Dihydrothienopyrimidine compound as well as preparation method and application thereof

Abstract

The invention belongs to the field of medicines, and relates to a dihydrothienopyrimidine compound as shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the oxide and application of the dihydrothienopyrimidine compound as a phosphodiesterase (PDEs) inhibitor, in particular to application of the dihydrothienopyrimidine compound in preparation of medicines for treating and / or preventing PDE4 enzyme mediated diseases or symptoms. # imgabs0 #

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine and relates to a dihydrothienopyrimidine compound, a preparation method thereof, and its application in medicine. Specifically, the present disclosure relates to a dihydrothienopyrimidine compound represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing such an oxide, and its use as a phosphodiesterase (PDEs) inhibitor, particularly its use in the preparation of a drug for treating and / or preventing a disease or disorder mediated by the PDE4 enzyme. Background Art

[0002] Phosphodiesterases (PDEs) have the function of hydrolyzing intracellular second messengers (cAMP, cyclic adenosine monophosphate or cGMP, cyclic guanosine monophosphate), degrading intracellular cAMP or cGMP, thereby terminating the biochemical actions conducted by these second messengers. Among the currently identified 11 phosphodiesterases, PDE4, PDE7, and PDE8 are cAMP-selective. PDE4 is the most important regulator of cAMP expressed in immune cells and inflammatory cells such as neutrophils, macrophages, and T-lymphocytes. Since cAMP is a key second messenger in regulating the inflammatory response, it has been found that PDE4 regulates the inflammatory response of inflammatory cells by regulating pro-inflammatory cytokines such as TNFα, IL-2, IFN-γ, GM-CSF, and LTB4. Therefore, inhibiting PDE4 has become an attractive target for treating inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, atopic dermatitis, psoriasis, inflammatory bowel disease such as Crohn's disease, etc. (M.D. Houslay et al, Drug Discovery Today, 2005, 10(22), 1503-1519). Since the PDE activity of patients with atopic dermatitis (AD) is elevated, inhibiting PDE4 also seems to be a viable treatment method for AD (Journal of Investigative Dermatology, 1986, 87(3), 372-376). Summary of the Invention

[0003] The present disclosure provides a compound represented by the general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts:

[0004]

[0005] Wherein:

[0006] L is selected from C 1-3 alkylene;

[0007] Ring A is selected from cycloalkyl, aryl, heteroaryl, and heterocyclic group;

[0008] R 1 is selected from hydroxy, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclic group, wherein the substitution is by at least one R Het substituted;

[0009] R 2 is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclic group, wherein the substitution is by at least one Q;

[0010] R 3 each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxy, halogen, amino, cyano, alkyl, haloalkyl, alkoxy, and alkylhydroxy;

[0011] R 4 , R 5 , R 6 and R 7 are the same or different and are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, alkyl, alkoxy, and alkylhydroxy; wherein the alkyl is optionally substituted by one or more substituents selected from halogen and hydroxy;

[0012] R Het is selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, nitro, -(CR b R c ) t -COR a , oxo group and

[0013] Q is selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, nitro, oxo group, alkyl, alkoxy, haloalkyl, haloalkoxy, and hydroxyalkyl;

[0014] R a , R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, and alkyl; wherein the alkyl is optionally substituted by one or more substituents selected from halogen and hydroxy;

[0015] n is 0, 1, 2, 3, 4, 5 or 6;

[0016] t is 0, 1 or 2;

[0017] provided that the compound represented by general formula I is not

[0018] Effect of the invention

[0019] The disclosed dihydrothienopyrimidine compounds have high inhibitory activity against phosphodiesterases (PDEs), specifically against PDE4, and at the same time have excellent pharmacodynamic, in vitro / in vivo pharmacokinetic properties and safety, with high clinical application prospects. In addition, the compounds of the present invention have a preferential selectivity for the PDE4B subtype. Detailed Embodiments

[0020] To make the technical solutions and beneficial effects of the present invention more obvious and understandable, the following will be described in detail by listing specific embodiments. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical and scientific fields to which this application belongs.

[0021] The present disclosure provides a compound of formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts:

[0022]

[0023] Wherein:

[0024] L is selected from C 1-3 alkylene;

[0025] Ring A is selected from cycloalkyl, aryl, heteroaryl, and heterocyclic group;

[0026] R 1 is selected from hydroxy, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclic group, and the substitution is by at least one R Het substitution;

[0027] R 2 is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclic group, and the substitution is by at least one Q substitution;

[0028] R 3 each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxy, halogen, amino, cyano, alkyl, haloalkyl, alkoxy, and alkyl hydroxy;

[0029] R 4 、R 5 、R 6 and R 7 are the same or different, and each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, alkyl, alkoxy, and alkyl hydroxy; wherein the alkyl is optionally substituted by one or more substituents selected from halogen and hydroxy;

[0030] R Het is selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, nitro, -(CR b Rc ) t -COR a 、 an oxo group and

[0031] Q is selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl;

[0032] R a 、 R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy and alkyl; wherein the alkyl is optionally substituted with one or more substituents selected from halogen and hydroxy;

[0033] n is 0, 1, 2, 3, 4, 5 or 6;

[0034] t is 0, 1 or 2;

[0035] provided that the compound represented by General Formula I is not

[0036] In certain embodiments, said L is selected from methylene and ethylene.

[0037] In certain embodiments, said L is selected from methylene.

[0038] In certain embodiments, said R 4 is selected from hydrogen, deuterium, halogen and amino.

[0039] In certain embodiments, said R 4 is selected from hydrogen and halogen.

[0040] In certain embodiments, said R 4 is selected from hydrogen.

[0041] In certain embodiments, said R 5 is selected from hydrogen, deuterium, halogen and amino.

[0042] In certain embodiments, said R 5 is selected from hydrogen and halogen.

[0043] In certain embodiments, said R 5 is selected from hydrogen.

[0044] In certain embodiments, said R 6 is selected from hydrogen, deuterium, halogen and amino.

[0045] In certain embodiments, said R 6 is selected from hydrogen and halogen.

[0046] In certain embodiments, said R 6Selected from hydrogen.

[0047] In certain embodiments, said R 7 is selected from hydrogen, deuterium, halogen, and amino.

[0048] In certain embodiments, said R 7 is selected from hydrogen and halogen.

[0049] In certain embodiments, said R 7 is selected from hydrogen.

[0050] In certain embodiments, ring A is selected from aryl and heteroaryl.

[0051] In certain embodiments, ring A is selected from C 6-10 aryl and 5- to 6-membered heteroaryl, the heteroaryl containing 1 to 4 heteroatoms selected from N and O.

[0052] In certain embodiments, ring A is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl.

[0053] In certain embodiments, ring A is selected from phenyl.

[0054] In certain embodiments, said R 3 is selected from hydrogen, deuterium, oxo, hydroxy, and halogen.

[0055] In certain embodiments, said R 3 is selected from hydrogen and halogen.

[0056] In certain embodiments, said R 3 is selected from hydrogen.

[0057] In certain embodiments, said R 2 is selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

[0058] In certain embodiments, said R 2 is selected from substituted or unsubstituted C 6-10 aryl and substituted or unsubstituted 5- to 6-membered heteroaryl, the heteroaryl containing 1 to 4 heteroatoms selected from N and O.

[0059] In certain embodiments, said R 2 is selected from phenyl, pyrazolyl, oxazolyl, imidazolyl, and pyrrolyl.

[0060] In certain embodiments, said R 2 is selected from oxazolyl.

[0061] In certain embodiments, Q is selected from hydrogen, deuterium, halogen, hydroxy, and amino.

[0062] In certain embodiments, Q is selected from hydrogen.

[0063] In certain embodiments, R 1 is selected from substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclic group.

[0064] In certain embodiments, R 1 is selected from substituted or unsubstituted 5-14 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S.

[0065] In certain embodiments, R 1 is selected from substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S.

[0066] In certain embodiments, R 1 is selected from substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted triazolyl,

[0067]

[0068] wherein v is 0, 1 or 2.

[0069] In certain embodiments, R 1 is selected from substituted or unsubstituted thienyl,

[0070] wherein v is 0, 1 or 2.

[0071] In certain embodiments, R Het is selected from hydrogen, deuterium, halogen, -COCH3, oxo group and

[0072] In certain embodiments, R Het is selected from hydrogen, halogen, -COCH3, oxo group and

[0073] In certain embodiments, R Het is selected from hydrogen, -COCH3 and

[0074] The present disclosure provides a compound of formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized by a compound having the structure of formula I-1:

[0075]

[0076] Wherein:

[0077] Ring A is selected from cycloalkyl, aryl, heteroaryl and heterocyclic group;

[0078] R 1 is selected from hydroxy, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclic group, and the substitution is by at least one R Het substitution;

[0079] R 2 is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclic group, and the substitution is by at least one Q;

[0080] R 3 each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxy, halogen, amino, cyano, alkyl, haloalkyl, alkoxy and alkylhydroxy;

[0081] R Het is selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, nitro, -(CR b R c ) t -COR a , oxo group and

[0082] Q is selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, nitro, oxo group, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl;

[0083] R a , R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy and alkyl; wherein the alkyl is optionally substituted by one or more substituents selected from halogen and hydroxy;

[0084] n is 0, 1, 2, 3, 4, 5 or 6;

[0085] t is 0, 1 or 2;

[0086] provided that the compound represented by general formula I is not

[0087] In certain embodiments, ring A is selected from aryl and heteroaryl.

[0088] In certain embodiments, ring A is selected from C 6-10 aryl and 5-6 membered heteroaryl, and the heteroaryl contains 1-4 heteroatoms selected from N and O.

[0089] In certain embodiments, Ring A is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl.

[0090] In certain embodiments, Ring A is selected from phenyl.

[0091] In certain embodiments, said R 3 is selected from hydrogen, deuterium, oxo, hydroxy, and halogen.

[0092] In certain embodiments, said R 3 is selected from hydrogen and halogen.

[0093] In certain embodiments, said R 3 is selected from hydrogen.

[0094] In certain embodiments, said R 2 is selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

[0095] In certain embodiments, said R 2 is selected from substituted or unsubstituted C 6-10 aryl and substituted or unsubstituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N and O.

[0096] In certain embodiments, said R 2 is selected from phenyl, pyrazolyl, oxazolyl, imidazolyl, and pyrrolyl.

[0097] In certain embodiments, said R 2 is selected from oxazolyl.;

[0098] In certain embodiments, Q is selected from hydrogen, deuterium, halogen, hydroxy, and amino.

[0099] In certain embodiments, Q is selected from hydrogen.

[0100] In certain embodiments, said R 1 is selected from substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclic group.

[0101] In certain embodiments, said R 1 is selected from substituted or unsubstituted 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S.

[0102] In certain embodiments, said R 1 is selected from substituted or unsubstituted 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S.

[0103] In certain embodiments, said R 1Selected from substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted triazolyl,

[0104]

[0105] wherein v is 0, 1 or 2.

[0106] In certain embodiments, said R 1 is selected from substituted or unsubstituted thienyl,

[0107] wherein v is 0, 1 or 2.

[0108] In certain embodiments, said R Het is selected from hydrogen, deuterium, halogen, -COCH3, oxo group and

[0109] In certain embodiments, said R Het is selected from hydrogen, halogen, -COCH3, oxo group and

[0110] In certain embodiments, said R Het is selected from hydrogen, -COCH3 and

[0111] The present disclosure provides a compound of formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized by a compound having the structure of formula I-2:

[0112]

[0113] Wherein:

[0114] R 1 is selected from hydroxy, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclic group, and the substitution is by at least one R Het substituted;

[0115] R 2 is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclic group, and the substitution is by at least one Q;

[0116] R Het is selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, nitro, -(CRb R c ) t -COR a , oxo group and

[0117] Q is selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl;

[0118] R a 、R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy and alkyl; wherein the alkyl is optionally substituted with one or more substituents selected from halogen and hydroxy;

[0119] t is 0, 1 or 2;

[0120] Provided that the compound of general formula I is not

[0121] In certain embodiments, the R 2 is selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

[0122] In certain embodiments, the R 2 is selected from substituted or unsubstituted C 6-10 aryl and substituted or unsubstituted 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N and O.

[0123] In certain embodiments, the R 2 is selected from phenyl, pyrazolyl, oxazolyl, imidazolyl and pyrrolyl.

[0124] In certain embodiments, the R 2 is selected from oxazolyl.;

[0125] In certain embodiments, the Q is selected from hydrogen, deuterium, halogen, hydroxy and amino.

[0126] In certain embodiments, the Q is selected from hydrogen.

[0127] In certain embodiments, the R 1 is selected from substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclic group.

[0128] In certain embodiments, the R 1 is selected from substituted or unsubstituted 5-14 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S.

[0129] In certain embodiments, the R 1Selected from substituted or unsubstituted 5- to 10-membered heteroaryl groups, said heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S.

[0130] In certain embodiments, said R 1 is selected from substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted triazolyl,

[0131]

[0132] wherein v is 0, 1, or 2.

[0133] In certain embodiments, said R 1 is selected from substituted or unsubstituted thienyl,

[0134] wherein v is 0, 1, or 2.

[0135] In certain embodiments, said R Het is selected from hydrogen, deuterium, halogen, -COCH3, oxo group and

[0136] In certain embodiments, said R Het is selected from hydrogen, halogen, -COCH3, oxo group and

[0137] In certain embodiments, said R Het is selected from hydrogen, -COCH3 and

[0138] The present disclosure provides a compound of general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts, characterized by a compound having the structure of formula I-3:

[0139]

[0140] Wherein:

[0141] R 1 is selected from hydroxy, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclic group, said substitution being by at least one R Het substituted;

[0142] R Het is selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, nitro, -COR a, an oxo group, and

[0143] R a is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, and alkyl; wherein the alkyl is optionally substituted with one or more substituents selected from halogen and hydroxy;

[0144] provided that the compound of general formula I is not

[0145] In certain embodiments, said R 1 is selected from substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclic group.

[0146] In certain embodiments, said R 1 is selected from substituted or unsubstituted 5-14 membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S.

[0147] In certain embodiments, said R 1 is selected from substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S.

[0148] In certain embodiments, said R 1 is selected from substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted triazolyl,

[0149]

[0150] wherein v is 0, 1, or 2.

[0151] In certain embodiments, said R 1 is selected from substituted or unsubstituted thienyl,

[0152] wherein v is 0, 1, or 2.

[0153] In certain embodiments, said R Het is selected from hydrogen, deuterium, halogen, -COCH3, oxo group, and

[0154] In certain embodiments, said R Het is selected from hydrogen, halogen, -COCH3, oxo group, and

[0155] In certain embodiments, the R Het is selected from hydrogen, -COCH3, and

[0156] In certain embodiments, the present disclosure provides a compound or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt, characterized in that the compound is any one of the following:

[0157]

[0158]

[0159] In certain embodiments, the present disclosure provides a compound or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt, characterized in that the compound is any one of the following:

[0160]

[0161]

[0162] The present disclosure also provides a method for preparing the compound represented by formula I, specifically as follows:

[0163]

[0164] The present disclosure also provides a pharmaceutical composition, which contains a therapeutically effective amount of the aforementioned compound or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt.

[0165] In certain embodiments, the unit dose of the pharmaceutical composition is 0.001 mg - 1000 mg.

[0166] In certain embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01% - 99.99% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 0.1% - 99.9% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 0.5% - 99.5% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 1% - 99% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 2% - 98% of the aforementioned compound.

[0167] In certain embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable carrier, diluent or excipient.

[0168] All compounds, mixtures, compositions, etc. involved in the present disclosure can be administered into a living body via any administration route. The administration route can be oral administration, intravenous injection, intramuscular injection, subcutaneous injection, rectal administration, vaginal administration, sublingual administration, nasal inhalation, oral inhalation, eye drops, or topical or systemic transdermal administration.

[0169] All compounds, mixtures, compositions, etc. involved in the present disclosure can be formulated into a single dose, which contains the active compound of the present invention as well as carriers, excipients, etc. The dosage forms can be tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches, lotions, etc. These dosage forms can contain common components used in pharmaceutical preparations, such as diluents, absorbents, wetting agents, binders, disintegrants, colorants, pH regulators, antioxidants, bacteriostatic agents, isotonicity regulators, anti-adhesives, etc.

[0170] Suitable formulations for the above various dosage forms can be obtained from public sources, such as Remington: The Science and Practice of Pharmacy, 21st Edition, published by Lippincott Williams & Wilkins in 2006 and Rowe, Raymond C. Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press in 2005. Therefore, those skilled in the art can easily prepare them.

[0171] According to factors such as the nature and intensity of the diseases suffered by different individuals, the age, gender, weight of the patients, and the administration route, different administration doses can be selected. The administration dose of the compounds of the present invention can be 0.01 to 500 mg / kg per day, preferably the daily dose is 1-100 mg / kg, and it can be administered once or multiple times.

[0172] The present disclosure also provides the use of the aforementioned compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts, or the aforementioned pharmaceutical composition, in the preparation of a drug for inhibiting PDEs enzymes, preferably in the preparation of a drug for inhibiting PDE4 enzymes, more preferably in the preparation of a drug for inhibiting PDE4B enzymes.

[0173] The present disclosure also provides the use of the aforementioned compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts, or the aforementioned pharmaceutical composition, in the preparation of a drug for treating and / or preventing diseases or disorders mediated by PDEs enzymes, preferably in the preparation of a drug for treating and / or preventing diseases or disorders mediated by PDE4 enzymes, more preferably in the preparation of a drug for treating and / or preventing diseases or disorders mediated by PDE4B enzymes.

[0174] In certain embodiments, the disease or disorder is selected from respiratory diseases, pulmonary diseases, gastrointestinal diseases, inflammatory diseases, cancers, and peripheral or central nervous system diseases.

[0175] In certain embodiments, the respiratory and pulmonary diseases are selected from respiratory and pulmonary diseases accompanied by increased mucus production, obstructive pulmonary diseases, and airway diseases, preferably selected from COPD, asthma, interstitial lung disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, α1-antitrypsin deficiency, chronic rhinosinusitis, chronic bronchitis, and pulmonary arterial hypertension.

[0176] In certain embodiments, the gastrointestinal diseases are selected from Crohn's disease, ulcerative colitis, and regional enteritis.

[0177] In certain embodiments, the inflammatory diseases are selected from proliferative and inflammatory skin diseases, arthritic diseases, and ocular inflammatory diseases; wherein the inflammatory skin diseases are preferably selected from atopic dermatitis, seborrheic dermatitis, contact dermatitis, epidermal inflammation, alopecia, alopecia areata, rosacea, SAPHO syndrome, skin atrophy, photoaging of the skin, acne vulgaris, hidradenitis suppurativa, urticaria, pruritus, hand eczema, and psoriasis; the arthritic diseases are preferably selected from rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis; the ocular inflammatory diseases are preferably glaucoma or dry eye syndrome.

[0178] In certain embodiments, wherein the peripheral or central nervous system disease is selected from Alzheimer's disease, age-associated memory impairment (AAMI), age-associated cognitive decline, vascular dementia, delirium, Parkinson's disease, Huntington's disease, Pick's disease, mental retardation, cerebrovascular disease, depression, schizophrenia, stroke, psychosomatic disorder, attention deficit disorder, subdural hematoma, normal pressure hydrocephalus, brain tumor, cerebral infarction, cognitive impairment due to sleep deprivation, intellectual and developmental disabilities, and multiple sclerosis.

[0179] In certain embodiments, wherein the cancer is selected from leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, endometrial cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, renal cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, small intestine cancer, gallbladder cancer, pediatric oncology, urothelial cancer, ureteral tumor, thyroid cancer, osteoma, neuroblastoma, brain tumor, and myeloma.

[0180] Term Explanation:

[0181] Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

[0182] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched-chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkyl group 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, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, etc. More preferably, it is a lower alkyl group 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, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any available attachment point, and the substituents are preferably independently optionally selected from one or more substituents of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycle, aryl, and heteroaryl.

[0183] The term "alkylene" refers to a saturated straight-chain or branched-chain aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, and is a straight-chain or branched-chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkylene containing 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2-), 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. The alkylene can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituents are preferably independently optionally selected from one or more substituents including alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, and oxo group.

[0184] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the cycloalkyl ring contains 3 to 20 carbon atoms, preferably contains 3 to 12 carbon atoms, preferably contains 3 to 8 (such as 3, 4, 5, 6, 7, and 8) carbon atoms, and more preferably contains 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro, fused, and bridged cycloalkyl.

[0185] The term "spiroalkyl" refers to a polycyclic group with 5 to 20 members, where a single carbon atom (called the spiro atom) is shared between monocyclic rings, and it can contain one or more double bonds. It is preferably 6 to 14 members, and more preferably 7 to 10 members (such as 7, 8, 9, or 10 members). Spiroalkyl is classified into monospiroalkyl, dispiroalkyl, or polyspiroalkyl according to the number of spiro atoms shared between rings, and is preferably monospiroalkyl and dispiroalkyl. More preferably, it is 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroalkyl. Non-limiting examples of spiroalkyl include:

[0186]

[0187] The term "fused cycloalkyl" refers to a fully carbon polycyclic group having 5 to 20 members, in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, and one or more of the rings may contain one or more double bonds. Preferably it has 6 to 14 members, more preferably 7 to 10 members (such as 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably bicyclic alkyl groups of 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 4, 5 / 5, 5 / 6, 6 / 3, 6 / 4, 6 / 5 and 6 / 6. Non-limiting examples of fused cycloalkyl include:

[0188]

[0189] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group having 5 to 20 members, in which any two rings share two non-directly connected carbon atoms, and it may contain one or more double bonds. Preferably it has 6 to 14 members, more preferably 7 to 10 members (such as 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0190]

[0191] The cycloalkyl ring includes the cycloalkyl as described above (including monocyclic, spiro, fused and bridged) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is cycloalkyl. Non-limiting examples include etc.; preferably

[0192] Cycloalkyl can be substituted or unsubstituted. When substituted, it can be substituted at any available connection point, and the substituents are preferably independently optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0193] The term "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), where alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy and butoxy. Alkoxy can be optionally substituted or unsubstituted. When substituted, it is preferably one or more of the following groups, which are independently selected from D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0194] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic ring substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen and sulfur, said sulfur being optionally oxidized (i.e., forming sulfoxide or sulfone), but excluding ring moieties of -O-O-, -O-S- or -S-S-, and the remaining ring atoms being carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, where 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7 and 8), where 1 - 3 (e.g., 1, 2 and 3) are heteroatoms; still more preferably, it contains 3 to 6 ring atoms, where 1 - 3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, where 1 - 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

[0195] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group having 5 to 20 members, with a single atom (called the spiro atom) shared between monocyclic rings, one or more of which are heteroatoms selected from nitrogen, oxygen and sulfur, said sulfur being optionally oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms being carbon. It may contain one or more double bonds. Preferably, it has 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). Spiroheterocyclic groups are classified into monospiroheterocyclic groups, dispiroheterocyclic groups or polyspiroheterocyclic groups according to the number of spiro atoms shared between rings, preferably monospiroheterocyclic groups and dispiroheterocyclic groups. More preferably, they are 3 - member / 5 - member, 3 - member / 6 - member, 4 - member / 4 - member, 4 - member / 5 - member, 4 - member / 6 - member, 5 - member / 5 - member or 5 - member / 6 - member monospiroheterocyclic groups. Non-limiting examples of spiroheterocyclic groups include:

[0196]

[0197] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group having 5 to 20 members, wherein each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, said sulfur may optionally be oxidized (i.e., form sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of the fused heterocyclic group include:

[0198]

[0199] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group having 5 to 14 members, wherein any two rings share two non-directly connected atoms, which may contain one or more double bonds, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, said sulfur may optionally be oxidized (i.e., form sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of the bridged heterocyclic group include:

[0200]

[0201] The heterocyclic group ring includes the heterocyclic groups (including monocyclic, spiro heterocyclic, fused heterocyclic, and bridged heterocyclic) as described above fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples thereof include:

[0202] etc.

[0203] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any available attachment point, and the substituents are preferably independently optionally selected from one or more substituents among halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl, and heteroaryl.

[0204] The term "aryl" refers to a 6- to 14-membered fully carbon monocyclic or fused polycyclic group (fused polycyclic rings are rings that share adjacent pairs of carbon atoms) having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, where the ring attached to the parent structure is the aryl ring, and non-limiting examples thereof include:

[0205]

[0206] Aryl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituents are preferably independently optionally selected from one or more substituents including halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0207] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5- to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5-membered or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclic, or cycloalkyl ring as described above, where the ring attached to the parent structure is the heteroaryl ring, and non-limiting examples thereof include:

[0208]

[0209] Heteroaryl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituents are preferably independently optionally selected from one or more substituents including halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0210] The above cycloalkyl, heterocyclic, aryl, and heteroaryl include residues derived by removing one hydrogen atom from the parent ring atoms, or residues derived by removing two hydrogen atoms from the same or two different ring atoms of the parent, i.e., "divalent cycloalkyl", "divalent heterocyclic", "arylene", "heteroarylene".

[0211] The term "haloalkyl" refers to an alkyl substituted with one or more halogens, where the alkyl is as defined above.

[0212] The term "haloalkoxy" refers to an alkoxy substituted with one or more halogens, where the alkoxy is as defined above.

[0213] The term "hydroxyalkyl" means an alkyl group substituted by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0214] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0215] The term "hydroxyl" means -OH.

[0216] The term "amino" means -NH2.

[0217] The term "cyano" means -CN.

[0218] The term "nitro" means -NO2.

[0219] The term "oxo group" or "oxo" means "=O".

[0220] The term "substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently replaced by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) the possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (such as olefinic) bond.

[0221] In the chemical structure of the compounds described in the present disclosure, the bond does not specify the configuration, that is, the bond can be or or simultaneously contain and both configurations. The bond represents a single configuration, which is or In the chemical structure of the compounds described in the present disclosure, the bond does not specify the configuration, that is, it can be in the Z configuration or the E configuration, or simultaneously contain both configurations.

[0222] The term "stereoisomer" refers to a compound having the same chemical constitution but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric (cis / trans) isomers, atropisomers, and so on.

[0223] The term "isotope derivative" refers to a compound that differs in structure only in the presence of one or more isotope-enriched atoms. For example, having the structure of the present disclosure, replacing hydrogen with "deuterium" or "tritium", or replacing fluorine with 18 F-fluorine labeling ( 18 F isotope), or replacing fluorine with 11 C-,13 C−, or 14 C−enriched carbon( 11 C−, 13 C−, or 14 C−carbon labeling; 11 C−, 13 C−, or 14 C−isotope) substituted for a carbon atom is within the scope of the present disclosure. Such compounds can be used as, for example, analytical tools or probes in biological assays, or can be used as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetic, or receptor studies. The various deuterated forms of the compounds of the present disclosure mean that each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of the compounds with reference to relevant literature. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of the compounds, or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated borane, tetrahydrofuran solution of tri−deuterated borane, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane, etc. Deuterated compounds generally can retain activities comparable to those of the non−deuterated compounds, and can achieve better metabolic stability when deuteration occurs at certain specific sites, thereby obtaining certain therapeutic advantages.

[0224] The term "pharmaceutically acceptable salt" means that the compounds of the present invention exist in the form of their medicinal salts, including acid addition salts and base addition salts. Pharmaceutically acceptable salts are described in pharmaceutically salts described by S.M. Berge in J. Pharmaceutical Sciences (Volume 66: pages 1−19, 1977). In the present invention, pharmaceutically acceptable non−toxic acid addition salts mean salts formed by the compounds in the present invention with organic or inorganic acids, and the organic or inorganic acids include but are not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p−toluenesulfonic acid, malic acid, etc. Pharmaceutically acceptable non−toxic base addition salts mean salts formed by the compounds in the present invention with organic or inorganic bases, including but not limited to alkali metal salts, such as lithium, sodium, or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic base salts, such as ammonium salts formed by reacting with organic bases containing N + (C 1-6 alkyl)4 salts.

[0225] The term "solvate" refers to the physical association of a compound of the present disclosure with one or more, preferably 1 - 3, solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain cases, for example, when one or more, preferably 1 - 3, solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0226] The term "hydrate" refers to the case where the solvent in the above - mentioned term "solvate" is water.

[0227] The term "prodrug" refers to a compound that can be converted in vivo under physiological conditions, for example, by hydrolysis in the blood, to produce the active parent drug compound.

[0228] The term "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, promote the absorption of the active ingredient, and thus exert its biological activity.

[0229] The above - mentioned terms related to the present invention are defined. Those skilled in the art can also understand these terms in combination with the prior art. The following further describes based on the content of the present invention and the definitions of the terms.

[0230] The preparation of the compounds and pharmaceutically acceptable salts described in the present disclosure is further described below in conjunction with examples, but these examples do not limit the scope of the present disclosure.

[0231] For the experimental methods without specific conditions indicated in the examples of the present disclosure, they are generally carried out under conventional conditions, or according to the conditions recommended by the raw material or commodity manufacturers. Reagents without specific sources indicated are conventional reagents purchased from the market.

[0232] The following describes the general test conditions in the examples of the present invention:

[0233] First, the reactions in the examples are generally carried out under nitrogen protection.

[0234] Furthermore, the intermediates and final products are separated and purified by chromatographic columns, preparative chromatographic plates, and ISCO rapid preparative chromatography systems. The chromatographic columns are packed with silica gel. The silica gel (300 - 400 mesh) is produced by Shanghai Titan Scientific Co., Ltd., the preparative chromatographic plates are produced by Yantai Jiangyou Silica Gel Development Co., Ltd., and the chromatographic columns used in ISCO (particle size 40 - 63μm, ) are produced by Changzhou Santai Technology Co., Ltd.

[0235] Further, the LC-MS liquid chromatography-mass spectrometry instrument used is the Waters ACQUITY Arc equipped with a QDa Detector. The Waters XBridge C18 chromatographic column (specification 2.1×50 mm, 3.5 μm) is used. The mass spectrometry (MS) uses an ESI source, and only the molecular weight M of the parent molecule is indicated, and usually [M+H] is reported. + . The injection volume is determined by the sample concentration; the flow rate is: 1.2 mL / min; the HPLC peaks are recorded and read at UV-Vis wavelengths of 220 nm and 254 nm. The mobile phase is an ultrapure aqueous solution of 0.01% formic acid (mobile phase A) and an acetonitrile solution of 0.01% formic acid (mobile phase B). The gradient elution conditions are shown in Tables 1 and 2 below:

[0236] Table 1: Gradient elution condition 1

[0237] Time (min) <![CDATA[A(H2O, 0.01% HCOOH)]]> <![CDATA[B(CH3CN,0.01%HCOOH)]]> 0.0-0.3 95-85 5-15 0.3-3.2 85-20 15-80 3.2-3.8 20-5 80-95 3.8-3.81 5-95 95-5 3.81-4.0 95 5

[0238] Table 2: Gradient elution condition 2

[0239] Time (min) <![CDATA[A(H2O, 0.01% HCOOH)]]> <![CDATA[B(CH3CN,0.01%HCOOH)]]> 0.00-5.90 95-5 5-95 5.90-5.91 5-95 95-5 5.91-6.00 95 5

[0240] Further, the NMR spectra are obtained Varian 400MHz Nuclear Magnetic Resonance Spectrometer by using CDCl3 and DMSO-d6 as solvents to report the chemical shifts in ppm. The descriptions of various peaks are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doubled doublet). The coupling constant is expressed in Hz.

[0241] Examples

[0242] Example 1

[0243] (R)-1-(5-(((2-(4-(oxazol-2-yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophen-2-yl)ethan-1-one (Compound 1)

[0244]

[0245] First step: Preparation of (5-(2-methyl-1,3-dioxolan-2-yl)thiophene-2-carbonitrile (Compound 1b)

[0246] At room temperature, 5-acetylthiophene-2-carbonitrile 1a (3.00 g, 20.0 mmol), ethylene glycol (2.50 g, 40.0 mmol) and p-toluenesulfonic acid (0.34 g, 2.00 mmol) were mixed in toluene (50 mL). The reaction mixture was stirred at 150 °C for 5 h with water separation using a water separator. After the reaction was completed, the solvent was removed by concentration under reduced pressure. Subsequently, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to give the title compound 1b (3.07 g).

[0247] Step 2: Preparation of (5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl)methanamine (Compound 1c)

[0248] Under nitrogen protection, compound 1b (1.00 g, 5.13 mmol) was dissolved in tetrahydrofuran (20 mL). The reaction mixture was placed in an ice bath, and then a solution of lithium aluminum hydride in tetrahydrofuran (4.1 mL, 10.26 mmol) was added and stirred for 3 h. Subsequently, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was washed successively with saturated ammonium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product (Compound 1c). This crude product (0.86 g) was used directly in the next step without purification.

[0249] Step 3: Preparation of 2-chloro-N-((5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl)methyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-amine (Compound 1d)

[0250] At room temperature, 2,4-dichloro-6,7-dihydrothieno[3,2-d] (0.52 g, 2.50 mmol), compound 1c (0.50 g, 2.50 mmol) and N,N-diisopropylethylamine (0.97 g, 7.50 mmol) were mixed in ethanol (30 mL). In a microwave reactor, the reaction mixture was stirred at 85 °C for 2 h. After the reaction was completed, the solvent was removed by concentration under reduced pressure. Subsequently, water (15 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 2). The combined organic phases were concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to give the title compound 1d (0.80 g).

[0251] Step 4: Preparation of (R)-2-chloro-4-(((5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl)methyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 1e)

[0252] At room temperature, compound 1d (0.80 g, 2.16 mmol), S-1,1'-bi-2-naphthol (63 mg, 0.22 mmol), titanium(IV) isopropoxide (31 mg, 0.11 mmol) and water (40 mg, 2.16 mmol) were mixed in dichloromethane (30 mL). The mixture was stirred at room temperature for 1 hour, then tert-butyl hydroperoxide (0.34 g, 2.60 mmol) was added and the reaction mixture was stirred at room temperature for 5 hours. After the reaction was completed, water (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 2). The combined organic phases were concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to give the title compound 1e (0.68 g).

[0253] Step 5: Preparation of (R)-4-(((5-(2-methyl-1,3-dioxolan-2-yl)thiophen-2-yl)methyl)amino)-2-(4-(oxazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 1f)

[0254] Under nitrogen protection, compound 1e (0.30 g, 0.78 mmol), (4-(oxazol-2-yl)phenyl)boronic acid (0.21 g, 0.78 mmol), potassium carbonate (0.22 g, 1.56 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (60 mg, 0.08 mmol) were mixed in a 1,4-dioxane (10 mL) / water (2 mL) solution. The reaction mixture was stirred at 80 °C for 3 hours. Ethyl acetate (20 mL) was added to the reaction mixture. The organic phase was washed successively with saturated ammonium chloride (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to give the title compound 1f (0.16 g). Step 6: Preparation of (R)-1-(5-(((2-(4-(oxazol-2-yl)phenyl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophen-2-yl)ethan-1-one (Compound 1)

[0255] Compound 1f (0.16 g, 0.32 mmol) was dissolved in tetrahydrofuran (3 mL), and hydrochloric acid (1 mL) was added. The reaction mixture was stirred at 25 °C for 3 hours. After the reaction was completed, the pH of the solution was adjusted to neutral with saturated sodium bicarbonate solution. Ethyl acetate (20 mL) was added for extraction. The organic phase was washed successively with saturated ammonium chloride (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to give the title compound 1 (60 mg, yield: 41%).

[0256] 11H NMR (400 MHz, DMSO-d6) δ ppm 9.08 (t, J = 5.77 Hz, 1H), 8.57 (m, J = 8.42 Hz, 2H), 8.32 (s, 1H), 8.14 (m, J = 8.42 Hz, 2H), 7.81 (d, J = 3.75 Hz, 1H), 7.47 (s, 1H), 7.25 (d, J = 3.75 Hz, 1H), 4.99 (br d, J = 5.77 Hz, 2H), 3.68 - 3.77 (m, 1H), 3.50 (dt, J = 13.73, 8.01 Hz, 1H), 3.27 - 3.33 (m, 1H), 3.10 (dt, J = 7.92, 5.74 Hz, 1H), 2.47 (s, 3H)

[0257] MS m / z (ESI): 451 [M + 1].

[0258] Example 2

[0259] ((R)-4-(((5-(Dimethylphosphoryl)thiophen-2-yl)methyl)amino)-2-(4-(oxazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 2)

[0260]

[0261] The first step: Preparation of tert-butyl ((5-(dimethylphosphoryl)thiophen-2-yl)methyl)carbamate (Compound 2c)

[0262] Under nitrogen protection, tert-butyl ((5-bromothiophen-2-yl)methyl)carbamate 2a (1 g, 3.4 mmol), dimethylphosphine oxide 2b (563 mg, 7.2 mmol), cesium carbonate (2.24 g, 6.9 mmol), bis(dibenzylideneacetone)palladium (311 mg, 0.34 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (398 mg, 0.269 mmol) were mixed in a 1,4-dioxane (10 mL) solution. The reaction mixture was stirred at 100 °C for 12 h. Ethyl acetate (30 mL) was added to the reaction mixture. The organic phase was washed successively with saturated ammonium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to give the title compound 2c (130 mg).

[0263] The second step: Preparation of ((5-(aminomethyl)thiophen-2-yl)dimethylphosphine oxide hydrochloride (Compound 2d)

[0264] At room temperature, a solution of hydrochloric acid in 1,4-dioxane (2 mL) was added dropwise to a solution of tert-butyl ((5-(dimethylphosphoryl)thiophen-2-yl)methyl)carbamate 2c (130 mg, 0.45 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent and excess hydrochloric acid solution were removed by concentration under reduced pressure to obtain a crude product as a yellow oil. This crude product, compound 2d (200 mg, crude product), was used directly in the next step of the reaction without purification.

[0265] Step 3: Preparation of (5-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophen-2-yl)dimethylphosphine oxide (Compound 2e)

[0266] At room temperature, 2,4-dichloro-6,7-dihydrothieno[3,2-d] (200 mg, 0.97 mmol), ((5-(aminomethyl)thiophen-2-yl)dimethylphosphine oxide hydrochloride 2d (crude product 200 mg, 0.81 mmol), and N,N-diisopropylethylamine (0.6 mL, 3.2 mmol) were mixed in ethanol (4 mL). In a microwave reactor, the reaction mixture was stirred at 85 °C for 2 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure. Subsequently, water (15 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 2). The combined organic phases were concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to give the title compound 2e (200 mg).

[0267] Step 4: Preparation of (R)-2-chloro-4-(((5-(dimethylphosphoryl)thiophen-2-yl)methyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 2f)

[0268] At room temperature, (5-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophen-2-yl)dimethylphosphine oxide 2e (200 mg, 0.56 mmol), S-1,1'-bi-2-naphthol (48 mg, 0.17 mmol), titanium(IV) isopropoxide (8 mg, 0.03 mmol), and water (10 mg, 0.56 mmol) were mixed in dichloromethane (5 mL). The mixture was stirred at room temperature for 1 hour. Subsequently, tert-butyl hydroperoxide (92 mg, 0.62 mmol) was added, and the reaction mixture was stirred at room temperature for 5 hours. After the reaction was completed, water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 2). The combined organic phases were concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to give the title compound 2f (120 mg).

[0269] Step 5: Preparation of ((R)-4-(((5-(Dimethylphosphoryl)thiophen-2-yl)methyl)amino)-2-(4-(oxazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 2))

[0270] Under nitrogen protection, compound (R)-2-chloro-4-(((5-(dimethylphosphoryl)thiophen-2-yl)methyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 2f (60 mg, 0.16 mmol), (4-(oxazol-2-yl)phenyl)boronic acid (65 mg, 0.24 mmol), potassium carbonate (66 mg, 0.48 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (12 mg, 0.016 mmol) were mixed in a 1,4-dioxane (5 mL) / water (1 mL) solution. The reaction mixture was stirred at 80 °C for 3 hours. Ethyl acetate (20 mL) was added to the reaction mixture. The organic phase was washed successively with saturated ammonium chloride (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to give the title compound 2 (4.8 mg, yield: 6.2%).

[0271] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.06 (t, J = 6.04 Hz, 1H) 8.61 (m, J = 8.51 Hz, 2H) 8.32 (s, 1H) 8.16 (m, J = 8.51 Hz, 2H) 7.48 (s, 1H) 7.45 (dd, J = 7.14, 3.57 Hz, 1H) 7.26 - 7.29 (m, 1H) 5.02 (d, J = 5.77 Hz, 2H) 3.69 - 3.77 (m, 1H) 3.50 (dt, J = 13.32, 7.58 Hz, 2H) 3.39 (brdd, J = 1.56, 0.73 Hz, 2H) 3.28 - 3.34 (m, 2H) 3.07 - 3.14 (m, 1H) 1.69 (s, 3H) 1.65 (s, 3H)

[0272] MS m / z (ESI): 485 [M + 1].

[0273] Example 3

[0274] (R)-4-(((4-(Dimethylphosphoryl)thiophen-2-yl)methyl)amino)-2-(4-(oxazol-2-yl)phenyl)-6,7-

[0275] dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 3)

[0276]

[0277] Step 1: Preparation of tert-butyl ((4-bromothiophen-2-yl)methyl)carbamate (Compound 3b)

[0278] At room temperature, di-tert-butyl dicarbonate (0.7 mL, 3.4 mmol) was added dropwise to a solution of (4-bromothiophen-2-yl)methanamine 3a (500 mg, 2.6 mmol) and pyridine (0.4 mL, 5.2 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was removed under reduced pressure. Subsequently, water (20 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 2). The combined organic phases were concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to give the title compound 3b (813 mg).

[0279] Step 2: Preparation of tert-butyl ((4-(dimethylphosphoryl)thiophen-2-yl)methyl)carbamate (Compound 3c)

[0280] Under nitrogen protection, tert-butyl ((4-bromothiophen-2-yl)methyl)carbamate 3b (813 mg, 2.8 mmol), dimethylphosphine oxide (239 mg, 3.1 mmol), potassium phosphate (650 mg, 3.1 mmol), bis(dibenzylideneacetone)palladium(0) (127 mg, 0.14 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (161 mg, 0.28 mmol) were mixed in 1,4-dioxane (10 mL solution). The reaction mixture was stirred at 100 °C for 12 hours. Ethyl acetate (30 mL) was added to the reaction mixture. The organic phase was washed successively with saturated ammonium chloride (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to give the title compound 3c (537 mg).

[0281] Step 3: Preparation of (5-(aminomethyl)thiophen-3-yl)dimethylphosphine oxide (Compound 3d)

[0282] At room temperature, a solution of hydrochloric acid in 1,4-dioxane (2 mL) was added dropwise to a solution of tert-butyl ((4-(dimethylphosphoryl)thiophen-2-yl)methyl)carbamate 3c (300 mg, 1.0 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent and excess hydrochloric acid solution were removed under reduced pressure to obtain a yellow oily crude product. This crude product, Compound 3d (322 mg, crude product), was used directly in the next step of the reaction without purification.

[0283] Step 4: Preparation of (5-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophen-3-yl)dimethylphosphine oxide (Compound 3e)

[0284] At room temperature, 2,4-dichloro-6,7-dihydrothieno[3,2-d] (257 mg, 1.2 mmol), (5-(aminomethyl)thiophen-3-yl)dimethylphosphine oxide (crude product, 1.2 mmol) and N,N-diisopropylethylamine (0.5 mL, 3.1 mmol) were mixed in ethanol (4 mL). In a microwave reactor, the reaction mixture was stirred at 85 °C for 2 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. Subsequently, water (15 mL) was added and the mixture was extracted with dichloromethane (15 mL × 2). The combined organic phases were concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to give the title compound 3e (535 mg).

[0285] Step 5: Preparation of (R)-2-chloro-4-(((4-(dimethylphosphoryl)thiophen-2-yl)methyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 3f)

[0286] At room temperature, compound (5-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophen-3-yl)dimethylphosphine oxide 3e (535 mg, 1.4 mmol), S-1,1'-bi-2-naphthol (85 mg, 0.24 mmol), titanium tetraisopropoxide (42 mg, 0.1 mmol) and water (40 mg, 2.2 mmol) were mixed in dichloromethane (5 mL). The mixture was stirred at room temperature for 1 hour. Subsequently, tert-butyl hydroperoxide (192 mg, 1.4 mmol) was added and the reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, water (10 mL) was added and the mixture was extracted with dichloromethane (20 mL × 2). The combined organic phases were concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to give the title compound 3f (440 mg).

[0287] Step 6: Preparation of (R)-4-(((4-(dimethylphosphoryl)thiophen-2-yl)methyl)amino)-2-(4-(oxazol-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 3)

[0288] Under nitrogen protection, compound (R)-2-chloro-4-(((4-(dimethylphosphoryl)thiophen-2-yl)methyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-5-oxide 3f (100 mg, 0.3 mmol), (4-(oxazol-2-yl)phenyl)boronic acid (142 mg, 0.4 mmol), potassium carbonate (92 mg, 0.5 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (19 mg, 0.03 mmol) were mixed in a 1,4-dioxane (5 mL) / water (1 mL) solution. The reaction mixture was stirred at 80 °C for 3 hours. Ethyl acetate (20 mL) was added to the reaction mixture. The organic phase was washed successively with saturated ammonium chloride (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to give the title compound 3 (31 mg, yield: 24%).

[0289] 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.05 (s, 1H) 8.61 (d, J = 8.06 Hz, 2H) 8.32 (s, 1H) 8.16 (d, J = 8.79 Hz, 2H) 7.89 (d, J = 7.32 Hz, 1H) 7.48 (s, 1H) 7.43 (d, J = 3.66 Hz, 1H) 4.97 (t, J = 4.76 Hz, 2H) 3.67 - 3.78 (m, 1H) 3.45 - 3.54 (m, 1H) 3.27 - 3.33 (m, 1H) 3.06 - 3.13 (m, 1H) 1.63 (d, J = 13.18 Hz, 6H)

[0290] MS m / z (ESI): 485 [M+1].

[0291] Biological evaluation

[0292] Test Example 1: Inhibitory effect of the compounds of the present disclosure on PDE4 enzyme

[0293] PDE4 enzyme can hydrolyze cAMP to produce AMP. We incubated a synthetic PDE4 enzyme inhibitor with PDE4 enzyme and substrate cAMP for a period of time, and detected it using the AMP-Glo TM Assay kit. The detection of this reagent is divided into two steps: one is to convert the generated AMP into ADP, and the other is to convert ADP into ATP. ATP binds to the reagent and emits fluorescence, and the fluorescence value is detected using an Echo 550. A graph is made using the fluorescence value to calculate the IC 50 of the PDE4 enzyme inhibitor. The specific content is as follows:

[0294] 1.1 Reagents and instruments

[0295] 1.1.1 Reagents

[0296] Material Name Manufacturer Product Number# PDE4B2 BPS bioscience 60042 Cyclic-3’,5’-AMP Sigma A6885 <![CDATA[AMP-Glo TM Assay kit]]> Promega V5011 Tris amresco T0497 BSA Perkin Elmer CR84-100 Magnesium chloride Sigma M1028 Tween-20 Solarbio T8220 DTT Invitrogen P2325 DMSO Sigma D8418

[0297] 1.1.2 Instruments

[0298]

[0299] 1.2 Experimental Procedures

[0300] 1.2.1 Preparation and Treatment of Compounds

[0301] a) Preparation of DMSO Stock Solutions of Compounds: All compounds were dissolved in DMSO to prepare stock solutions with a concentration of 10 mM.

[0302] b) Storage of Compounds: All compounds dissolved in DMSO were stored in a desiccator at room temperature for short-term storage.

[0303] 1.2.2 Preparation of Working Stock Solutions

[0304] a) The positive control AKEX0834 (the compound in Example 2 of WO2013026797A1) was serially diluted 3-fold with DMSO, starting from 100 μM and making a total of 10 concentrations.

[0305] b) The test compounds were serially diluted 3-fold with DMSO, starting from 100 μM and making a total of 10 concentrations.

[0306] c) Prepare 200X positive control (1 mM AKEX0834) and 200X solvent control (100% DMSO). Centrifuge the compound plate at 1000 rpm for 1 minute.

[0307] 1.2.3 Compound Screening

[0308] a) Use an Echo 550 to transfer 20 nL of the compound dilution to each well of the detection plate.

[0309] b) Seal the assay plate and centrifuge the compound plate at 1000 rpm for 1 minute.

[0310] c) Prepare 2X PDE4B2 or PDE4D2 in the frozen PDE assay buffer.

[0311] d) Add 2 μL of 2X PDE4B2 or PDE4D2 to a single well of the detection plate (prepared in step b).

[0312] e) Seal the detection plate and equilibrate at room temperature for 10 minutes.

[0313] f) Prepare 2X Cyclic-3′,5′-AMP in the PDE detection buffer.

[0314] g) Start the reaction by adding 2 μL of 2X Cyclic-3′,5′-AMP (prepared in step f) to each well of the detection plate (prepared in step e). Incubate at room temperature for 60 minutes.

[0315] h) Add 4 μL of AMP-Glo Reagent I and incubate at room temperature for 60 minutes.

[0316] i) Add 8 μL of AMP detection solution and incubate at room temperature for 60 minutes.

[0317] j) Read the RLU signal on an Envision 2105 plate reader.

[0318] 1.3 Data analysis

[0319] The calculation formula is as follows:

[0320] % Inhibition rate = {1 - (Average RLU of the compound - Average RLU of the positive control for the whole plate) / (Average RLU of the negative control for the whole plate - Average RLU of the positive control for the whole plate)}

[0321] Calculate the IC by fitting the % inhibition value and the logarithm of the compound concentration to a non-linear regression (dose response - variable slope) using Graphpad 8.0 50 .

[0322] Table 1 Inhibitory effect of the compounds of the present disclosure on PDE4 enzyme

[0323]

[0324]

[0325] Note: "-" indicates not tested.

[0326] Conclusion: The compounds of the present disclosure have a significant inhibitory effect on PDE4 enzyme.

[0327] It should be understood that the above embodiments are all exemplary and do not cover all possible implementation manners included in the claims. Without departing from the scope of the present disclosure, various deformations and changes can also be made on the basis of the above embodiments. Similarly, the various technical features of the above embodiments can also be arbitrarily combined to form additional embodiments of the present invention that may not be clearly described. Therefore, the above embodiments only represent several implementation manners of the present invention and do not limit the protection scope of the present invention patent.

Claims

1. A compound of formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts thereof: Wherein: L is selected from C 1-3 an alkylene group; Ring A is selected from cycloalkyl, aryl, heteroaryl, and heterocyclic group; R 1 Selected from a hydroxyl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocyclic group, wherein the substitution is by at least one R Het substitution; R 2 selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclic group, wherein the substitution is by at least one Q; R 3 Each occurrence is independently selected from hydrogen, deuterium, oxo, hydroxy, halogen, amino, cyano, alkyl, haloalkyl, alkoxy, and alkylhydroxy; R 4 、R 5 、R 6 and R 7 are the same or different and each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, alkyl, alkoxy and alkyl hydroxy; wherein said alkyl is optionally substituted with one or more substituents selected from halogen and hydroxy; R Het Selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, nitro, -(CR b R c ) t -COR a , oxo group and Q is selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, nitro, oxo group, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl; R a 、R b and R c each independently selected from hydrogen, deuterium, halogen, amino, hydroxy and alkyl; wherein said alkyl is optionally substituted by one or more substituents selected from halogen and hydroxy; n is 0, 1, 2, 3, 4, 5, or 6; t is 0, 1, or 2; provided that the compound of formula I is not 2. The compound of formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts thereof according to claim 1, wherein L is selected from methylene and ethylene; preferably methylene.

3. A compound of general formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein the R 4 is selected from hydrogen, deuterium, halogen and amino; preferably from hydrogen and halogen; more preferably from hydrogen.

4. A compound of general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts according to any one of claims 1-3, wherein the R 5 is selected from hydrogen, deuterium, halogen and amino; preferably from hydrogen and halogen; more preferably from hydrogen.

5. A compound of general formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein R 6 is selected from hydrogen, deuterium, halogen and amino; preferably from hydrogen and halogen; more preferably from hydrogen.

6. A compound of general formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein R 7 is selected from hydrogen, deuterium, halogen and amino; preferably from hydrogen and halogen; more preferably from hydrogen.

7. The compound of formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts thereof according to any one of claims 1-6, characterized in that it is a compound having the structure of formula I-1: Among them, A, R 1 , R 2 , R 3 , n is as defined in any one of claims 1 - 6.

8. A compound of general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts according to any one of claims 1-7, wherein ring A is selected from aryl and heteroaryl; preferably from C 6-10 aryl and 5- or 6-membered heteroaryl, said heteroaryl containing 1-4 heteroatoms selected from N and O; more preferably from phenyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl; most preferably from phenyl.

9. A compound of general formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein R 3 is selected from hydrogen, deuterium, oxo, hydroxy, and halogen; preferably from hydrogen and halogen; more preferably from hydrogen.

10. The compound of formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts thereof according to any one of claims 1-9, characterized in that it is a compound having the structure of formula I-2: Among them, R 1 and R 2 as defined in any one of claims 1-10.

11. A compound of general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts according to any one of claims 1-10, wherein R 2 is selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; preferably from substituted or unsubstituted C 6-10 aryl and substituted or unsubstituted 5- or 6-membered heteroaryl, said heteroaryl containing 1-4 heteroatoms selected from N and O; more preferably from phenyl, pyrazolyl, oxazolyl, imidazolyl and pyrrolyl; most preferably from oxazolyl.

12. The compound of formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts thereof according to any one of claims 1-11, wherein Q is selected from hydrogen, deuterium, halogen, hydroxyl, and amino; preferably hydrogen.

13. The compound of formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts thereof according to any one of claims 1-12, characterized in that it is a compound having the structure of formula I-3: Among them, R 1 As defined in any one of claims 1 - 12.

14. A compound of general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts according to any one of claims 1-11, wherein R 1 is selected from substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclic group; preferably from substituted or unsubstituted 5-14 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S; more preferably from substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S; particularly preferably from substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted triazolyl, Most preferably selected from substituted or unsubstituted thienyl, Wherein v is 0, 1, or 2.

15. A compound of general formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof according to any one of claims 1-14, wherein R Het is selected from hydrogen, deuterium, halogen, -COCH3, oxo, and is preferably selected from hydrogen, halogen, -COCH3, oxo, and is more preferably selected from hydrogen, -COCH3, and 16. A compound or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt, characterized in that, The compound is any one of the following:

17. A compound or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt, characterized in that, The compound is any one of the following:

18. A pharmaceutical composition comprising a therapeutically effective amount of the compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts thereof according to any one of claims 1 to 17.

19. Use of the compound of formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts thereof according to any one of claims 1 to 17 or the pharmaceutical composition according to claim 18 in the preparation of a drug for the treatment and / or prevention of diseases or disorders mediated by PDEs enzymes, preferably in the preparation of a drug for the treatment and / or prevention of diseases or disorders mediated by PDE4 enzyme, more preferably in the preparation of a drug for the treatment and / or prevention of diseases or disorders mediated by PDE4B enzyme.

20. The use according to claim 19, wherein the diseases or disorders are selected from respiratory diseases, pulmonary diseases, gastrointestinal diseases, inflammatory diseases, cancers, and peripheral or central nervous system diseases.

21. The use according to claim 20, wherein the respiratory and pulmonary diseases are selected from respiratory and pulmonary diseases accompanied by increased mucus production, obstructive pulmonary diseases, and airway diseases, preferably selected from COPD, asthma, interstitial lung disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, α1-antitrypsin deficiency, chronic rhinosinusitis, chronic bronchitis, and pulmonary arterial hypertension; the gastrointestinal diseases are selected from Crohn's disease, ulcerative colitis, and Crohn's disease; the inflammatory diseases are selected from proliferative and inflammatory skin diseases, arthritic diseases, and ocular inflammatory diseases; wherein the inflammatory skin diseases are preferably selected from atopic dermatitis, seborrheic dermatitis, contact dermatitis, epidermal inflammation, alopecia, alopecia areata, rosacea, SAPHO syndrome, skin atrophy, photoaging of the skin, acne vulgaris, hidradenitis suppurativa, urticaria, pruritus, hand eczema dermatitis, and psoriasis; the arthritic diseases are preferably selected from rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis; the ocular inflammatory diseases are preferably glaucoma or dry eye syndrome; the peripheral or central nervous system diseases are selected from Alzheimer's disease, age-associated memory impairment (AAMI), age-associated cognitive decline, vascular dementia, delirium, Parkinson's disease, Huntington's disease, Pick's disease, mental retardation, cerebrovascular diseases, depression, schizophrenia, stroke, neurofunctional disorders, attention deficit disorder, subdural hematoma, normal pressure hydrocephalus, brain tumor, stroke, cognitive impairment due to sleep deprivation, intellectual and developmental disabilities, and multiple sclerosis; the cancers are selected from leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, endometrial cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, kidney cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, small intestine cancer, gallbladder cancer, pediatric tumors, urothelial cancer, ureteral tumors, thyroid cancer, osteoma, neuroblastoma, brain tumor, and myeloma.

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