Macrocyclic compound as well as preparation method and application thereof

Abstract

The present disclosure relates to a compound represented by general formula I, or a stereoisomer, a solvate, a hydrate, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof, which has very high inhibitory activity and excellent selectivity on phosphodiesterase (PDEs), particularly on PDE4, meanwhile, the medicine effect, the solubility, the in-vitro / in-vivo pharmacokinetic property and the safety are excellent, and the clinical application prospect is high. # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to the field of medicine, and in particular to a macrocyclic compound and a preparation method thereof and use thereof as a phosphodiesterase (PDEs) inhibitor. 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 effects transmitted by these second messengers. cAMP and cGMP play an important regulatory role in cell activity. The regulation of their concentration is mainly determined by the balance between the synthesis of adenylate cyclase and the hydrolysis of phosphodiesterases (PDEs). PDEs are widely distributed in the human body, and their physiological effects involve multiple research fields.

[0003] Among the 11 phosphodiesterases that have been confirmed so far, PDE4, PDE7 and PDE8 are cAMP selective. The PDE4 family includes four subtypes (PDE4A, B, C and D) with more than 20 splice variants, making it one of the largest PDE subfamilies (Bender and Beavo, 2006). The above four subtypes are differentially expressed in different tissues and cell types, such as PDE4B is mainly expressed in monocytes and neutrophils, but not in cortical cells and epithelial cells, while PDE4D is expressed in the lungs, cortex, cerebellum and T cells (C. Kroegel and M. Foerster, Exp. Opinion Investig. Drugs, 16 (1), 2007, 109-124). PDE4B is mainly expressed when PDE4 enzyme hydrolyzes cAMP, and the substrate apparent K of cAMP is m1-5 μM. 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 inflammatory responses, it has been found that PDE4 regulates the inflammatory response of inflammatory cells by regulating proinflammatory cytokines such as TNFα, IL-2, IFN-γ, GM-CSF and LTB4. Therefore, inhibiting PDE4 becomes an attractive target for treating inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, atopic dermatitis, psoriasis, inflammatory bowel diseases such as Crohn's disease, etc. (MD Houslay et al, Drug Discovery Today, 2005, 10 (22), 1503-1519). Since the PDE activity of patients with atopic dermatitis (AD) increases, inhibiting PDE4 seems to be a feasible treatment for AD (Journal of Investigative Dermatology, 1986, 87 (3), 372-376). However, in clinical studies of PDE4 inhibitors that have been marketed, it was found that most drugs had a high incidence of gastrointestinal adverse reactions such as nausea and vomiting, which limited their clinical application. These adverse reactions are believed to be caused by the inhibition of PDE4D subtypes.

[0004] Therefore, there is an urgent need to develop highly selective PDE4B and / or PDE4D inhibitors with good activity, high safety, few side effects, and better pharmacokinetic properties. Summary of the invention

[0005] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts:

[0006]

[0007] in:

[0008] M is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by one or more R M replaced by;

[0009] R M Each occurrence is independently selected from H, D, halogen, hydroxy, amino, and alkyl;

[0010] At each occurrence, R 1 Each is independently selected from H, D, halogen, hydroxyl, amino and alkyl;

[0011] W is selected from a bond, O, a carbonyl group, an imino group, an amide group, a sulfone group, a sulfoxide group, Alkylene, cycloalkyl and aryl, the imino, amide, Alkylene, cycloalkyl and aryl are optionally substituted with one or more R W replaced by;

[0012] R W Each occurrence is independently selected from H, D, halogen, hydroxy, amino, and alkyl;

[0013] Y is selected from a bond, O, carbonyl, imino, amide, sulfone, sulfoxide, alkylene, -alkylene-O-, cycloalkyl and aryl, wherein the imino, amide, alkylene, -alkylene-O-, cycloalkyl and aryl are optionally substituted by one or more R Y replaced by;

[0014] R Y Each occurrence is independently selected from H, D, halogen, hydroxy, amino, and alkyl;

[0015] Z is selected from a bond, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more R Z replaced by;

[0016] R Z Each occurrence is independently selected from H, D, halogen, hydroxy, amino, and alkyl;

[0017] At each occurrence, R 2 and R 3 are the same or different and are each independently selected from H, D, halogen, hydroxyl, amino and alkyl;

[0018] or, at each occurrence, R 2 and R 3 and the atoms to which it is attached form a cycloalkyl group which is optionally substituted by D, halogen, hydroxyl or unsubstituted;

[0019] R 4 is selected from H, D, halogen, hydroxy, amino and alkyl;

[0020] m is 0 or 1;

[0021] n is 1, 2, 3 or 4;

[0022] p is 0, 1 or 2.

[0023] Effects of the Invention

[0024] The macrocyclic compound provided by the present disclosure has high inhibitory activity and excellent selectivity against PDE4B and PDE4D, and also has excellent pharmacodynamics, solubility, in vitro / in vivo pharmacokinetic properties and safety, and has high prospects for clinical application. DETAILED DESCRIPTION

[0025] To make the technical solutions and beneficial effects of the present disclosure more clearly understood, the following is a detailed description by listing specific embodiments. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which the present application belongs.

[0026] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts:

[0027]

[0028] in:

[0029] M is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by one or more R M replaced by;

[0030] R M Each occurrence is independently selected from H, D, halogen, hydroxy, amino, and alkyl;

[0031] At each occurrence, R 1 Each is independently selected from H, D, halogen, hydroxyl, amino and alkyl;

[0032] W is selected from a bond, O, a carbonyl group, an imino group, an amide group, a sulfone group, a sulfoxide group, Alkylene, cycloalkyl and aryl, the imino, amide, Alkylene, cycloalkyl and aryl are optionally substituted with one or more R W replaced by;

[0033] R W Each occurrence is independently selected from H, D, halogen, hydroxy, amino, and alkyl;

[0034] Y is selected from a bond, O, carbonyl, imino, amide, sulfone, sulfoxide, alkylene, -alkylene-O-, cycloalkyl and aryl, wherein the imino, amide, alkylene, -alkylene-O-, cycloalkyl and aryl are optionally substituted by one or more R Y replaced by;

[0035] R Y Each occurrence is independently selected from H, D, halogen, hydroxy, amino, and alkyl;

[0036] Z is selected from a bond, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more R Z replaced by;

[0037] RZ Each occurrence is independently selected from H, D, halogen, hydroxy, amino, and alkyl;

[0038] At each occurrence, R 2 and R 3 are the same or different and are each independently selected from H, D, halogen, hydroxyl, amino and alkyl;

[0039] or, at each occurrence, R 2 and R 3 and the atoms to which it is attached form a cycloalkyl group which is optionally substituted by D, halogen, hydroxyl or unsubstituted;

[0040] R 4 is selected from H, D, halogen, hydroxy, amino and alkyl;

[0041] m is 0 or 1;

[0042] n is 1, 2, 3 or 4;

[0043] p is 0, 1 or 2.

[0044] In certain embodiments, the M is selected from C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, the C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl are optionally substituted by one or more R M replaced.

[0045] In certain embodiments, the M is selected from C 3-6 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 The 4-9-membered heterocyclic group and the 5-10-membered heteroaryl group contain 1-4 heteroatoms selected from N, O and S, and the C 3-6 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R M replaced.

[0046] In certain embodiments, the M is selected from C 6-10 Aryl and 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-2 heteroatoms selected from N, the C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R M replaced.

[0047] In certain embodiments, M is selected from a benzene ring, a pyridyl group and The benzene ring, pyridyl and Optionally one or more R M replaced.

[0048] The present disclosure provides a compound represented by general formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by general formula II or general formula III:

[0049]

[0050] in:

[0051] R M Each occurrence is independently selected from H, D, halogen, hydroxy, amino, and alkyl;

[0052] At each occurrence, R 1 Each is independently selected from H, D, halogen, hydroxyl, amino and alkyl;

[0053] W is selected from a bond, O, a carbonyl group, an imino group, an amide group, a sulfone group, a sulfoxide group, Alkylene, cycloalkyl and aryl, the imino, amide, Alkylene, cycloalkyl and aryl are optionally substituted with one or more R W replaced by;

[0054] R W Each occurrence is independently selected from H, D, halogen, hydroxy, amino, and alkyl;

[0055] Y is selected from a bond, O, carbonyl, imino, amide, sulfone, sulfoxide, alkylene, -alkylene-O-, cycloalkyl and aryl, wherein the imino, amide, alkylene, -alkylene-O-, cycloalkyl and aryl are optionally substituted by one or more R Y replaced by;

[0056] R Y Each occurrence is independently selected from H, D, halogen, hydroxy, amino, and alkyl;

[0057] Z is selected from a bond, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more R Z replaced by;

[0058] R Z Each occurrence is independently selected from H, D, halogen, hydroxy, amino, and alkyl;

[0059] At each occurrence, R 2 and R 3 are the same or different and are each independently selected from H, D, halogen, hydroxyl, amino and alkyl;

[0060] or, at each occurrence, R 2 and R 3 and the atoms to which it is attached form a cycloalkyl group which is optionally substituted by D, halogen, hydroxyl or unsubstituted;

[0061] R 4 is selected from H, D, halogen, hydroxy, amino and alkyl;

[0062] m is 0 or 1;

[0063] n is 1, 2, 3 or 4;

[0064] p is 0, 1 or 2.

[0065] In certain embodiments, the R M Each occurrence is independently selected from H, D, halogen, hydroxy, amino and C 1-6 alkyl.

[0066] In certain embodiments, the R M Each occurrence is independently selected from H, D, halogen, hydroxy, amino and C 1-3 alkyl.

[0067] In certain embodiments, the R M Each occurrence is independently selected from H and halogen.

[0068] In certain embodiments, the R M Each occurrence is independently selected from H, F and Cl.

[0069] In certain embodiments, at each occurrence, the R 1 are each independently selected from H, D, halogen, hydroxyl, amino and C 1-6 alkyl.

[0070] In certain embodiments, at each occurrence, the R 1 are each independently selected from H, D, halogen, hydroxyl, amino and C 1-3 alkyl.

[0071] In certain embodiments, at each occurrence, the R 1 Each independently selected from H and C 1-3 alkyl.

[0072] In certain embodiments, at each occurrence, the R 1 are each independently selected from H and methyl.

[0073] In certain embodiments, W is selected from a bond, O, a carbonyl group, an imino group, an amide group, a sulfone group, a sulfoxide group, C1-6 Alkylene, C 3-8 Cycloalkyl and C 6-10 Aryl, the imino, amide, C 1-6 Alkylene, C 3-8 Cycloalkyl and C 6-10 The aryl group is optionally substituted with one or more R W replaced.

[0074] In certain embodiments, W is selected from a bond, O, a carbonyl group, an imino group, an amide group, a sulfone group, a sulfoxide group, C 1-3 Alkylene, C 3-5 Cycloalkyl and C 6-10 Aryl, the imino, amide, C 1-3 Alkylene, C 3-5 Cycloalkyl and C 6-10 The aryl group is optionally substituted with one or more R W replaced.

[0075] In certain embodiments, W is selected from O, amide, sulfone and The amide group and Optionally one or more R W replaced.

[0076] In certain embodiments, the R W Each occurrence is independently selected from H, D, halogen, hydroxy, amino and C 1-6 alkyl.

[0077] In certain embodiments, the R W Each occurrence is independently selected from H, D, halogen, hydroxy, amino and C 1-3 alkyl.

[0078] In certain embodiments, the R W Each occurrence is independently selected from H and C 1-3 alkyl.

[0079] In certain embodiments, the R W Each occurrence is independently selected from H and methyl.

[0080] In certain embodiments, Y is selected from a bond, O, a carbonyl group, an imino group, an amide group, a sulfone group, a sulfoxide group, a C 1-6 Alkylene, -C 1-6 Alkylene-O-, C 3-8 Cycloalkyl and C 6-10 Aryl, the imino, amide, C 1-6 Alkylene, -C1-6 Alkylene-O-, C 3-8 Cycloalkyl and C 6-10 The aryl group is optionally substituted with one or more R Y replaced.

[0081] In certain embodiments, Y is selected from a bond, O, a carbonyl group, an imino group, an amide group, a sulfone group, a sulfoxide group, a C 1-3 Alkylene, -C 1-3 Alkylene-O-, C 3-5 Cycloalkyl and C 6-10 Aryl, the imino, amide, C 1-3 Alkylene, -C 1-3 Alkylene-O-, C 3-5 Cycloalkyl and C 6-10 The aryl group is optionally substituted with one or more R Y replaced.

[0082] In certain embodiments, Y is selected from a bond, C 1-3 Alkylene and -C 1-3 Alkylene-O-, the C 1-3 Alkylene and -C 1-3 Alkylene-O- is optionally substituted with one or more R Y replaced.

[0083] In certain embodiments, Y is selected from a bond, methylene, ethylene, and -ethylene-O-, wherein the methylene, ethylene, and -ethylene-O- are optionally substituted by one or more R Y replaced.

[0084] In certain embodiments, the R Y Each occurrence is independently selected from H, D, halogen, hydroxy, amino and C 1-6 alkyl.

[0085] In certain embodiments, the R Y Each occurrence is independently selected from H, D, halogen, hydroxy, amino and C 1-3 alkyl.

[0086] In certain embodiments, the R Y Each occurrence is independently selected from H.

[0087] In certain embodiments, Z is selected from a bond, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, the C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl are optionally substituted by one or more R Zreplaced.

[0088] In certain embodiments, Z is selected from a bond, C 3-5 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10 The 4-8 membered heterocyclic group and the 5-8 membered heteroaryl group contain 1-4 heteroatoms selected from N, O and S, and the C 3-5 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10 Aryl and 5-8 membered heteroaryl are optionally substituted by one or more R Z replaced.

[0089] In certain embodiments, Z is selected from a bond, C 6-10 Aryl and 5-8 membered heteroaryl, wherein the 5-8 membered heteroaryl contains 1-2 heteroatoms selected from N, O or S, and the C 6-10 Aryl and 5-8 membered heteroaryl are optionally substituted by one or more R Z replaced.

[0090] In certain embodiments, Z is selected from a bond, a benzene ring, and a thienyl group, wherein the benzene ring and the thienyl group are optionally substituted by one or more R Z replaced.

[0091] In certain embodiments, the R Z Each occurrence is independently selected from H, D, halogen, hydroxy, amino and C 1-6 alkyl.

[0092] In certain embodiments, the R Z Each occurrence is independently selected from H, D, halogen, hydroxy, amino and C 1-3 alkyl.

[0093] In certain embodiments, the R Z Each occurrence is independently selected from H.

[0094] In certain embodiments, at each occurrence, the R 2 and R 3 are the same or different and are each independently selected from H, D, halogen, hydroxyl, amino and C 1-6 alkyl.

[0095] In certain embodiments, at each occurrence, the R 2 and R 3 are the same or different and are each independently selected from H, D, halogen, hydroxyl, amino and C 1-3 alkyl.

[0096] In certain embodiments, at each occurrence, the R 2 and R3 are the same or different and are each independently selected from H and C 1-3 alkyl.

[0097] In certain embodiments, at each occurrence, the R 2 and R 3 are the same or different and are each independently selected from H and methyl.

[0098] In certain embodiments, at each occurrence, the R 2 and R 3 and the atoms connected thereto form C optionally substituted or unsubstituted by D, halogen, hydroxyl 3-8 Cycloalkyl.

[0099] In certain embodiments, at each occurrence, the R 2 and R 3 and the atoms connected thereto form C optionally substituted or unsubstituted by D, halogen, hydroxyl 3-5 Cycloalkyl.

[0100] In certain embodiments, at each occurrence, the R 2 and R 3 and the atoms to which it is attached form a cyclopropyl group which may be optionally substituted by D, halogen, or hydroxy.

[0101] In certain embodiments, at each occurrence, the R 2 and R 3 and the atoms to which it is attached form an unsubstituted cyclopropyl

[0102] In certain embodiments, the R 4 Selected from H, D, halogen, hydroxyl, amino and C 1-6 alkyl.

[0103] In certain embodiments, the R 4 Selected from H, D, halogen, hydroxyl, amino and C 1-3 alkyl.

[0104] In certain embodiments, the R 4 Selected from H and C 1-3 alkyl.

[0105] In certain embodiments, the R 4 Selected from H and methyl.

[0106] 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:

[0107]

[0108]

[0109] 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:

[0110]

[0111] The present disclosure also provides a pharmaceutical composition, which contains a therapeutically effective amount of the aforementioned compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0112] In certain embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0113] In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of the aforementioned compound based on the total weight of the composition. 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.

[0114] In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable carrier, diluent or excipient, based on the total weight of the composition. 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.

[0115] All compounds involved in the present disclosure and mixtures and compositions containing the compounds of the present disclosure can be administered to 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, and local or systemic transdermal administration.

[0116] All compounds involved in the present disclosure and mixtures, compositions, etc. containing the compounds of the present disclosure can be formulated into a single dose, which contains the active compounds of the present disclosure and carriers, excipients, etc., and the dosage form 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 may contain ingredients commonly used in pharmaceutical preparations, such as diluents, absorbents, wetting agents, binders, disintegrants, colorants, pH adjusters, antioxidants, antibacterial agents, isotonicity adjusters, anti-adhesive agents, etc. In some embodiments, the single dose includes but is not limited to 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg of a compound of the present disclosure or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0117] Suitable formulations of the above-mentioned various dosage forms are available from public sources, such as Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins published in 2006 and Rowe, Raymond C. Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press published in 2005. Therefore, those skilled in the art can easily prepare.

[0118] Different dosages can be selected according to the nature and intensity of the disease suffered by different individuals, the age, sex, weight of the patient, the route of administration and other factors. The dosage of the compound disclosed herein can be 0.01 to 500 mg / kg per day, preferably 1-100 mg / kg per day, and can be administered once or multiple times. Examples of daily dosages include, but are not limited to, 0.01-500 mg, 0.01-400 mg, 0.01-300 mg, 0.01-200 mg, 0.01-100 mg, 0.01-50 mg, 0.1-500 mg, 0.1-400 mg, 0.1-300 mg, 0.1-200 mg, 0.1-100 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-2 00mg, 1-125mg, 1-100mg, 1-80mg, 1-60mg, 1-50mg, 1-40mg, 1-25mg, 1-20mg, 5-500mg, 5-400mg , 5-300mg, 5-250mg, 5-200mg, 5-150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5- 50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-200mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10- 40mg, 10-30mg, 10-20mg; 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-250mg, 20-200mg, 20-1 50mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg.

[0119] 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 compositions in the preparation of drugs for inhibiting PDEs enzymes.

[0120] The present disclosure also provides use of the aforementioned compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts or the aforementioned pharmaceutical compositions in the preparation of drugs for inhibiting PDE4 enzymes.

[0121] The present disclosure also provides use of the aforementioned compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts or the aforementioned pharmaceutical compositions in the preparation of drugs for inhibiting PDE4B enzyme and / or PDE4D enzyme.

[0122] 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 compositions in the preparation of drugs for treating and / or preventing diseases or conditions mediated by PDEs enzymes.

[0123] In certain embodiments, the disease or condition is selected from respiratory diseases, pulmonary diseases, gastrointestinal diseases, inflammatory diseases, cancer, and peripheral or central nervous system diseases.

[0124] In certain embodiments, the disease or condition is cancer, COPD, idiopathic pulmonary fibrosis, or interstitial lung disease.

[0125] The present disclosure also provides use of the aforementioned compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts or the aforementioned pharmaceutical compositions in the preparation of drugs for treating and / or preventing diseases or conditions mediated by PDE4 enzymes.

[0126] In certain embodiments, the disease or condition is selected from respiratory diseases, pulmonary diseases, gastrointestinal diseases, inflammatory diseases, cancer, and peripheral or central nervous system diseases.

[0127] In certain embodiments, the disease or condition is cancer, COPD, idiopathic pulmonary fibrosis, or interstitial lung disease.

[0128] 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 compositions in the preparation of drugs for treating and / or preventing diseases or conditions mediated by PDE4B enzymes and / or PDE4D enzymes.

[0129] In certain embodiments, the disease or condition is selected from respiratory diseases, pulmonary diseases, gastrointestinal diseases, inflammatory diseases, cancer, and peripheral or central nervous system diseases.

[0130] In certain embodiments, the disease or condition is cancer, COPD, idiopathic pulmonary fibrosis, or interstitial lung disease.

[0131] Terminology explanation:

[0132] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0133] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight 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 chain isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which 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, and the like. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0134] The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group, which is a residue derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, and is a straight or branched group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably 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-), and the like. The alkylene group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and oxo.

[0135] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above. Alkenyl can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from one or more substituents in alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0136] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein the definition of alkyl is as described above. Alkynyl can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from one or more substituents in alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0137] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, condensed, and bridged rings.

[0138] The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 yuan, a carbon atom (called spiral atom) shared between monocyclic rings, which may contain one or more double bonds. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0139]

[0140] The term "condensed cycloalkyl" refers to 5 to 20 yuan, and each ring in the system shares a pair of adjacent carbon atoms with other rings in the system. All carbon polycyclic groups, wherein one or more rings can contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (such as 7,8,9 or 10 yuan). According to the number of the composition ring, dicyclo, tricyclo, tetracycle or polycyclic condensed cycloalkyl can be divided, preferably dicyclo or tricyclo, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan of dicycloalkyl. The limiting examples of condensed cycloalkyl include:

[0141]

[0142] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, it is 6 to 14 members, and more preferably, it is 7 to 10 members (e.g., 7, 8, 9, or 10 members). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic, or tetracyclic, more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0143]

[0144] The cycloalkyl ring includes a cycloalkyl group as described above (including a monocyclic ring, a spirocyclic ring, a condensed ring and a bridged ring) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; preferred

[0145] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0146] The term "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), wherein 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, and when substituted, it is preferably one or more of the following groups, which are independently selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0147] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic cyclic substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxo-substituted (i.e. forming a sulfoxide or sulfone), but excluding the ring part of -OO-, -OS- or -SS-, 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, of which 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), of which 1-3 (e.g. 1, 2 and 3) are heteroatoms; more preferably, it contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

[0148] The term "spiro heterocyclic group" refers to a non-aromatic polycyclic heterocyclic group of 5 to 20 members, one atom (called spiral atom) shared between monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of spiral atoms shared between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. It is more preferably a 3-yuan / 5-yuan, 3-yuan / 6-yuan, 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 5-yuan or 5-yuan / 6-yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0149]

[0150] The term "fused heterocyclic radical" refers to a non-aromatic polycyclic heterocyclic group of 5 to 20 yuan, each ring in the system shares a pair of atoms adjacent to other rings in the system, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 yuan, and more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic radical, preferably a bicyclic or tricyclic, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan bicyclic fused heterocyclic radical. Non-limiting examples of fused heterocyclic radicals include:

[0151]

[0152] The term "bridged heterocyclic group" refers to a non-aromatic polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming 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 bridged heterocyclic groups include:

[0153]

[0154] The heterocyclic ring includes a heterocyclic group as described above (including a monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

[0155] wait.

[0156] The heterocyclyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0157] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and its non-limiting examples include:

[0158]

[0159]

[0160] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0161] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9, or 10 yuan), more preferably 5 yuan or 6 yuan, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

[0162]

[0163] The heteroaryl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents preferably being independently selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0164] The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same or two different ring atoms of the parent by removing two hydrogen atoms, i.e., "divalent cycloalkyl", "divalent heterocyclic", "arylene" and "heteroarylene".

[0165] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0166] The term "hydroxy" refers to -OH.

[0167] The term "amino" refers to -NH2.

[0168] The term "imino" refers to -NH-.

[0169] The term "oxo" or "oxo" refers to "=0".

[0170] The term "carbonyl" refers to C=O.

[0171] The term "sulfone" refers to -SO2-.

[0172] The term "sulfoxide" refers to -SO-.

[0173] The term "amido" refers to -NH-CO-.

[0174] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or include both Two configurations. Key Can be Although all the above structural formulas are drawn as certain isomers for the sake of simplicity, the present disclosure may include all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates and enantiomers. In the chemical structures of the compounds described in the present disclosure, the bonds No configuration is specified, i.e., the bond The configuration can be E-type or Z-type, or include both E and Z configurations.

[0175] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0176] "Substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently by a corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) 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.

[0177] The term "stereoisomers" refers to compounds that have identical chemical constitution, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric (cis / trans) isomers, atropisomers, and the like.

[0178] The term "solvate" refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. The physical association includes hydrogen bonding. In some 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.

[0179] The term "hydrate" refers to the case where the solvent in the above-mentioned term "solvate" is water.

[0180] The term "prodrug" refers to a compound that can be transformed in vivo under physiological conditions, for example by hydrolysis in the blood, to yield the active prodrug.

[0181] The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, a compound having a structure disclosed herein with "deuterium" or "tritium" replacing hydrogen, or with 18 F-fluorine labeling ( 18 F isotope) instead of fluorine, or with 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14Compounds in which a carbon atom is replaced by a C-isotope) are within the scope of the present disclosure. Such compounds can be used as analytical tools or probes in, for example, biological assays, or can be used as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics or receptor studies. The various deuterated forms of the compounds disclosed herein refer to compounds in which 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 compounds with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing deuterated forms of compounds, or they can be synthesized using deuterated reagents using conventional techniques, and deuterated reagents include but are not limited to deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Deuterated substances can generally retain activity comparable to undeuterated compounds, and when deuterated at certain specific sites, better metabolic stability can be achieved, thereby obtaining certain therapeutic advantages.

[0182] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0183] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts of the disclosed compounds that are safe and effective for use in mammals and have the desired biological activity. Salts can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, as well as organic bases. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0184] 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 a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0185] The term "carrier" refers to a system that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug and deliver the drug to the targeted organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0186] The term "excipient" refers to a substance that is not a therapeutic agent in itself but is used as a diluent, adjuvant, binder and / or vehicle that is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration. As known to those skilled in the art, pharmaceutical excipients can serve a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose and cross-linked carboxymethylcellulose (e.g., cross-linked sodium carboxymethylcellulose); (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other nontoxic compatible substances used in pharmaceutical preparations.

[0187] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0188] The terms involved in the present disclosure are defined above. Those skilled in the art can also understand the above terms in combination with the prior art. The following is a further description based on the content of the present disclosure and the definitions of the terms.

[0189] 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 are not intended to limit the scope of the present disclosure.

[0190] The experimental methods in the examples of this disclosure that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by raw material or product manufacturers. Reagents that do not specify specific sources are conventional reagents purchased from the market.

[0191] The following describes the general test conditions in the embodiments of the present disclosure:

[0192] First, the reactions in the examples are generally carried out under nitrogen protection.

[0193] Furthermore, the intermediates and final products were separated and purified by chromatographic columns, preparative chromatographic plates and ISCO rapid preparative chromatographic system. The chromatographic columns were filled with silica gel, the silica gel (300-400 mesh) was produced by Shanghai Titan Technology Co., Ltd., the preparative chromatographic plates were produced by Yantai Jiangyou Silica Gel Development Co., Ltd., and the chromatographic columns used by ISCO (particle size 40-63 μm, ) is produced by Changzhou Santai Technology Co., Ltd.

[0194] Furthermore, the LC-MS liquid chromatography-mass spectrometry instrument used was Waters ACQUITYArc equipped with QDa Detector. A Waters XBridge C18 chromatographic column (specifications 2.1×50 mm, 3.5 μm) was used. The mass spectrometry (MS) used an ESI source and only indicated the molecular weight M of the parent molecule, usually reporting [M+H] + The injection volume was determined by the sample concentration; the flow rate was 1.2 mL / min; the HPLC peak was recorded and read at UV-Vis wavelengths of 220 nm and 254 nm. The mobile phases were 0.01% formic acid in ultrapure water (mobile phase A) and 0.01% formic acid in acetonitrile (mobile phase B). The gradient elution conditions are shown in Tables 1 and 2 below:

[0195] Table 1: Gradient elution conditions 1

[0196]

[0197]

[0198] Table 2: Gradient elution conditions 2

[0199] 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

[0200] Further, NMR spectra were obtained using a Varian 400 MHz nuclear magnetic resonance spectrometer, often using CDCl3, DMSO-d6 as solvents, and chemical shifts were reported in ppm. The descriptions of the various peaks are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets). Coupling constants are expressed in Hz.

[0201] Example

[0202] Example 1

[0203] (R)-2 6 ,2 7-Dihydro-11-oxa-3,7-diaza-2(2,4)-thieno[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocycloundecane-6-one 25-oxide (Compound 1)

[0204]

[0205] Step 1: Preparation of tert-butyl (3-(3-bromophenoxy)propyl)carbamate (Compound 1b)

[0206] Compound 1a (500 mg, 2.89 mmol), tert-butyl (3-bromopropyl)carbamate (822 mg, 3.47 mmol) and potassium carbonate (800 mg, 5.78 mmol) were dissolved in N, N-dimethylformamide (15 mL), and the mixture was heated to 60 ° C and stirred for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate (EA, 50 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 1b (650 mg).

[0207] Step 2: Preparation of (3-((tert-butyloxycarbonyl)amino)propoxy)phenyl)boronic acid (Compound 1c)

[0208] Under N2 atmosphere, compound 1b (650mg, 1.98mmol), bis-pinacol borate (753mg, 2.96mmol), potassium acetate (581mg, 5.94mmol) and Pd(dppf)Cl2 (145mg, 0.20mmol) were dissolved in 1.4-dioxane (18mL). The reaction mixture was stirred at 85°C for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated and diluted with EA (100mL). The mixture was then washed with brine (50mL), dried and concentrated to give crude compound 1c (900mg).

[0209] Step 3: Preparation of methyl 2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (1e)

[0210] Compound 1d (0.5 g, 2.43 mmol), methyl 2-(4-aminophenyl)acetate (601 mg, 3.64 mmol) and N,N-diisopropylethylamine (DIEA, 0.94 g, 7.29 mmol) were dissolved in ethanol (10 mL), and the mixture was heated to 85 ° C and stirred for 3 hours. The reaction mixture was poured into water and extracted with EA (50 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 1e (600 mg).

[0211] Step 4: Preparation of methyl 2-(4-((2-(3-((tert-butyloxycarbonyl)amino)propoxy)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (Compound 1f)

[0212] Under N2 atmosphere, compound 1e (280 mg, 0.84 mmol), 1c (370 mg, 1.25 mmol), K2CO3 (350 mg, 2.52 mmol) and Pd(dppf)Cl2 (61 mg, 0.084 mmol) were dissolved in 1.4-dioxane (8 mL) and H2O (2 mL). The reaction mixture was stirred at 85 °C for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated and diluted with EA (100 mL). The mixture was then washed with brine (50 mL), dried and concentrated to give a crude product. The crude product was purified by flash column chromatography to give the title compound 1f (0.15 g).

[0213] Step 5: Preparation of 2-(4-((2-(3-((tert-butyloxycarbonyl)amino)propoxy)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 1g)

[0214] To a solution of compound 1f (150 mg, 0.27 mmol) in methanol (5 mL) and water (1 mL) was added lithium hydroxide (35 mg, 0.82 mmol), and the reaction mixture was stirred at 20 °C for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated and diluted with EA (100 mL). The mixture was then washed with brine (50 mL), dried and concentrated to give a crude compound 1g (150 mg). Step 6: Preparation of 2-(4-((2-(3-aminopropoxy)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (compound 1h)

[0215] Dichloromethane (5 mL) and trifluoroacetic acid (1 mL) were added to compound 1g (150 mg, 0.27 mmol), and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by flash column chromatography to give the title compound 1h (130 mg).

[0216] Step 7: 2 6 ,2 7 Preparation of dihydro-11-oxa-3,7-diaza-2(2,4-)-thieno[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocycloundecane-6-one (Compound 1i)

[0217] Compound 1h (130 mg, 0.27 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (133 mg, 0.35 mmol), and triethylamine (105 mg, 0.81 mmol) were dissolved in dichloromethane (DCM, 100 mL), and the reaction mixture was heated to 25°C and stirred for 5 hours. The reaction mixture was poured into water and extracted with DCM (50 mL×2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 1i (0.12 g). Step 8: (R)-2 6 ,2 7 Preparation of dihydro-11-oxa-3,7-diaza-2(2,4)-thieno[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocycloundecane-6-one 25-oxide (Compound 1)

[0218] Compound 1i (120 mg, 0.29 mmol), S-(-)-binaphthol (25 mg, 0.083 mmol), DCM (5 mL), Ti(OiPr)4 (4.5 mg, 0.015 mmol) and water (5.3 mg, 0.29 mmol) were placed in a multi-necked flask under nitrogen at 20°C and stirred for 1 hour; the mixture became completely homogeneous, and tert-butyl peroxide (33 mg, 0.32 mmol) was added, and the temperature was raised to about 30°C, and the mixture was allowed to reach normal room temperature and stirred for 1.5 hours; the reaction mixture was poured into water and extracted with DCM (50 ml × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 1 (7 mg).

[0219] 1 H NMR(400MHz,DMSO-d6)δppm 10.32(s,1H)8.11(t,J=5.17Hz,1H)7.98(d,J=7.69Hz,1H)7.66(s,1H)7.41-7.45(m,2H)7.34-7.40 (m,3H)7.02(dd,J=8.10,1.88Hz,1H)3.62-3.83(m,3H)3.37-3.53(m,5H)3.25-3.34(m,2H)3.16(br dd,J=13.87,5.63Hz,1H)1.98-2.09(m,2H)

[0220] MS m / z(ESI):435[M+1].

[0221] Example 2

[0222] (R, Z)-26,27-dihydro-11-oxa-3,7-diaza-2(2,4-)-thieno[3,2-d]pyrimidin-5(2,4-)thiophene-1(1,3)-benzocycloundecane-6-one 25-oxide (Compound 2)

[0223]

[0224] Step 1: Preparation of methyl 5-(((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylate (2b)

[0225] Compound 1d (0.5 g, 2.4 mmol), 5-(aminomethyl)thiophene-3-carboxylic acid methyl ester (492 mg, 2.88 mmol) and DIEA (0.94 g, 7.29 mmol) were dissolved in ethanol (10 mL), and the mixture was heated to 85 ° C and stirred for 3 hours. The reaction mixture was poured into water and extracted with EA (50 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 2b (600 mg).

[0226] Step 2: Preparation of methyl 5-(((2-(3-((tert-butyloxycarbonyl)amino)propoxy)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylate (Compound 2c)

[0227] Under N2 atmosphere, compound 2b (300 mg, 0.88 mmol), 1c (370 mg, 1.25 mmol), K2CO3 (242 mg, 1.7 mmol) and Pd(dppf)Cl2 (61 mg, 0.084 mmol) were dissolved in 1.4-dioxane (8 mL) and H2O (2 mL). The reaction mixture was stirred at 85 °C for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated and diluted with EA (100 mL). The mixture was then washed with brine (50 mL), dried and concentrated to give a crude product. The crude product was purified by flash column chromatography to give the title compound 2c (280 mg).

[0228] Step 3: Preparation of 5-(((2-(3-((tert-butyloxycarbonyl)amino)propoxy)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (Compound 2d)

[0229] To a solution of compound 2c (200 mg, 0.36 mmol) in methanol (5 mL) and water (1 mL) was added lithium hydroxide (45 mg, 1.1 mmol), and the reaction mixture was stirred at 20 °C for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated and diluted with EA (100 mL). The mixture was then washed with brine (50 mL), dried and concentrated to give a crude compound 2d (200 mg). Step 4: Preparation of 5-(((2-(3-aminopropoxy)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)methyl)thiophene-3-carboxylic acid (compound 2e)

[0230] Dichloromethane (5 mL) and trifluoroacetic acid (1 mL) were added to compound 2d (200 mg, 0.37 mmol), and the mixture was stirred at room temperature for 2 hours, and then the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography to give the title compound 2e (170 mg).

[0231] Step 5: Preparation of (Z)-26,27-dihydro-11-oxa-3,7-diaza-2(2,4-)-thieno[3,2-d]pyrimidin-5(2,4-)thiophene-1(1,3)-benzocycloundecane-6-one (Compound 2f)

[0232] Compound 2e (100 mg, 0.23 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (133 mg, 0.35 mmol), triethylamine (105 mg, 0.81 mmol) were dissolved in DCM (100 mL), and the reaction mixture was heated to 25 ° C and stirred for 5 hours. The reaction mixture was poured into water and extracted with DCM (50 mL×2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 2f (70 mg).

[0233] Step 6: Preparation of (R, Z)-26,27-dihydro-11-oxa-3,7-diaza-2(2,4-)-thieno[3,2-d]pyrimidine-5(2,4-)thiophene-1(1,3)-benzocycloundecane-6-one 25-oxide (Compound 2)

[0234] Compound 2f (70 mg, 0.16 mmol), S-(-)-binaphthol (9 mg, 0.03 mmol), DCM (5 mL), Ti(OiPr)4 (4.5 mg, 0.015 mmol) and water (5.3 mg, 0.29 mmol) were placed in a multi-necked flask under nitrogen at 20°C and stirred for 1 hour; the mixture became completely homogeneous, and tert-butyl peroxide (26 mg, 0.2 mmol) was added and the temperature was raised to about 30°C, and the mixture was allowed to reach normal room temperature and stirred for 1.5 hours. The reaction mixture was poured into water and extracted with DCM (50 ml × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 2 (30 mg).

[0235] 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.95(t,J=4.90Hz,1H),8.05(t,J=5.13Hz,1H),7.90(s,1H),7.85(d,J=1.2 8Hz,1H),7.76(d,J=8.15Hz,1H),7.60-7.64(m,1H),7.39(t,J=7.92Hz,1H) ,7.33(s,1H),7.20(s,1H),4.73(d,J=4.94Hz,2H),4.21(t,J=4.94Hz,2H), 3.60-3.71(m,1H),3.41-3.54(m,4H),3.04-3.28(m,2H),2.01-2.09(m,2H),

[0236] MS m / z(ESI):441.5[M+1].

[0237] Example 3

[0238] (2 5 R, 8S)-3,8-dimethyl-2 6 ,2 7 -Dihydro-11-oxa-3,7-diaza-2(2,4-)-thieno[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocycloundecane-6-one 25-oxide (Compound 3)

[0239]

[0240]

[0241] Step 1: Preparation of tert-butyl (S)-(4-(3-bromophenoxy)butan-2-yl)carbamate (Compound 3b)

[0242] Compound 3a (600 mg, 3.52 mmol), (S)-(4-hydroxybutyl-2-yl)carbamic acid tert-butyl ester (1 g, 5.29 mmol), diisopropyl azodicarboxylate (DIAD, 783 mg, 3.87 mmol) and triphenylphosphine (1.02 g, 3.87 mmol) were dissolved in tetrahydrofuran (50 mL), and the mixture was heated to 20 ° C and stirred for 3 hours. The reaction mixture was poured into water and extracted with EA (200 mL × 2). The organic phases were combined and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography to give the title compound 3b (1.3 g).

[0243] Step 2: Preparation of (S)-(3-(3-(tert-butyloxycarbonyl)amino)butoxy)phenyl)boronic acid (Compound 3c)

[0244] Under N2 atmosphere, compound 3b (1.3 g, 3.79 mmol), bis-pinacol borate (1.44 g, 5.68 mmol), potassium acetate (1.11 g, 11.36 mmol) and Pd(dppf)Cl2 (278 mg, 0.38 mmol) were dissolved in 1.4-dioxane (18 mL), and the title compound 3c (1.5 g) was prepared according to the method of the second step of Example 1.

[0245] Step 3: Preparation of methyl 2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (3e)

[0246] Compound 1d (0.69 g, 3.35 mmol), methyl 2-(4-(methylamino)phenyl)acetate (500 mg, 2.79 mmol) and DIEA (1.04 g, 8.37 mmol) were dissolved in ethanol (10 mL) and the title compound 3e (0.6 g) was prepared according to the method of the third step of Example 1.

[0247] Step 4: Preparation of (S)-methyl 2-(4-((2-(3-((tert-butyloxycarbonyl)amino)butoxy)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(methyl)amino)phenyl)acetate (Compound 3f)

[0248] Under N2 atmosphere, compounds 3e (400 mg, 1.15 mmol), 3c (676 mg, 2.30 mmol), K2CO3 (477 mg, 3.45 mmol) and Pd(dppf)Cl2 (88 mg, 0.12 mmol) were dissolved in 1.4-dioxane (8 mL) and H2O (2 mL), and the title compound 3f (0.4 g) was prepared according to the method of the fourth step of Example 1.

[0249] Step 5: Preparation of (S)-2-(4-((2-(3-((tert-butyloxycarbonyl)amino)butoxy)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(methyl)amino)phenyl)acetic acid (Compound 3g)

[0250] To a solution of compound 3f (400 mg, 0.69 mmol) in methanol (10 mL) and water (2 mL) was added lithium hydroxide (87 mg, 0.82 mmol), and the title compound 3g (0.38 g) was prepared according to the method of step 5 of Example 1.

[0251] Step 6: Preparation of (S)-2-(4-((2-(3-aminobutoxy)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(methyl)amino)phenyl)acetic acid (Compound 3h)

[0252] Dichloromethane (5 mL) and trifluoroacetic acid (1 mL) were added to compound 3g (380 mg, 0.67 mmol), and the title compound 3h (0.26 g) was prepared according to the method of step 6 of Example 1.

[0253] Step 7: (S)-3,8-dimethyl-2 6 ,2 7 Preparation of dihydro-11-oxa-3,7-diaza-2(2,4-)-thieno[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocycloundecane-6-one (Compound 3i)

[0254] Compound 3h (213 mg, 0.43 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (213 mg, 0.56 mmol) and triethylamine (134 mg, 1.29 mmol) were dissolved in DCM (100 mL) and the title compound 3i (0.20 g) was prepared according to the method of step 7 of Example 1.

[0255] Step 8: (2 5 R, 8S)-3,8-dimethyl-2 6 ,2 7 Preparation of dihydro-11-oxa-3,7-diaza-2(2,4-)-thieno[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocycloundecane-6-one 25-oxide (Compound 3)

[0256] Compound 3i (200 mg, 0.45 mmol), S-(-)-binaphthol (36 mg, 0.13 mmol), DCM (10 mL), Ti(OiPr)4 (7 mg, 0.023 mmol) and water (8 mg, 0.45 mmol) were placed in a multi-necked flask under nitrogen at 20°C and stirred for 1 hour; the mixture became completely homogeneous, and tert-butyl peroxide (52 mg, 0.50 mmol) was added, and the temperature was raised to about 30°C, and the mixture was allowed to reach normal room temperature and stirred for 1.5 hours; the reaction mixture was poured into water and extracted with DCM (50 ml × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 3 (30 mg).

[0257] 1 H NMR (400MHz, DMSO-d6) δppm 8.11 (dd, J=11.95, 8.74Hz, 1H) 8.00 (dd, J=7.64, 4.35Hz, 1H) 7.46-7.54 (m, 2H) 7.30-7.39 (m, 3H) 7.22-7.25 (m, 1H) 6.97 (br d,J=8.06Hz,1H)3.92-4.02(m,1H)3.89(s,3H)3.71-3.84(m,2H)3.35-3.54(m,4H)3.23-3.33(m,3H)1.88-1.97(m,2H)1.18(d,J=6.50Hz,3H)

[0258] MS m / z(ESI):463[M+1].

[0259] Example 4

[0260] (2 5 R, 8S)-3,8-dimethyl-2 6 ,2 7 -Dihydro-11-oxa-3,7-diaza-2(2,4-)-thieno[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocycloundecane-6-one 25-oxide (Compound 4)

[0261]

[0262] Step 1: Preparation of (S)-2-(4-((2-(3-((tert-butyloxycarbonyl)amino)butoxy)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (Compound 4b)

[0263] Under N2 atmosphere, compound 1e (400 mg, 1.19 mmol), 3c (554 mg, 1.79 mmol), K2CO3 (495 mg, 3.57 mmol) and Pd(dppf)Cl2 (87 mg, 0.12 mmol) were dissolved in 1.4-dioxane (8 mL) and H2O (2 mL), and the title compound 4b (0.52 g) was prepared according to the method of the fourth step of Example 1.

[0264] Step 2: Preparation of (S)-(3-(3-(tert-butyloxycarbonyl)amino)butoxy)phenyl)boronic acid (Compound 4c)

[0265] To a solution of compound 4b (520 mg, 0.92 mmol) in methanol (10 mL) and water (2 mL) was added lithium hydroxide (116 mg, 2.76 mmol) and the title compound 4c (0.35 g) was prepared according to the method of step 5 of Example 1.

[0266] Step 3: Preparation of (S)-2-(4-((2-(3-aminobutoxy)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (4d)

[0267] Dichloromethane (5 mL) and trifluoroacetic acid (1 mL) were added to compound 3g (0.35 g, 0.78 mmol), and the title compound 4d (0.26 g) was prepared according to the method of step 6 of Example 1.

[0268] Step 4: (S)-8-methyl-2 6 ,2 7 Preparation of dihydro-11-oxa-3,7-diaza-2(2,4-)-thieno[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocycloundecane-6-one (Compound 4e)

[0269] Compound 4d (200 mg, 0.41 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (203 mg, 0.54 mmol) and triethylamine (128 mg, 1.23 mmol) were dissolved in DCM (100 mL) and the title compound 4e (0.13 g) was prepared according to the method of step 7 of Example 1.

[0270] Step 5: (2 5 R, 8S)-3,8-dimethyl-2 6 ,2 7Preparation of dihydro-11-oxa-3,7-diaza-2(2,4-)-thieno[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocycloundecane-6-one 25-oxide (Compound 4)

[0271] Compound 4e (130 mg, 0.30 mmol), S-(-)-binaphthol (26 mg, 0.09 mmol), DCM (10 mL), Ti(OiPr)4 (5 mg, 0.019 mmol) and water (6 mg, 0.30 mmol) were placed in a multi-necked flask under nitrogen at 20°C and stirred for 1 hour; the mixture became completely homogeneous, and the temperature rose to about 30°C after the addition of tert-butyl peroxide (35 mg, 0.33 mmol). The mixture was allowed to reach normal room temperature and stirred for 1.5 hours; the reaction mixture was poured into water and extracted with DCM (50 ml×2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 4 (76 mg).

[0272] 1 H NMR (400MHz, DMSO-d6) δppm 10.31-10.35 (m, 1H) 8.13-8.22 (m, 1H) 8.00 (d, J = 7.60Hz, 1H) 7.64-7.68 (m, 1H) 7.44 (br s,1H)7.38(t,J=7.92Hz,1H)7.03(dd,J=8.10,1.97Hz,1H)3.88-4.08(m,2H)3.62-3.81(m,2H)3.42-3.55(m,2H)3.38(br s,1H)3.13-3.35(m,4H)1.91-2.06(m,2H)1.26-1.33(m,2H)1.18(d,J=6.50Hz,3H)

[0273] MS m / z(ESI):449[M+1].

[0274] Example 5

[0275] (R)-1 4 -fluoro-3,8-dimethyl-2 6 ,2 7 -Dihydro-11-oxa-3,8-diaza-2(2,4-)-thieno[3,2-d]pyrimidin-1(1,3),4(1,4)-dibenzocycloundecane-7-one 5 -oxide (Compound 5)

[0276]

[0277] Step 1: Preparation of methyl 3-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(methyl)amino)phenyl)propanoate (Compound 5b)

[0278] Compound 5a (1.00 g, 4.83 mmol), methyl 3-(4-(methylamino)phenyl)propionate (932.19 mg, 4.83 mmol) and DIEA (1.87 g, 14.49 mmol) were dissolved in ethanol (10 mL), and the mixture was heated to 85 ° C and stirred for 3 hours under microwave conditions. The reaction mixture was poured into water and extracted with EA (50 mL×2). The organic phases were combined and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography to give the title compound 5b (1.00 g).

[0279] Step 2: Preparation of methyl 3-(4-((2-(3-(2-((tert-butyloxycarbonyl)(methyl)amino)ethoxy)-4-fluorophenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(methyl)amino)phenyl)propanoate (Compound 5c)

[0280] Under N2 atmosphere, compound 5b (500.00 mg, 1.37 mmol), (3-(2-((tert-butyloxycarbonyl)(methyl)amino)ethoxy)-4-fluorophenyl)boric acid (428.81 mg, 1.37 mmol), K2CO3 (567.18 mg, 4.11 mmol) and Pd(dppf)Cl2 (99.42 mg, 0.14 mmol) were dissolved in 1.4-dioxane (8 mL) and H2O (2 mL). The reaction mixture was stirred at 85°C for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated and diluted with EA (100 mL). The mixture was then washed with brine (50 mL), dried and concentrated to give a crude product. The crude product was purified by flash column chromatography to give the title compound 5c (0.45 g).

[0281] Step 3: Preparation of methyl (3-(4-(2-(4-fluoro-3-(2-(methylamino)ethoxy)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(methyl)amino)phenyl)propanoate (Compound 5d)

[0282] Compound 5c (450.00 mg, 0.755 mmol) was dissolved in dichloromethane (3 mL), and dioxane hydrochloride (3 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours, and then concentrated directly to obtain a crude product of the title compound 5d (0.38 g).

[0283] Step 4: Preparation of 3-(4-(2-(4-fluoro-3-(2-(methylamino)ethoxy)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(methyl)amino)phenyl)propanoic acid (Compound 5e)

[0284] Compound 5d (380 mg, 0.755 mmol) was dissolved in a mixed solvent of methanol:tetrahydrofuran:water (3 mL:3 mL:1 mL), LiOH.H2O (126.84 mg, 3.02 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Dilute hydrochloric acid (1 M) was added dropwise to adjust to acidity. Solid precipitated and was filtered to give the title compound 5e (0.20 g).

[0285] Step 5: 1 4 -fluoro-3,8-dimethyl-2 6 ,2 7 Preparation of dihydro-11-oxa-3,8-diaza-2(2,4-)-thieno[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocycloundecane-7-one (Compound 5f)

[0286] Compound 5e (200.00 mg, 0.41 mmol), HATU (233.7 mg, 0.61 mmol) and DIEA (159.9 mg, 1.23 mmol) were dissolved in DCM (20 mL), and the mixture was heated to 25 ° C and stirred for 10 hours. The reaction mixture was poured into water and extracted with DCM (50 mL×2). The organic phases were combined and concentrated under reduced pressure and column chromatography to give the title compound 5f (0.08 g).

[0287] Step 6: ((R)-1 4 -fluoro-3,8-dimethyl-2 6 ,2 7 -Dihydro-11-oxa-3,8-diaza-2(2,4-)-thieno[3,2-d]pyrimidin-1(1,3),4(1,4)-dibenzocycloundecane-7-one 5 - Preparation of oxide (Compound 5)

[0288] Compound 5f (80 mg, 0.17 mmol), S-(-)-binaphthol (4.57 mg, 0.016 mmol), DCM (3 mL), Ti(OiPr)4 (2.27 mg, 0.008 mmol) and water (2.88 mg, 0.17 mmol) were placed in a multi-necked flask under nitrogen at 20 ° C and stirred for 3 hours. The reaction mixture was poured into water and extracted with DCM (50 ml × 2). The organic phases were combined and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography to give the title compound 5 (10.00 mg).

[0289] 1 H NMR (400MHz, DMSO-d6, 24℃) δppm 7.43 (br s, 1H) 7.39 (m, 1H) 7.27 (m, 1H) 7.18 (m, 2H) 7.03 (m, 2H) 4.2 (m, 2H) 3.53-3.56 (m, 2H) 2.94-3.31 (br s,6H)2.89-2.9(br s,4H)2.51-2.71(br s,4H)

[0290] MS m / z(ESI):481[M+1].

[0291] Example 6

[0292] (R)-1 4 -Chloro-2 6 ,2 7 -Dihydro-3,7-diaza-2(2,4)-thieno[3,2-d]pyrimidin-1(1,3),4(1,4)-dibenzocyclononane-6-one 2 5 -oxide (Compound 6)

[0293]

[0294] Step 1: Preparation of methyl 2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (Compound 6b) Compound 6a (1.00 g, 4.83 mmol), methyl 2-(4-aminophenyl)acetate (796.95 mg, 4.83 mmol) and DIEA (1.87 g, 14.49 mmol) were dissolved in ethanol (10 mL), and the mixture was heated to 85 ° C under microwave conditions and stirred for 3 hours. The reaction mixture was poured into water and extracted with EA (50 mL×2). The organic phases were combined and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography to give the title compound 6b (1.00 g).

[0295] Step 2: Preparation of 2-(4-((2-(3-(2-(tert-butoxycarbonyl)amino)ethyl)-4-chlorophenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (Compound 6c)

[0296] Under N2 atmosphere, compound 6b (500.00 mg, 1.49 mmol), (tert-butyl(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenethyl)carbamate (568.66 mg, 1.49 mmol), K2CO3 (616.86 mg, 4.47 mmol) and Pd(dppf)Cl2 (109.65 mg, 0.15 mmol) were dissolved in 1.4-dioxane (8 mL) and H2O (2 mL). The reaction mixture was stirred at 85°C for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated and diluted with EA (100 mL). The mixture was then washed with brine (50 mL), dried and concentrated to give the crude product. The crude product was purified by flash column chromatography to give the title compound 6c (0.55 g).

[0297] Step 3: Preparation of methyl (2-(4-((2-(3-(2-)2-aminoethyl)-4-chlorophenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (Compound 6d)

[0298] Compound 6c (550.00 mg, 0.99 mmol) was dissolved in dichloromethane (3 mL), and dioxane hydrochloride (3 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours and directly concentrated to obtain a crude product of the title compound 6d (0.45 g).

[0299] Step 4: Preparation of 2-(4-((2-(3-(2-(2-aminoethyl)-4-chlorophenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 6e)

[0300] Compound 5d (450 mg, 0.99 mmol) was dissolved in a mixed solvent of methanol:tetrahydrofuran:water (3 mL:3 mL:1 mL), LiOH.H2O (166.32 mg, 3.96 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Dilute hydrochloric acid (1 M) was added dropwise to adjust to acidity. Solid precipitated and was filtered to give the title compound 6e (0.30 g).

[0301] Step 5: 1 4 -Chloro-2 6 ,2 7 Preparation of dihydro-3,7-diaza-2(2,4-)-thieno[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocyclononane-6-one (Compound 6f)

[0302] Compound 6e (300.00 mg, 0.68 mmol), HATU (387.6 mg, 1.02 mmol) and DIEA (265.2 mg, 2.04 mmol) were dissolved in DCM (20 mL), and the mixture was heated to 25 ° C and stirred for 10 hours. The reaction mixture was poured into water and extracted with DCM (50 mL×2). The organic phases were combined and concentrated under reduced pressure and column chromatography to give the title compound 6f (0.08 g).

[0303] Step 6: (R)-1 4 -Chloro-2 6 ,2 7 -Dihydro-3,7-diaza-2(2,4)-thieno[3,2-d]pyrimidin-1(1,3),4(1,4)-dibenzocyclononane-6-one 2 5 - Preparation of oxide (Compound 6)

[0304] Compound 6f (80 mg, 0.19 mmol), S-(-)-binaphthol (4.57 mg, 0.016 mmol), DCM (3 mL), Ti(OiPr) 4 (2.27 mg, 0.008 mmol) and water (2.88 mg, 0.17 mmol) were placed in a multi-necked flask under nitrogen at 20°C and stirred for 3 hours. The reaction mixture was poured into water and extracted with DCM (50 ml × 2). The organic phases were combined and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography to give the title compound 6 (10.00 mg).

[0305] 1 H NMR (400MHz, DMSO-d6, 24℃) δppm 10.39 (br s, 1H) 7.99-8.06 (m, 1H) 7.40-7.49 (m, 2H) 7.25-7.32 (m, 2H) 7.13-7.23 (m, 3H) 3.53-3.56 (m, 2H) 2.66 (br s,2H)1.22-1.32(m,6H)

[0306] MS m / z(ESI):439[M+1].

[0307] Example 7

[0308] (R)-1 4 -Fluorine-2 6 ,2 7 -Dihydro-6,11-dioxa-3,8-diaza-2(2,4)-thieno[3,2-d]pyrimidin-1(1,3),4(1,4)-dibenzocycloundecane-7-one 5 -oxide (Compound 7)

[0309]

[0310] Step 1: Preparation of (4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)methanol (Compound 7b)

[0311] Compound 7a (1.00 g, 4.83 mmol), p-aminobenzyl alcohol (654.22 mg, 5.31 mmol) and DIEA (1.87 g, 14.49 mmol) were dissolved in ethanol (10 mL), and the mixture was heated to 85 ° C and stirred for 3 hours. The reaction mixture was poured into water and extracted with EA (50 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 7b (1.20 g).

[0312] Step 2: Preparation of 2-fluoro-5-(4-(4-(hydroxymethyl)phenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenol (Compound 7c)

[0313] Under N2 atmosphere, compound 7b (400.00 mg, 1.36 mmol), 7h (254.76 mg, 1.63 mmol), K2CO3 (564.54 mg, 4.08 mmol) and Pd(dppf)Cl2 (99.42 mg, 0.14 mmol) were dissolved in 1.4-dioxane (8 mL) and H2O (2 mL). The reaction mixture was stirred at 85 °C for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated and diluted with EA (100 mL). The mixture was then washed with brine (50 mL), dried and concentrated to give a crude product. The crude product was purified by flash column chromatography to give the title compound 7c (0.48 g).

[0314] Step 3: Preparation of tert-butyl (2-(2-fluoro-5-(4-(4-(hydroxymethyl)phenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenoxy)ethyl)carbamate (Compound 7d)

[0315] Compound 7c (400.00 mg, 1.08 mmol), compound 7i (291.18 mg, 1.30 mmol) and K2CO3 (448.94 mg, 3.25 mmol) were dissolved in DMF (10 mL), and the mixture was heated to 90 ° C and stirred for 8 hours. The reaction mixture was poured into water and extracted with EA (50 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 7d (0.38 g).

[0316] Step 4: Preparation of 4-((2-(3-((tert-butyloxycarbonyl)amino)ethoxy)-4-fluorophenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)1H-imidazole-1-carboxylic acid benzyl ester (Compound 7e)

[0317] Compound 7d (200.00 mg, 0.39 mmol), N,N'-carbonyldiimidazole (CDI, 75.92 mg, 0.47 mmol) and DIEA (100.86 mg, 0.78 mmol) were dissolved in DCM (5 mL), and the mixture was heated to 25 °C and stirred for 3 hours. The reaction mixture was poured into water and extracted with DCM (50 mL × 2). The organic phases were combined, concentrated under reduced pressure, and column chromatography was performed to obtain the title compound 7e (0.31 g).

[0318] Step 5: Preparation of 4-((2-(3-(2-aminoethoxy)-4-fluorophenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)1H-imidazole-1-carboxylic acid benzyl ester (Compound 7f)

[0319] Dichloromethane (5 mL) and trifluoroacetic acid (1 mL) were added to compound 7e (310 mg, 0.51 mmol), and the mixture was stirred at room temperature for 2 hours, and then the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography to give the title compound 7f (0.265 g).

[0320] Step 6: 1 4 -Fluorine-2 6 ,2 7 Preparation of dihydro-6,11-dioxa-3,8-diaza-2(2,4)-thieno[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocycloundecane-7-one (Compound 7g)

[0321] Compound 7f (265.00 mg, 0.52 mmol) and Et3N (158.50 mg, 1.56 mmol) were dissolved in THF (5 mL), and the mixture was heated to 25 ° C and stirred for 5 hours. The reaction mixture was poured into water and extracted with DCM (50 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 7g (0.07 g).

[0322] Step 7: (R)-1 4 -Fluorine-2 6 ,2 7 -Dihydro-6,11-dioxa-3,8-diaza-2(2,4)-thieno[3,2-d]pyrimidin-1(1,3),4(1,4)-dibenzocycloundecane-7-one 5- Preparation of oxide (Compound 7)

[0323] Compound 7g (70 mg, 0.16 mmol), S-(-)-binaphthol (4.57 mg, 0.016 mmol), DCM (3 mL), Ti(OiPr)4 (2.27 mg, 0.008 mmol) and water (2.88 mg, 0.17 mmol) were placed in a multi-necked flask under nitrogen at 20°C and stirred for 1 hour; the mixture became completely homogeneous and the temperature rose to about 40°C. The mixture was allowed to reach normal room temperature and stirred for 1.5 hours. The reaction mixture was poured into water and extracted with DCM (50 ml x 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 7 (10.00 mg).

[0324] 1 H NMR (400MHz, DMSO-d6) δppm 10.32 (s, 1H), 7.90-8.02 (m, 1H), 7.80 (br d, J = 9.06Hz, 1H), 7.22-7.60 (m, 8H), 5.12 (br s,2H),3.64-3.92(m,4H),3.40-3.58(m,2H),3.08-3.20(m,1H)

[0325] MS m / z(ESI):455[M+1].

[0326] Example 8

[0327] (3'R)-1',2',10',11'-tetrahydro-5'H,7'H,9'H,17'H-spiro[cyclopropane-1,6'-[4,19](azepine)[16,18]ethylbenzo[1]thieno[2,3-f][1,14]dioxa[4,8,10]triazepane]3'-oxide (Compound 8)

[0328]

[0329] Step 1: Preparation of tert-butyl (1-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)methyl)cyclopropyl)carbamate (Compound 8b)

[0330] Under nitrogen protection, sodium hydride (0.22 g, 5.61 mmol) was mixed with DMF (20 mL) and placed in an ice bath, followed by the addition of compound 8a (0.70 g, 3.74 mmol), and 2-(2-bromoethoxy)tetrahydro-2H-pyran (1.17 g, 5.61 mmol) after 1 hour. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, water (30 mL) was added and extracted with ethyl acetate (40 mL×2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 8b (0.32 g). Step 2: Preparation of tert-butyl (1-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)methyl)cyclopropyl)carbamate (Compound 59c)

[0331] Compound 8b (0.32 g, 0.70 mmol) was stirred in a 1,4-dioxane hydrochloric acid solution (4 M, 5 mL) for 16 hours at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the title compound 8c (0.12 g).

[0332] Step 3: Preparation of (2-((1-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)cyclopropyl)methoxy)ethane-1-ol (Compound 8d)

[0333] At room temperature, compound 1d (0.19 g, 0.92 mmol), compound 8c (0.12 g, 0.92 mmol) and triethylamine (0.38 g, 2.76 mmol) were mixed in ethanol (20 mL). The reaction solution was stirred at 85 ° C for 8 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and then water (10 mL) was added and extracted with dichloromethane (20 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 8d (0.11 g).

[0334] Step 4: Preparation of 2-(4-((1-((3-hydroxypropoxy)methyl)cyclopropyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-8-ol (Compound 8f)

[0335] Diisopropylethylamine (129 mg, 1.0 mmol) was added to a 1,4-dioxane solution (4 mL) of compound 8d (100 mg, 0.32 mmol) and compound 8e (60 mg, 0.4 mmol). The reaction solution was stirred at 120°C for 50 min under microwave conditions. Ethyl acetate (30 mL) was added to the reaction solution, and the organic phase was washed with saturated sodium chloride (20 mL) and saturated brine (20 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography to obtain the title compound 8f (110 mg).

[0336] Step 5: Preparation of 1',2',10',11'-tetrahydro-5'H,7'H,9'H,17'H-spiro[cyclopropane-1,6'-[4,19](azetidine)[16,18]ethylbenzo[1]thieno[2,3-f][1,14]dioxa[4,8,10]triazepane] (Compound 8g)

[0337] Compound 8f (110 mg, 0.33 mmol), triphenylphosphine (272 mg, 1.05 mmol), diisopropyl azodicarboxylate (212 mg, 1.05 mmol) were dissolved in THF (40 mL), and the reaction mixture was stirred at 25 ° C for 5 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with DCM (50 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 8g (60 mg).

[0338] Step 6: Preparation of (3'R)-1',2',10',11'-tetrahydro-5'H,7'H,9'H,17'H-spiro[cyclopropane-1,6'-[4,19](azepine)[16,18]ethylbenzo[1]thieno[2,3-f][1,14]dioxa[4,8,10]triazacycloheptane]3'-oxide (Compound 8)

[0339] Compound 8g (60mg, 0.15mmol), S-(-)-binaphthol (5mg, 0.017mmol), DCM (5mL), Ti(OiPr)4 (5mg, 0.017mmol) and water (1mg, 0.057mmol) were placed in a multi-necked flask under nitrogen at 20°C and stirred for 1 hour; the mixture became completely uniform, and tert-butyl peroxide (26mg, 0.2mmol) was added and the temperature was raised to about 30°C, and the mixture was allowed to reach normal room temperature and stirred for 1.5 hours. The reaction mixture was poured into water and extracted with DCM (50ml×2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 8 (21mg).

[0340] MS m / z(ESI):427.53[M+1].

[0341] Example 9

[0342] (R)-14-Fluoro-3,6-dimethyl-26,27-dihydro-11-oxa-3,6-diaza-2(2,4-)-thieno[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocycloundecane-7-one 25-oxide (Compound 9)

[0343]

[0344] Step 1: Preparation of methyl 4-(5-bromo-2-fluorophenoxy)butyrate (Compound 9b)

[0345] Compound 9a (500 mg, 2.63 mmol), tert-butyl (3-bromopropyl)carbamate (822 mg, 3.47 mmol) and potassium carbonate (800 mg, 5.78 mmol) were dissolved in N,N-dimethylformamide (15 mL), and the mixture was heated to 60 ° C and stirred for 3 hours. The reaction mixture was poured into water and extracted with EA (50 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 9b (650 mg).

[0346] Step 2: Preparation of (4-fluoro-3-(4-methoxy-4-oxobutoxy)phenyl)boronic acid (Compound 9c)

[0347] Under N2 atmosphere, compound 9b (650mg, 2.2mmol), bis-pinacol borate (753mg, 2.96mmol), potassium acetate (581mg, 5.94mmol) and Pd(dppf)Cl2 (145mg, 0.20mmol) were dissolved in 1.4-dioxane (18mL). The reaction mixture was stirred at 85°C for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated and diluted with EA (100mL). The mixture was then washed with brine (50mL), dried and concentrated to give crude compound 9c (700mg).

[0348] Step 3: Preparation of tert-butyl (4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)(methyl)amino)benzyl)carbamate (9e)

[0349] Compound 9d (200 mg, 0.8 mmol), compound 1c (207 mg, 1.0 mmol) and DIEA (310 mg, 2.4 mmol) were dissolved in ethanol (10 mL), and the mixture was heated to 85 ° C and stirred for 3 hours. The reaction mixture was poured into water and extracted with EA (50 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 9e (210 mg).

[0350] Step 4: Preparation of methyl 4-(5-(4-((((tert-butoxycarbonyl)(methyl)amino)methyl)phenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-fluorophenoxy)butanoate (Compound 9f)

[0351] Under N2 atmosphere, compound 9e (210 mg, 0.5 mmol), 9c (205 mg, 0.8 mmol), K2CO3 (138 mg, 1.0 mmol) and Pd(dppf)Cl2 (61 mg, 0.084 mmol) were dissolved in 1.4-dioxane (8 mL) and H2O (2 mL). The reaction mixture was stirred at 85 °C for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated and diluted with EA (100 mL). The mixture was then washed with brine (50 mL), dried and concentrated to give a crude product. The crude product was purified by flash column chromatography to give the title compound 9f (150 mg).

[0352] Step 5: Preparation of methyl 4-(2-fluoro-5-(4-(4-((methylamino)methyl)phenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenoxy)butanoate (Compound 9g)

[0353] To a solution of compound 9f (150 mg, 0.25 mmol) in methanol (5 mL) and water (1 mL) was added lithium hydroxide (45 mg, 1.1 mmol), and the reaction mixture was stirred at 20 °C for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated and diluted with EA (100 mL). The mixture was then washed with brine (50 mL), dried and concentrated to give a crude compound 9g (170 mg). Step 6: Preparation of 4-(2-fluoro-5-(4-(methyl(4-((methylamino)methyl)phenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenoxy)butanoic acid (compound 9h)

[0354] Dichloromethane (5 mL) and trifluoroacetic acid (1 mL) were added to compound 9g (170 mg, 0.37 mmol), and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by flash column chromatography to give the title compound 9h (140 mg).

[0355] Step 7: Preparation of 14-fluoro-3,6-dimethyl-26,27-dihydro-11-oxa-3,6-diaza-2(2,4-)-thienyl[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocycloundecane-7-one (Compound 9i)

[0356] Compound 9h (110 mg, 0.23 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (133 mg, 0.35 mmol), triethylamine (105 mg, 0.81 mmol) were dissolved in DCM (100 mL), and the reaction mixture was heated to 25 ° C and stirred for 5 hours. The reaction mixture was poured into water and extracted with DCM (50 mL×2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 9i (70 mg).

[0357] Step 8: Preparation of (R)-14-fluoro-3,6-dimethyl-26,27-dihydro-11-oxa-3,6-diaza-2(2,4-)-thieno[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocycloundecane-7-one 25-oxide (Compound 9)

[0358] Compound 9i (70 mg, 0.15 mmol), S-(-)-binaphthol (9 mg, 0.03 mmol), DCM (5 mL), Ti(OiPr)4 (4.5 mg, 0.015 mmol) and water (5.3 mg, 0.29 mmol) were placed in a multi-necked flask under nitrogen at 20°C and stirred for 1 hour; the mixture became completely homogeneous, and tert-butyl peroxide (26 mg, 0.2 mmol) was added and the temperature was raised to about 30°C, and the mixture was allowed to reach normal room temperature and stirred for 1.5 hours. The reaction mixture was poured into water and extracted with DCM (50 ml × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 9 (20 mg).

[0359] MS m / z(ESI):481[M+1].

[0360] Example 10

[0361] (R)-1 4 -Chloro-2 6 ,27 -Dihydro-11-oxa-6-thia-2-(2,4-)-thieno[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocycloundecane 25,6,6-trioxide (Compound 10)

[0362]

[0363] Step 1: Preparation of (2-(3-((4-nitrobenzyl)thio)propoxy)tetrahydro-2H-pyran (Compound 10b)

[0364] Compound 10a (1 g, 5.90 mmol), 2-(3-bromopropoxy)tetrahydro-2H-pyran (1.2 g, 8.90 mmol) and potassium carbonate (2.45 g, 17.7 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the mixture was heated to 60 ° C and stirred for 3 hours. The reaction mixture was poured into water and extracted with EA (200 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 10b (1.3 g).

[0365] Step 2: Preparation of 2-(3-((4-nitrobenzyl)sulfonyl)propoxy)tetrahydro-2H-pyran (Compound 10c)

[0366] Compound 10b (1.3 g, 4.18 mmol) and m-chloroperbenzoic acid (2.5 g, 14.7 mmol) were dissolved in dichloromethane (50 mL), and the reaction mixture was stirred at 20 ° C for 2 hours. After the reaction was completed, the reaction mixture was poured into water, quenched with saturated sodium sulfite aqueous solution, and extracted with EA (300 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 10c (0.9 g).

[0367] Step 3: Preparation of 4-((3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)sulfonyl)methyl)aniline (10d)

[0368] Compound 10c (0.8 g, 2.33 mmol), ammonium chloride (0.27 mg, 4.64 mmol) and iron powder (0.38 g, 7.00 mmol) were dissolved in methanol (30 mL) and water (6 mL), and the mixture was heated to 85 ° C and stirred for 2 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with EA (200 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 10d (720 mg).

[0369] Step 4: Preparation of 2-chloro-N-(4-((3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)sulfonyl)methyl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-amine (Compound 10e)

[0370] Compound 1d (0.47 g, 2.28 mmol), compound 10d (0.65 mg, 2.08 mmol) and DIEA (0.78 g, 6.24 mmol) were dissolved in ethanol (10 mL), and the title compound 10e (0.60 g) was prepared according to the method of step 3 of Example 1. Step 5: Preparation of 3-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)benzyl)sulfonyl)propan-1-ol (Compound 10f)

[0371] Diluted hydrochloric acid (4M, 5mL) was added to a solution of compound 10e (600mg, 1.24mmol) in methanol (5mL), and the reaction mixture was stirred at 20°C for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated and diluted with EA (100mL). The mixture was then washed with saline (50mL), dried and concentrated to give a crude product, which was purified by flash column chromatography to give the title compound 10f (200mg).

[0372] Step 6: Preparation of 2-chloro-5-(4-(4-((3-hydroxypropyl)sulfonyl)methyl)phenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenol (Compound 10h)

[0373] Under N2 atmosphere, compounds 10h (180 mg, 0.45 mmol), 10g (554 mg, 1.79 mmol), K2CO3 (187 mg, 1.35 mmol) and Pd(dppf)Cl2 (33 mg, 0.045 mmol) were dissolved in 1.4-dioxane (8 mL) and H2O (2 mL), and the title compound 10h (0.17 g) was prepared according to the method of the fourth step of Example 1.

[0374] Step 7: 1 4 -Chloro-2 6 ,2 7 Preparation of dihydro-11-oxa-6-thioxo-3-aza-2(2,4-)-thieno[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocycloundecane 6,6-dioxide (Compound 10i)

[0375] Compound 10h (170 mg, 0.35 mmol), triphenylphosphine (272 mg, 1.05 mmol), diisopropyl azodicarboxylate (212 mg, 1.05 mmol) were dissolved in THF (40 mL), and the reaction mixture was stirred at 25 ° C for 5 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with DCM (50 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 10i (0.02 g).

[0376] Step 8: (R)-1 4 -Chloro-2 6 ,2 7 Preparation of dihydro-11-oxa-6-thia-2-(2,4-)-thieno[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocycloundecane 25,6,6-trioxide (Compound 10)

[0377] Compound 10i (20 mg, 0.042 mmol), S-(-)-binaphthol (4 mg, 0.013 mmol), DCM (5 mL), Ti(OiPr)4 (0.6 mg, 0.0021 mmol) and water (1 mg, 0.042 mmol) were placed in a multi-necked flask under nitrogen at 20°C and stirred for 1 hour; the mixture became completely homogeneous, and tert-butyl peroxide (7 mg, 0.046 mmol) was added and the temperature was raised to about 30°C, and the mixture was allowed to reach normal room temperature and stirred for 1.5 hours. The reaction mixture was poured into water and extracted with DCM (50 ml × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 10 (5.4 mg).

[0378] MS m / z(ESI):504[M+1].

[0379] Embodiment 11

[0380] (R)-1 4 -Chloro-2 6 ,2 7 -Dihydro-5,8,11-trioxa-3-aza-2(2,4)-thieno[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocycloundecane 25-oxide (Compound 11)

[0381]

[0382]

[0383] Step 1: Preparation of 2-(2-(5-bromo-2-chlorophenoxy)ethoxy)ethanol-1-ol (Compound 11b)

[0384] Compound 11a (1 g, 3.85 mmol), 5-bromo-2-chlorophenol (720 mg, 3.50 mmol) and potassium carbonate (1.45 g, 10.49 mmol) were dissolved in N,N-dimethylformamide (25 mL), and the mixture was heated to 80 ° C and stirred for 3 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with EA (50 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 11b (900 mg).

[0385] Step 2: Preparation of ((4-chloro-3-(2-(2-hydroxyethyl)ethoxy)phenyl)boronic acid (Compound 11c)

[0386] Under N2 atmosphere, compound 11b (900 mg, 3.06 mmol), bis-pinacol borate (1.17 g, 4.59 mmol), potassium acetate (900 mg, 9.18 mmol) and Pd(dppf)Cl2 (224 mg, 0.31 mmol) were dissolved in 1.4-dioxane (18 mL). The title compound 11c (1.5 g) was prepared according to the method of the second step of Example 1.

[0387] Step 3: Preparation of 3-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenol (11e)

[0388] Compound 11d (0.53 g, 4.86 mmol), 1d (1 g, 4.86 mmol) and DIEA (1.81 g, 14.58 mmol) were dissolved in ethanol (10 mL), and the mixture was heated to 85° C. and stirred for 3 hours. The title compound 11e (1.5 g) was prepared according to the method of the third step of Example 1.

[0389] Step 4: Preparation of 3-(2-(4-chloro-3-(2-(2-hydroxyethoxy)ethoxyphenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenol (Compound 11f)

[0390] Under N2 atmosphere, compound 11e (600 mg, 2.14 mmol), 11c (0.84 mg, 3.22 mmol), K2CO3 (887 mg, 6.42 mmol) and Pd(dppf)Cl2 (157 mg, 0.21 mmol) were dissolved in 1.4-dioxane (8 mL) and H2O (2 mL). The title compound 11f (0.15 g) was prepared according to the method of step 4 of Example 1.

[0391] Step 5: Preparation of 2-(4-((2-(3-((tert-butyloxycarbonyl)amino)propoxy)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (Compound 11g)

[0392] Compound 11f (150 mg, 0.33 mmol), triphenylphosphine (257 mg, 0.99 mmol) and diisopropyl azodicarboxylate (200 mg, 0.99 mmol) were dissolved in THF (40 mL), and the title compound 11g (25 mg) was prepared according to the method of step 7 of Example 10.

[0393] Step 6: (R)-1 4 -Chloro-2 6 ,2 7 Preparation of dihydro-5,8,11-trioxa-3-aza-2(2,4)-thieno[3,2-d]pyrimidine-1(1,3),4(1,4)-dibenzocycloundecane 25-oxide (Compound 11)

[0394] Compound 11g (25mg, 0.057mmol), S-(-)-binaphthol (5mg, 0.017mmol), DCM (5mL), Ti(OiPr)4 (1mg, 0.0029mmol) and water (1mg, 0.057mmol) were placed in a multi-necked flask under nitrogen at 20°C and stirred for 1 hour; the mixture became completely uniform, and tert-butyl peroxide (7mg, 0.063mmol) was added and the temperature was raised to about 30°C, and the mixture was allowed to reach normal room temperature and stirred for 1.5 hours. The reaction mixture was poured into water and extracted with DCM (50ml×2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 11 (2.6mg).

[0395] MS m / z(ESI):458[M+1].

[0396] Example 12

[0397] (R)-2 6 ,2 7 -Dihydro-6,9-dioxa-2-(2,4)-thieno[3,2-d]pyrimidine-1,4(1,3)-dibenzocyclononane 2 5 -oxide (Compound 12)

[0398]

[0399] Step 1: Preparation of 2-((3-nitrobenzyl)oxy)ethanol-1-ol (Compound 12b)

[0400] Under nitrogen protection, sodium hydride (60% oil dispersion; 741 mg, 18.52 mmol) was slowly added to a solution of ethylene glycol (1.2 g, 18.52 mmol) in DMF (40 mL). The reaction solution was stirred at 20 ° C for 40 minutes, and 1-(bromomethyl)-3-nitrobenzene 1a (4.0 g, 18.52 mmol) was added. The reaction solution was stirred at 20 ° C for 3 hours. Phosphate buffer (pH 6.5, 50 mL) was added and the mixture was stirred for 10 minutes. Extracted with ethyl acetate (50 mL × 2), the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 12b (1.5 g).

[0401] Step 2: Preparation of 2-((3-aminobenzyl)oxy)ethanol-1-ol (Compound 12c)

[0402] Under hydrogen protection, 2-((3-nitrobenzyl)oxy)ethanol-1-ol 12b (1.5 g, 7.61 mmol) and palladium hydroxide on carbon (110 mg, 0.76 mmol) were mixed in a methanol solution (20 mL). The reaction solution was stirred at 20°C for 8 hours, filtered after the reaction was completed, and concentrated under reduced pressure to obtain the title compound 12c (1.2 g, crude product).

[0403] Step 3: Preparation of 2-((3-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)benzyl)oxy)ethanol-1-ol (Compound 12d)

[0404] At room temperature, 2,4-dichloro-6,7-dihydrothiophene[3,2-d](500mg, 2.4mmol), 2-((3-aminobenzyl)oxy)ethanol-1-ol 12c(600mg, 3.6mmol) and triethylamine (734mg, 7.3mmol) were mixed in ethanol (10mL). The reaction solution was stirred at 85°C for 8 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and then water (20mL) was added and extracted with dichloromethane (30mL×2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 12d (700mg).

[0405] Step 4: Preparation of 3-(4-((3-((2-hydroxyethoxy)methyl)phenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenol (Compound 12f)

[0406] Under nitrogen protection, 2-((3-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)benzyl)oxy)ethanol-1-ol 12d (700 mg, 2.1 mmol), (3-hydroxyphenyl)boronic acid 1e (286 mg, 2.1 mmol), potassium carbonate (573 mg, 4.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (156 mg, 0.21 mmol) were mixed in a 1,4-dioxane (10 mL) / water (1 mL) solution. The reaction solution was stirred at 80°C for 3 hours. Ethyl acetate (100 mL) was added to the reaction solution. The organic phase was washed with saturated ammonium chloride (20 mL) and saturated brine (20 mL) in sequence, 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 obtain the title compound 12f (700 mg).

[0407] Step 5: 2 6 ,2 7 Preparation of dihydro-6,9-dioxa-2-(2,4-)-thieno[3,2-d]pyrimidine-1,4(1,3)-dibenzocyclononane (Compound 12g)

[0408] Under hydrogen protection, 3-(4-((3-((2-hydroxyethoxy)methyl)phenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenol 12f (120 mg, 0.31 mmol) and triphenylphosphine (239 mg, 0.91 mmol) were mixed in tetrahydrofuran (8 mL) solution, stirred at 25°C for 10 minutes, and DIAD (185 mg, 0.91 mmol) was added. The reaction mixture was stirred at 25°C for 4 hours, water (10 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the organic phase was washed with saturated ammonium chloride (20 mL) and saturated brine (20 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography to obtain the title compound 12g (100 mg).

[0409] Step 6: (R)-2 6 ,2 7 -Dihydro-6,9-dioxa-2-(2,4)-thieno[3,2-d]pyrimidine-1,4(1,3)-dibenzocyclononane 2 5 - Preparation of oxide (Compound 12)

[0410] At room temperature, 2 6 ,2 7-Dihydro-6,9-dioxa-2-(2,4-)-thieno[3,2-d]pyrimidine-1,4(1,3)-dibenzocyclononane 12g (100mg, 0.26mmol), S-1,1'-bi-2-naphthol (8mg, 0.03mmol), tetraisopropoxytitanium (4mg, 0.01mmol) and water (11mg, 0.31mmol) were mixed in dichloromethane (5mL), stirred at room temperature for 1 hour, then tert-butyl peroxide (50mg, 0.31mmol) was added and the reaction solution was stirred at room temperature for 1.5 hours. After the reaction was completed, water (10mL) was added and extracted with dichloromethane (40mL×2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 12 (35mg, yield: 34%).

[0411] 1 H NMR(400MHz,DMSO-d6)δppm 10.15(s,1H),9.13(s,1H),8.58-8.61(m,1H),7.94(d,J=7.32Hz,1H),7.37(t,J=7.69Hz,1H),7.28-7.33(m,2H),7.07-7.10(m,1H), 6.97-6.99(m,1H),4.61-4.69(m,2H),4.34-4.41(m,2H),3.88-3.95(m,2H),3.72-3.81(m,1H),3.33-3.52(m,2H),3.12-3.18(m,1H).

[0412] MS m / z(ESI):393.9[M+1].

[0413] Example 13

[0414] (1 5 R, 6S)-6-methyl-1 6 ,1 7 -Dihydro-4-oxa-7-aza-1-(2,4-)-thienyl[3,2-d]pyrimidine-2(3,5)-pyridine-5(1,2)-benzocycloheptane 1 5 -oxide (Compound 13)

[0415]

[0416]

[0417] Step 1: Preparation of ((S)-2-(1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)ethyl)phenol (Compound 13b)

[0418] Compound 13a (1.00 g, 4.83 mmol), compound 13e (728.73 mg, 5.31 mmol) and DIEA (1.87 g, 14.49 mmol) were dissolved in ethanol (10 mL), and the mixture was heated to 85 ° C and stirred for 3 hours. The reaction mixture was poured into water. It was extracted with EA (50 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 13b (1.10 g).

[0419] Step 2: Preparation of (S)-2-(1-((2-(5-(hydroxymethyl)pyridin-3-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)ethyl)phenol (Compound 13c)

[0420] Under N2 atmosphere, compound 13b (380.00 mg, 1.23 mmol), compound 13f (226.59 mg, 1.48 mmol), K2CO3 (511.88 mg, 3.70 mmol) and Pd(dppf)Cl2 (87.72 mg, 0.12 mmol) were dissolved in 1.4-dioxane (8 mL) and H2O (2 mL). The reaction mixture was stirred at 85 ° C for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated and diluted with EA (100 mL). The mixture was then washed with brine (50 mL), dried and concentrated to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 13c (0.46 g).

[0421] Step 3: (S)-6-methyl-1 6 ,1 7 Preparation of -dihydro-4-oxa-7-aza-1(2,4)-thieno[3,2-d]pyrimidine-2(3,5)-pyridine-5(1,2)-benzocycloheptane (Compound 13d)

[0422] Compound 13c (400.00 mg, 1.05 mmol) and Ph3P (827.28 mg, 3.15 mmol) were added to THF (80 mL), stirred at 25 ° C for 10 minutes, and DIAD (637.78 mg, 3.11 mmol) was added under N2 atmosphere. The reaction mixture was stirred at 25 ° C for 4 hours. LCMS showed that the reaction was complete. The reaction mixture was poured into water and extracted with EA (50 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound 13d (0.06 g).

[0423] Step 4: (1 5 R, 6S)-6-methyl-1 6,1 7 -Dihydro-4-oxa-7-aza-1-(2,4-)-thienyl[3,2-d]pyrimidine-2(3,5)-pyridine-5(1,2)-benzocycloheptane 1 5 Preparation of -oxide (Compound 13)

[0424] Compound 13d (60 mg, 0.16 mmol), S-(-)-binaphthol (4.74 mg, 0.016 mmol), DCM (3 mL), Ti(OiPr)4 (2.35 mg, 0.008 mmol) and water (2.98 mg, 0.17 mmol) were placed in a multi-necked flask under nitrogen at 20°C and stirred for 1 hour; the mixture became completely homogeneous and the temperature rose to about 40°C. The mixture was allowed to reach normal room temperature and stirred for 1.5 hours, the reaction mixture was poured into water and extracted with DCM (50 mL×2). The organic phases were combined and concentrated under reduced pressure to give the title compound 13 (8.00 mg).

[0425] 1 H NMR(400MHz,DMSO-d6)δppm 9.12-9.30(m,1H),8.49-8.74(m,2H),8.10-8.24(m,1H),7.23-7.42(m,3H),6.86-7.06(m,1 H),5.68(s,1H),4.89-5.32(m,2H),3.42-3.68(m,2H),2.99-3.19(m,2H),1.38-1.54(m,3H)

[0426] MS m / z(ESI):379[M+1].

[0427] Biological evaluation

[0428] Effect Example 1: Inhibitory effect of the disclosed compounds on PDE4 enzyme

[0429] PDE4 enzyme can hydrolyze cAMP to produce AMP. We used synthetic PDE4 enzyme inhibitors to act on PDE4 enzyme and substrate cAMP for a period of time, and then used AMP-Glo TM The assay kit is used for testing. The test is divided into two steps: first, the AMP produced by the reaction is converted into ADP, and second, ADP is converted into ATP. ATP combines with the reagent to emit fluorescence, and the fluorescence value is detected by Echo 550. The fluorescence value is used to draw a graph to calculate the IC value of the PDE4 enzyme inhibitor. 50 The specific contents are as follows:

[0430] 1.1 Reagents and instruments

[0431] The reagents used in this example are listed in Table 3, and the instruments used are listed in Table 4.

[0432] Table 3

[0433] Material Name Manufacturer Item# PDE4B2 BPS bioscience 60042 Cyclic-3',5'-AMP Sigma A6885 <![CDATA[AMP-Glo TM Assay kit]]> Promega V5011 Tris amresco T0497 BSA PerkinElmer CR84-100 Magnesium chloride Sigma M1028 Tween-20 Solarbio T8220 DTT Invitrogen P2325 DMSO Sigma D8418

[0434] Table 4

[0435] Instrument Name Manufacturer Item# 96-well plate Nunc 249944 384-well plate Greiner 784075 Orifice plate oscillator QILINBEIER QB-9002 Centrifuge Eppendorf 5810R Envision Multi-Index Plate Reader PerkinElmer Envision 2105 Vortexer IKA MS3 digital Echo Labcyte 550

[0436] 1.2 Experimental procedures

[0437] 1.2.1 Compound preparation and handling

[0438] a) Preparation of DMSO stock solutions of compounds: All compounds were dissolved in DMSO to prepare stock solutions at a concentration of 10 mM.

[0439] b) Compound Storage: All compounds dissolved in DMSO were stored short term in a desiccator at room temperature.

[0440] 1.2.2 Preparation of working stock solution

[0441] a) The positive control BI1015550 was diluted 3-fold with DMSO, starting from 100 μM, for a total of 10 concentrations.

[0442] b) The test compound was diluted 3-fold with DMSO, starting from 100 μM, for a total of 10 concentrations.

[0443] c) Prepare 200X positive control (1 mM BI1015550) and 200X solvent control (100% DMSO). Centrifuge the compound plate at 1000 rpm for 1 minute.

[0444] 1.2.3 Compound screening

[0445] a) Using the Echo 550, transfer 20 nL of compound dilution to each well of the assay plate.

[0446] b) Seal the assay plate and centrifuge the compound plate at 1000 rpm for 1 minute.

[0447] c) Prepare 2X PDE4B2 or PDE4D2 in chilled PDE assay buffer.

[0448] d) Add 2 μL of 2X PDE4B2 or PDE4D2 to individual wells of the assay plate (prepared in step b).

[0449] e) Seal the assay plate and equilibrate at room temperature for 10 minutes.

[0450] f) Prepare 2X Cyclic-3',5'-AMP in PDE Assay Buffer.

[0451] g) Start the reaction by adding 2 μL of 2X Cyclic-3',5'-AMP (prepared in step f) to each well of the assay plate (prepared in step e). Incubate at room temperature for 60 minutes.

[0452] h) Add 4 μL AMP-Glo ​​Reagent I and incubate at room temperature for 60 minutes.

[0453] i) Add 8 μL of AMP detection solution and incubate at room temperature for 60 minutes.

[0454] j) Read the RLU signal on an Envision 2105 plate reader.

[0455] 1.3 Data Analysis

[0456] The calculation formula is as follows:

[0457] % Inhibition = {1-(average RLU of compound-average RLU of positive control of the whole plate) / (average RLU of negative control of the whole plate-average RLU of positive control of the whole plate)}

[0458] IC was calculated by fitting the logarithm of % inhibition values ​​and compound concentration to a nonlinear regression (dose response - variable slope) using Graphpad 8.0. 50 The test results are shown in Table 5.

[0459] Table 5 Inhibitory effect of the disclosed compounds on PDE4 enzyme

[0460]

[0461] Note: The structure of BI1015550 is

[0462] Conclusion: The disclosed compounds have significantly excellent inhibitory activity against PDE4 enzyme.

[0463] It should be understood that the above embodiments are exemplary and are not intended to include all possible implementations included in the claims. Various modifications and changes may be made on the basis of the above embodiments without departing from the scope of the present disclosure. Similarly, the various technical features of the above embodiments may be arbitrarily combined to form other embodiments of the present disclosure that may not be explicitly described. Therefore, the above embodiments only express several implementations of the present disclosure and do not limit the scope of protection of the patent of the present disclosure.

Claims

1. A compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts: in: M is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by one or more R M replaced by; R M Each occurrence is independently selected from H, D, halogen, hydroxy, amino, and alkyl; At each occurrence, R 1 Each is independently selected from H, D, halogen, hydroxyl, amino and alkyl; W is selected from a bond, O, a carbonyl group, an imino group, an amide group, a sulfone group, a sulfoxide group, Alkylene, cycloalkyl and aryl, the imino, amide, Alkylene, cycloalkyl and aryl are optionally substituted with one or more R W replaced by; R W Each occurrence is independently selected from H, D, halogen, hydroxy, amino, and alkyl; Y is selected from a bond, O, carbonyl, imino, amide, sulfone, sulfoxide, alkylene, -alkylene-O-, cycloalkyl and aryl, wherein the imino, amide, alkylene, -alkylene-O-, cycloalkyl and aryl are optionally substituted by one or more R Y replaced by; R Y Each occurrence is independently selected from H, D, halogen, hydroxy, amino, and alkyl; Z is selected from a bond, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more R Z replaced by; R Z Each occurrence is independently selected from H, D, halogen, hydroxy, amino, and alkyl; At each occurrence, R 2 and R 3 are the same or different and are each independently selected from H, D, halogen, hydroxyl, amino and alkyl; or, at each occurrence, R 2 and R 3 and the atoms to which it is attached form a cycloalkyl group which is optionally substituted by D, halogen, hydroxyl or unsubstituted; R 4 is selected from H, D, halogen, hydroxy, amino and alkyl; m is 0 or 1; n is 1, 2, 3 or 4; p is 0, 1 or 2.

2. The compound of formula I according to claim 1 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: The M is selected from C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, the C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl are optionally substituted by one or more R M replaced by; Preferably, the M is selected from C 3-6 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 The 4-9-membered heterocyclic group and the 5-10-membered heteroaryl group contain 1-4 heteroatoms selected from N, O and S, and the C 3-6 Cycloalkyl, 4-9 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R M replaced by; More preferably, the M is selected from C 6-10 Aryl and 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-2 heteroatoms selected from N, the C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R M replaced by; Most preferably, the M is selected from a benzene ring, a pyridyl group and The benzene ring, pyridyl and Optionally one or more R M replaced.

3. The compound of formula I according to claim 1 or 2, or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: The compound has a structure as shown in Formula II or Formula III: Among them, R 1 , R 2 , R 3 , R 4 , R M , W, Y, Z, m, n and p are as defined in claim 1 or 2.

4. The compound of formula I or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt according to any one of claims 1 to 3, characterized in that: The R M Each occurrence is independently selected from H, D, halogen, hydroxy, amino and C 1-6 alkyl; Preferably, the R M Each occurrence is independently selected from H, D, halogen, hydroxy, amino and C 1-3 alkyl; More preferably, the R M Each occurrence is independently selected from H and halogen; Most preferably, the R M Each occurrence is independently selected from H, F and Cl.

5. The compound of general formula I or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt according to any one of claims 1 to 4, characterized in that: At each occurrence, the R 1 are each independently selected from H, D, halogen, hydroxyl, amino and C 1-6 alkyl; Preferably, at each occurrence, the R 1 are each independently selected from H, D, halogen, hydroxyl, amino and C 1-3 alkyl; More preferably, at each occurrence, the R 1 Each independently selected from H and C 1-3 alkyl; Most preferably, at each occurrence, the R 1 are each independently selected from H and methyl.

6. The compound of formula I or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt according to any one of claims 1 to 5, characterized in that: The W is selected from a bond, O, a carbonyl group, an imino group, an amide group, a sulfone group, a sulfoxide group, C 1-6 Alkylene, C 3-8 Cycloalkyl and C 6-10 Aryl, the imino, amide, C 1-6 Alkylene, C 3-8 Cycloalkyl and C 6-10 The aryl group is optionally substituted with one or more R W replaced by; Preferably, W is selected from a bond, O, a carbonyl group, an imino group, an amide group, a sulfone group, a sulfoxide group, C 1-3 Alkylene, C 3-5 Cycloalkyl and C 6-10 Aryl, the imino, amide, C 1-3 Alkylene, C 3-5 Cycloalkyl and C 6-10 The aryl group is optionally substituted with one or more R W replaced by; More preferably, W is selected from O, amide, sulfone and The amide group and Optionally one or more R W replaced.

7. The compound of formula I or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt according to any one of claims 1 to 6, characterized in that: The R W Each occurrence is independently selected from H, D, halogen, hydroxy, amino and C 1-6 alkyl; Preferably, the R W Each occurrence is independently selected from H, D, halogen, hydroxy, amino and C 1-3 alkyl; More preferably, the R W Each occurrence is independently selected from H and C 1-3 alkyl; Most preferably, the R W Each occurrence is independently selected from H and methyl.

8. The compound of formula I or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt according to any one of claims 1 to 7, characterized in that: The Y is selected from a bond, O, a carbonyl group, an imino group, an amide group, a sulfone group, a sulfoxide group, a C 1-6 Alkylene, -C 1-6 Alkylene-O-, C 3-8 Cycloalkyl and C 6-10 Aryl, the imino, amide, C 1-6 Alkylene, -C 1-6 Alkylene-O-, C 3-8 Cycloalkyl and C 6-10 The aryl group is optionally substituted with one or more R Y replaced by; Preferably, Y is selected from a bond, O, a carbonyl group, an imino group, an amide group, a sulfone group, a sulfoxide group, a C 1-3 Alkylene, -C 1-3 Alkylene-O-, C 3-5 Cycloalkyl and C 6-10 Aryl, the imino, amide, C 1-3 Alkylene, -C 1-3 Alkylene-O-, C 3-5 Cycloalkyl and C 6-10 The aryl group is optionally substituted with one or more R Y replaced by; More preferably, said Y is selected from a bond, C 1-3 Alkylene and -C 1-3 Alkylene-O-, the C 1-3 Alkylene and -C 1-3 Alkylene-O- is optionally substituted with one or more R Y replaced by; Most preferably, Y is selected from a bond, methylene, ethylene and -ethylene-O-, wherein the methylene, ethylene and -ethylene-O- are optionally replaced by one or more R Y replaced.

9. The compound of formula I or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt according to any one of claims 1 to 8, characterized in that: The R Y Each occurrence is independently selected from H, D, halogen, hydroxy, amino and C 1-6 alkyl; Preferably, the R Y Each occurrence is independently selected from H, D, halogen, hydroxy, amino and C 1-3 alkyl; More preferably, the R Y Each occurrence is independently selected from H.

10. The compound of general formula I or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt according to any one of claims 1 to 9, characterized in that: The Z is selected from a bond, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, the C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl are optionally substituted by one or more R Z replaced by; Preferably, Z is selected from a bond, C 3-5 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10 The 4-8 membered heterocyclic group and the 5-8 membered heteroaryl group contain 1-4 heteroatoms selected from N, O and S, and the C 3-5 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10 Aryl and 5-8 membered heteroaryl are optionally substituted by one or more R Z replaced by; More preferably, Z is selected from a bond, C 6-10 Aryl and 5-8 membered heteroaryl, wherein the 5-8 membered heteroaryl contains 1-2 heteroatoms selected from N, O or S, and the C 6-10 Aryl and 5-8 membered heteroaryl are optionally substituted by one or more R Z replaced by; Most preferably, Z is selected from a bond, a benzene ring and a thienyl group, wherein the benzene ring and the thienyl group are optionally substituted by one or more R Z replaced.

11. The compound of formula I according to any one of claims 1 to 10 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: The R Z Each occurrence is independently selected from H, D, halogen, hydroxy, amino and C 1-6 alkyl; Preferably, the R Z Each occurrence is independently selected from H, D, halogen, hydroxy, amino and C 1-3 alkyl; More preferably, the R Z Each occurrence is independently selected from H.

12. The compound of formula I according to any one of claims 1 to 11 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: At each occurrence, the R 2 and R 3 are the same or different and are each independently selected from H, D, halogen, hydroxyl, amino and C 1-6 alkyl; Preferably, at each occurrence, the R 2 and R 3 are the same or different and are each independently selected from H, D, halogen, hydroxyl, amino and C 1-3 alkyl; More preferably, at each occurrence, the R 2 and R 3 are the same or different and are each independently selected from H and C 1-3 alkyl; Most preferably, at each occurrence, the R 2 and R 3 are the same or different and are each independently selected from H and methyl; or, at each occurrence, the R 2 and R 3 and the atoms connected thereto form C optionally substituted or unsubstituted by D, halogen, hydroxyl 3-8 Cycloalkyl; Preferably, at each occurrence, the R 2 and R 3 and the atoms connected thereto form C optionally substituted or unsubstituted by D, halogen, hydroxyl 3-5 Cycloalkyl; More preferably, at each occurrence, the R 2 and R 3 and the atoms to which it is attached form a cyclopropyl group which is optionally substituted or unsubstituted by D, halogen, or hydroxy; Most preferably, at each occurrence, the R 2 and R 3 and the atom to which it is attached form an unsubstituted cyclopropyl group.

13. The compound of formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts according to any one of claims 1 to 12, characterized in that: The R 4 Selected from H, D, halogen, hydroxyl, amino and C 1-6 alkyl; Preferably, the R 4 Selected from H, D, halogen, hydroxyl, amino and C 1-3 alkyl; More preferably, the R 4 Selected from H and C 1-3 alkyl; Most preferably, the R 4 Selected from H and methyl.

14. A compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: The compound is any of the following:

15. A compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: The compound is any of the following:

16. A pharmaceutical composition, characterized in that The pharmaceutical composition contains a therapeutically effective amount of a compound of formula I according to any one of claims 1 to 15 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.

17. Use of the compound of general formula I according to any one of claims 1 to 15 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts or the pharmaceutical composition according to claim 16 in the preparation of a medicament for inhibiting PDEs enzymes, preferably in the preparation of a medicament for inhibiting PDE4 enzymes, more preferably in the preparation of a medicament for inhibiting PDE4B enzymes and / or PDE4D enzymes.

18. Use of the compound of general formula I according to any one of claims 1 to 15 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts or the pharmaceutical composition according to claim 16 in the preparation of a medicament for treating and / or preventing a disease or condition mediated by PDEs enzymes, preferably in the preparation of a medicament for treating and / or preventing a disease or condition mediated by PDE4 enzymes, more preferably in the preparation of a medicament for treating and / or preventing a disease or condition mediated by PDE4B enzymes and / or PDE4D enzymes.

19. The use according to claim 18, characterized in that The disease or condition is selected from respiratory diseases, lung diseases, gastrointestinal diseases, inflammatory diseases, cancer and peripheral or central nervous system diseases; Preferably, the disease or disorder is cancer, COPD, idiopathic pulmonary fibrosis or interstitial lung disease.

Images