory activity against PDE3A enzyme, and has good development prospects.

[0236] Test Example 3 Pharmacokinetic (PK) experiment of intratracheal administration

[0237] 1. Experimental Purpose

[0238] To evaluate the pharmacokinetic characteristics and lung tissue distribution of the test article in SD rats after intratracheal administration

[0239] 2. Experimental plan

[0240] 2.1 Investigational Drugs

[0241] Compound 1, Compound 2, and RPL-554

[0242] 2.2 Experimental animals

[0243] ICR mice (Shanghai Slake Laboratory Animal Co., Ltd.), 198, half male and half female.

[0244] 2.3 Drug preparation

[0245] 1) Full solution:

[0246] Weigh 0.5 g of Tween 80 and dissolve it in 50 ml of pH 2.5 citric acid / disodium hydrogen phosphate buffer solution for later use.

[0247] Weigh 1.0 mg of the test drug and dissolve it in an appropriate amount of Tween solution to prepare a 0.03 mg / ml solution for later use.

[0248] 2) Suspension:

[0249] Weigh 0.5 g of CMC-Na and 0.5 g of Tween 20, add 50 ml of 0.9% saline solution and stir evenly to obtain a 1% CMC-Na and Tween 20 solution for later use.

[0250] Weigh 1.0 mg of the test drug and add it to 10 ml of the above solution, disperse it by ultrasonic and stir it evenly to obtain a suspension for later use.

[0251] 2.4 Dosage regimen

[0252] Regimen 1 (suspension) Regimen 2 (full solution) Dosing concentration 0.15 mg / mL 0.03 mg / mL

[0253] Dosing volume 40μL40μL Dose 6μg / animal 1.2μg / animal

[0254] 3. Experimental operation / process

[0255] 3.1 Intratracheal administration of mice

[0256] Mice were anesthetized with isoflurane gas and administered intratracheally. Plasma was collected at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours. 200 μL of whole blood was collected, anticoagulated with EDTA-K2, and centrifuged at approximately 6800 g for 6 minutes at 2-8°C. The resulting plasma was transferred to appropriately labeled tubes within 1 hour of blood collection / centrifugation and stored frozen at -80°C. Lung tissue was collected at 0.5, 2, 8, and 24 hours. Tissue samples were transferred to appropriately labeled tubes and stored frozen at -80°C.

[0257] 3.2 Plasma processing and LC-MS / MS analysis

[0258] Take 30.0 μL of plasma sample to a 1.5 mL centrifuge tube, add 150 μL of internal standard working solution, vortex mix for 1 min, centrifuge for 5 min (13000 rpm, 4 ° C), take 70.0 μL of supernatant to a 96-well plate, add 70.0 μL of deionized water, shake well, and inject 2.00 μL for LC-MS / MS analysis.

[0259] 3.3 Lung tissue processing

[0260] Accurately weigh an appropriate amount of lung tissue sample and place it in a homogenizer tube. Add acetonitrile equal to 5 times its weight and mix the mixture. Sonicate for 5 minutes. Take 20.0 μL of lung tissue homogenate sample, add 30.0 μL of internal standard working solution and 200 μL of acetonitrile, vortex for 1 minute, and centrifuge for 10 minutes (4000 rpm, 4°C). Transfer 100 μL of the supernatant to a 96-well plate, add 100 μL of deionized water, shake the plate to mix (1000 rpm, RT), and inject 1.00 μL for LC-MS / MS analysis.

[0261] 4. Pharmacokinetic parameter results

[0262] Compared to RPL-554, Compound 1 and Compound 2 had higher in vivo exposure and maintained longer in the lungs. Relevant data are shown in Tables 3 and 4.

[0263] Table 3: PK and tissue distribution test results of suspension solution formulation

[0264]

[0265] Table 4: PK and tissue distribution test results of full solution formulation

[0266]

[0267]

Claims

1. A compound of formula II or a pharmaceutically acceptable salt thereof wherein each R2 is C1-6alkoxy, and the C1-6alkoxy is optionally substituted with one or more RA2; each RA2 is independently selected from the group consisting of deuterium, halogen, hydroxy, nitro, amino, cyano; each R3 is C1-6 alkyl and each C1-6 alkyl is independently optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, oxo, nitro, cyano and amino; o is selected from the group consisting of 0, 1, 2, 3 and 4; E1 is -(CH2)2-; E2 is a single bond; m represents 1 or 2; n is selected from the group consisting of 0, 1, 2, 3, and 4; L represents a single bond; ring Cy is optionally substituted with one or more RA3; each RA3 is independently selected from the group consisting of deuterium, halogen, hydroxy, nitro, cyano, C1-6 alkyl, and C1-6 alkyl is independently optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, oxo, nitro, cyano and amino.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein o is selected from the group consisting of 0, 2 and 3.

3. A compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula IV or a pharmaceutically acceptable salt thereof. wherein R4 is selected from the group consisting of hydrogen and C1-6 alkyl, and C1-6 alkyl is independently optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, oxo, nitro, cyano and amino; each R5 is independently selected from the group consisting of deuterium, halogen, hydroxy, nitro, cyano, C1-6 alkyl, and C1-6 alkyl is independently optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, oxo, nitro, cyano and amino; p is selected from the group consisting of 0, 1, 2, 3, and 4; R2, m and n are as defined in paragraph 1, and R3 and o are as defined in paragraph 1.

4. The compound or pharmaceutically acceptable salt thereof according to claim 3, wherein R4 is hydrogen or C1-6 alkyl, and C1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, and amino; and each R5 is independently selected from the group consisting of deuterium, halogen, hydroxy, nitro, and cyano.

5. A compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula V or a pharmaceutically acceptable salt thereof. wherein R7 is C1-6 alkyl and C1-6 alkyl is independently optionally substituted with one or more RA4; RA4 is selected from the group consisting of deuterium, halogen, hydroxy, oxo, nitro, amino and cyano; R8 is C1-6 alkyl and C1-6 alkyl is independently optionally substituted with one or more RA5; RA5 is selected from the group consisting of deuterium, halogen, hydroxy, oxo, nitro, amino and cyano; m is as defined in paragraph 1; R3 and o are as defined in paragraph 1; and R4, R5 and p are as defined in paragraph 3.

6. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of 7. A pharmaceutical composition containing a therapeutically effective amount of at least one of the compounds or their pharmaceutically acceptable salts according to any one of claims 1 to 6 and a pharmaceutically acceptable excipient.

8. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 for the preparation of a medicament for the prevention and / or treatment of a disorder associated with PDE (phosphodiesterase).

9. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 for the preparation of a medicament for the prevention and / or treatment of asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis or rheumatism.

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