Polycyclic PDE4B selective inhibitor and application thereof

Abstract

The invention discloses a polycyclic PDE4B selective inhibitor and an application thereof. Specifically, the invention discloses a compound as shown in a formula (I), and a stereoisomer, a tautomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof. The compound provided by the invention is a PDE4B selective inhibitor, and can be used for preparing drugs for treating and / or preventing diseases related to PDE4B. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a polycyclic PDE4B selective inhibitor and application thereof. Background Art

[0002] Phosphodiesterases (PDEs) are a large family of enzymes in the human body, encompassing 11 types and over 100 subtypes. They regulate a wide range of physiological functions in the central nervous system, cardiovascular system, and immune system by catalyzing the hydrolysis of the second messenger molecules cAMP and / or cGMP. PDE4 is the most diverse of the PDE family, comprising four subtypes (A, B, C, and D) and over 25 subtypes. PDE4 proteins are widely distributed in various cell types throughout the body, specifically hydrolyzing cAMP and participating in numerous physiological functions, such as brain function, monocyte and macrophage activation, neutrophil infiltration, vascular smooth muscle proliferation, and myocardial contraction. Therefore, PDE4 is an important therapeutic target for a variety of inflammatory diseases, such as eczema, chronic obstructive pulmonary disease, and rheumatoid arthritis. Its role in cardiovascular disease, autoimmune diseases, and cancer is also being extensively explored. Currently, several PDE4 inhibitors have been approved, such as roflumilast for the treatment of COPD, crisaborole for the treatment of atopic dermatitis, and apremilast for the treatment of psoriatic arthritis. Overall, these approved drugs have relatively good efficacy, but side effects such as nausea and vomiting are more obvious in clinical use, which also limits the application of this type of drug. A large number of studies have shown that PDE4B is closely related to inflammatory responses, and the inhibition of PDE4D may be an important factor leading to side effects such as vomiting. However, currently available drugs such as roflumilast are non-selective PDE4 inhibitors that indiscriminately inhibit PDE4B and PDE4D. Therefore, the development of new inhibitors that selectively target PDE4B is of great significance for reducing toxic side effects and expanding treatment options. Summary of the Invention

[0003] To solve the above problems, the present invention provides a polycyclic compound that acts on PDE4B protein.

[0004] The purpose of this application is also to provide a method for preparing the polycyclic compound as described above.

[0005] The present application also aims to provide a use of the polycyclic compound as described above as a PDE4B selective inhibitor. The present application also aims to provide a pharmaceutical composition comprising the polycyclic compound as described above and a pharmaceutically acceptable carrier, adjuvant or excipient.

[0006] The present application also aims to provide a kit comprising the polycyclic compound or pharmaceutical composition as described above.

[0007] The present application also aims to provide a use of the polycyclic compound as described above in the preparation of a medicament for PDE4B-related diseases.

[0008] The present application also aims to provide a method for preventing or treating PDE4B-related diseases.

[0009] In order to solve the above technical problems, this application provides the following technical solutions.

[0010] In the first aspect of the present invention, there is provided a compound represented by formula (I), its stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs,

[0011]

[0012] in,

[0013] m is 0, 1, or 2;

[0014] n is 2 or 3;

[0015] s and t are each independently 0, 1, 2, 3 or 4;

[0016] X and Y are each independently N or CR, and X and Y are not CR at the same time;

[0017] Each R is independently selected from the group consisting of H, D, halogen, cyano, hydroxy, NR 10 R 11 , carboxyl, -S(O)2C 1-6 Alkyl, -CONR 10 R 11 、-S(O)2(NR 10 R 11 )、-COO(C 1-6 alkyl), -P(O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkyloxy, C 2-6 Alkynyl, 4-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; wherein the hydrogen atoms on the above groups may be optionally further replaced by one or more R a Substituted, the R a Selected from the group consisting of D, halogen, cyano, hydroxy, amino, carboxyl, C1-6 Alkylsulfone, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkyloxy, 4-8 membered heterocyclic group;

[0018] R 1 and R 2 Each independently selected from the group consisting of H, D, halogen, cyano, hydroxyl, NR 10 R 11 、C 1-6 Alkyl, C 1-6 Alkoxy, -S(O)2C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyloxy, 4-8 membered heterocyclic group;

[0019] Alternatively, R attached to the same carbon atom 1 、R 2 The carbon atoms connected thereto together form a 3-7 membered carbocyclic ring or a 4-7 membered heterocyclic ring, wherein the carbocyclic ring and the heterocyclic ring may be optionally further substituted by one or more selected from deuterium, halogen, =O, CN, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 substituted by a haloalkoxy substituent;

[0020] Alternatively, two R atoms connected to two adjacent carbon atoms 1 Together with the two carbon atoms where they are located, they form a 3-7 membered carbocyclic ring or a 4-7 membered heterocyclic ring, wherein the carbocyclic ring and the heterocyclic ring may be optionally further substituted with one or more selected from deuterium, halogen, =O, CN, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 substituted by a haloalkoxy substituent;

[0021] Alternatively, two R atoms connected to two adjacent carbon atoms 1 Directly bond, and together with the two carbon atoms where they are located, form a carbon-carbon double bond;

[0022] R 3 Selected from the group consisting of H, unsubstituted or substituted with one or more R b Substituted C 1-6 alkyl, and the R b Selected from the group consisting of D, halogen, cyano, hydroxyl, NR 10 R 11 , carboxyl, -CONR 10 R 11、-S(O)2(C 1-6 Alkyl), -S(O)2(NR 10 R 11 )、-COO(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-15 membered heteroaryl;

[0023] R 4 Select from the following group: C 1-10 Alkyl, C 3-10 Carbocyclic group, 4-14 membered heterocyclic group, C 6-10 Aryl, 5-15 membered heteroaryl, the alkyl, carbocyclic, heterocyclic, aryl, heteroaryl may be further optionally substituted by one or more independent R e replace;

[0024] Each R e are independently selected from the group consisting of H, D, halogen, cyano, nitro, hydroxy, oxo (=O), =C(R 12 )2, carboxyl, NR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyloxy, 4-10 membered heterocyclyl, 4-10 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -COO(C 1-6 alkyl), -CO(C 1-6 alkyl), -CO(C 3-10 Cycloalkyl), -CO(4-10 membered heterocyclic group), -CONR 10 R 11 、-NR 10 CONR 10 R 11 、-SO2NR 10 R 11 、-NR 10 S(O)2NR 10 R 11 、-S(O)2(C 1-6 Alkyl), -S(O)2(C 3-10 Cycloalkyl), -S(O)2(4-10 membered heterocyclic group), -S(O)(C 1-6 alkyl), -S(O)(NR10 )(C 1-6 alkyl), -S(O)(NR 10 )(NR 10 R 11 )、-P(O)(C 1-6 Alkyl)2, -(C 1-4 Alkylene) hydroxyl, -(C 1-4 Alkylene) carboxyl, -(C 1-4 alkylene)NR 10 R 11 、-(C 1-4 alkylene)COO(C 1-4 Alkyl), -(C 1-4 alkylene)CONR 10 R 11 、-(C 1-4 alkylene)NR 10 CONR 10 R 11 、-(C 1-4 Alkylene)SO2NR 10 R 11 、-(C 1-4 alkylene)NR 10 S(O)2NR 10 R 11 、-(C 1-4 Alkylene)S(O)2(C 1-6 Alkyl), -(C 1-4 Alkylene)S(O)(NR 10 )(C 1-6 Alkyl), -(C 1-4 Alkylene)S(O)2(C 3-10 Cycloalkyl), -(C 1-4 Alkylene) S (O) 2 (4-10 membered heterocyclic group), each of the above groups may be further optionally substituted with one or more deuterium, halogen, =O, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SO2(C 1-6 alkyl), -CO(C 1-6 Alkyl), C 3-6 substituted by a cycloalkyl group or a 4-10 membered heterocyclic group;

[0025] Z is selected from the following group: -S-, -O-, -NR', -CR m R m '; wherein the R m and R m 'Selected from the following group: H, D, halogen, cyano, hydroxyl, amino, C1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, the above groups may be optionally further substituted with one or more selected from halogen, C 1-3 Alkyl, C 1-3 substituted by an alkoxy substituent;

[0026] Said R' is selected from the following group: H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -C 1-6 Alkylene-C 3-10 Cycloalkoxy, -C 1-6 Alkylene-(4-10 membered heterocyclic group), C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, -S(O)2(C 1-6 Alkyl), -S(O)2(C 1-6 Alkylene)-C 3-10 Cycloalkyl, -S(O)2(C 1-6 Alkylene-(4-10 membered heterocyclic group), -CO(C 1-6 alkyl), -CO(C 1-6 Alkylene)-C 3-10 Cycloalkyl, -CO(C 1-6 Alkylene)-(4-10 membered heterocyclic group), said group may be further optionally substituted by one or more selected from the group consisting of deuterium, halogen, =O, CN, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 substituted by a haloalkoxy substituent;

[0027] L is selected from the group consisting of none, unsubstituted or replaced by one or more R d Substituted C 1-6 Alkylene; wherein, the R d Selected from the group consisting of deuterium, oxo (=O), halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocyclic group, each of the above groups may be optionally further substituted by one or more selected from halogen, C 1-3 Alkyl, C 1-3 substituted with an alkoxy group;

[0028] Ring A is selected from the group consisting of: C 3-10 Carbocyclic ring, 4-14 membered heterocyclic ring;

[0029] Ring B is selected from the group consisting of: C 6-14 Aromatic ring, 5-15 membered heteroaromatic ring;

[0030] Each R 5 Independently selected from the group consisting of H, D, halogen, cyano, oxo (=O), =C(R 12 )2, hydroxyl, NR 10 R 11 , carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-8 membered heterocyclic group, -S(O)2C 1-6 Alkyl, -COC 1-6 Alkyl, -CONR 10 R 11 The above groups may be optionally further substituted by one or more selected from halogen, oxo (=O), C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 substituted with a haloalkoxy group;

[0031] Each R 6 Independently selected from the group consisting of H, D, halogen, cyano, hydroxyl, NR 10 R 11 , carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, SF5, C 6-10 Aryl, 5-15 membered heteroaryl, C 6-10 Aryloxy, 5-15 membered heteroaryloxy, -COO(C 1-6 alkyl), -CONR 10 R 11 、-NR 10 CONR 10 R 11 、-SO2NR 10 R 11 、-NR 10 S(O)2NR 10 R 11 、-S(O)2(C 1-6 Alkyl), -S(O)2(C 3-10 Cycloalkyl), -S(O)2(4-10 membered heterocyclic group), -S(O)(C 1-6 alkyl), -S(O)(NR 10 )(C1-6 alkyl), -S(O)(NR 10 )(NR 10 R 11 )、-P(O)(C 1-6 Alkyl)2, -(C 1-4 Alkylene) carboxyl, -(C 1-4 alkylene)NR 10 R 11 、-(C 1-4 alkylene)COO(C 1-4 Alkyl), -(C 1-4 alkylene)CONR 10 R 11 、-(C 1-4 alkylene)NR 10 CONR 10 R 11 、-(C 1-4 Alkylene)SO2NR 10 R 11 、-(C 1-4 alkylene)NR 10 S(O)2NR 10 R 11 、-(C 1-4 Alkylene)S(O)2(C 1-6 Alkyl), -(C 1-4 Alkylene)S(O)(NR 10 )(C 1-6 Alkyl), -(C 1-4 Alkylene)S(O)2(C 3-10 Cycloalkyl), -(C 1-4 Alkylene) S (O) 2 (4-10 membered heterocyclic group), each of the above groups may be optionally further substituted by one or more selected from deuterium, halogen, =O, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SO2(C 1-6 alkyl), -CO(C 1-6 Alkyl), C 3-6 substituted by a cycloalkyl group or a 4-10 membered heterocyclic group;

[0032] Alternatively, two R atoms attached to two adjacent atoms 6 The groups and the atoms they are located on together form the C 4-8 Carbocyclic or 4-8 membered heterocyclic rings, wherein the carbocyclic and heterocyclic rings may be further optionally substituted by one or more selected from deuterium, halogen, =O, =C(R 12 )2, cyano, hydroxyl, C 1-4 Alkyl, C1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SO2(C 1-6 alkyl), -CO(C 1-6 Alkyl), C 3-6 substituted by a cycloalkyl group or a 4-10 membered heterocyclic group;

[0033] Each R 10 , each R 11 Independently selected from the group consisting of H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, -S(O)2(C 1-6 alkyl), -CO(C 1-6 alkyl), which may be further optionally substituted by one or more radicals selected from deuterium, halogen, =O, CN, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-10 Cycloalkyl, C 3-10 Halogenated cycloalkyl, 4-10 membered heterocyclic group, -S(O)2(C 1-6 alkyl), -CONH2, -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl)2 is substituted by a substituent;

[0034] Alternatively, R attached to the same nitrogen atom 10 and R 11 Together with the nitrogen atom, a 4-10 membered heterocyclic ring is formed, wherein the heterocyclic ring may be optionally further substituted with one or more selected from deuterium, halogen, =O, CN, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SO2(C 1-6 alkyl), -CO(C 1-6 alkyl) substituent;

[0035] Each R 12 are independently selected where present: hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 alkyl halide;

[0036] Or, two R 12 Together with the carbon atoms they are located on, they form a C 3-6 Carbocyclic or 4-6 membered heterocyclic ring, wherein the carbocyclic ring and the heterocyclic ring may be further optionally substituted by one or more selected from halogen, C 1-4 Alkoxy, C1-4 substituted by a haloalkoxy substituent;

[0037] The carbocyclic or heterocyclic group may be saturated or partially unsaturated, but does not include an aromatic ring;

[0038] The heterocyclic and heteroaryl groups each independently contain 1, 2, 3 or 4 heteroatoms selected from N, S or O.

[0039] In another preferred embodiment, each R is independently selected from the following group: H, D, halogen, cyano, hydroxyl, amino, carboxyl, -CONR 10 R 11 、C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl.

[0040] In another preferred embodiment, the R a Selected from the group consisting of D, halogen, cyano, hydroxy, amino, carboxyl, C 1-4 Alkylsulfone, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 4-6 membered heterocyclic group.

[0041] In another preferred embodiment, the R 1 and R 2 Each independently selected from the group consisting of H, D, halogen, cyano, hydroxyl, NR 10 R 11 、C 1-4 Alkyl, C 1-4 Alkoxy, -S(O)2C 1-4 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 4-6 membered heterocyclic group.

[0042] In another preferred embodiment, R 1 、R 2 The carbon atoms connected thereto together form a 3-6 membered carbocyclic ring, which may be optionally further substituted with one or more deuterium, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 The alkyl group is substituted with a haloalkoxy substituent.

[0043] In another preferred embodiment, R 1 、R 2The carbon atoms to which it is connected together form a 4-6 membered heterocyclic ring, which may be optionally further substituted with one or more selected from deuterium, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 In another preferred embodiment, the two R 1 Together with the two carbon atoms where they are located, they form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring, wherein the carbocyclic ring and the heterocyclic ring may be further optionally substituted by one or more selected from deuterium, halogen, =O, CN, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 The alkyl group is substituted with a haloalkoxy substituent.

[0044] In another preferred embodiment, the two R 1 Together with the two carbon atoms they are located on, they form a carbon-carbon double bond.

[0045] In another preferred embodiment, the R 3 Selected from the group consisting of H, unsubstituted or substituted with 1, 2, 3 or 4 R b Substituted C 1-4 alkyl.

[0046] In another preferred embodiment, the R b Selected from the group consisting of D, halogen, cyano, hydroxyl, NR 10 R 11 , carboxyl, -CONR 10 R 11 、-S(O)2(C 1-6 Alkyl), -S(O)2(NR 10 R 11 )、-COO(C 1-4 Alkyl), C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl.

[0047] In a preferred embodiment, the R 4 Select from the following group: C 1-6 Alkyl, C 3-10 Saturated carbocyclic group, C 4-10 Unsaturated carbocyclic group, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl;

[0048] Preferably, the R 4 Select from the following group: C1-6 Alkyl, C 3-8 Saturated carbocyclic group, C 4-8 Unsaturated carbocyclic group, 4-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl;

[0049] More preferably, the R 4 Select from the following group: C 1-6 Alkyl, C 3-8 Cycloalkyl, C 4-8 cycloalkenyl, 4-6 membered heterocyclyl, aryl, naphthyl, 5-10 membered heteroaryl.

[0050] In another preferred embodiment, each R e are independently selected from the group consisting of H, D, halogen, cyano, nitro, hydroxy, oxo (=O), =C(R 12 )2, carboxyl, NR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 4-8 membered heterocyclyl, 4-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -COO(C 1-6 alkyl), -CO(C 1-6 alkyl), -CO(C 3-6 Cycloalkyl), -CO(4-8 membered heterocyclic group), -CONR 10 R 11 、-NR 10 CONR 10 R 11 、-SO2NR 10 R 11 、-NR 10 S(O)2NR 10 R 11 、-S(O)2(C 1-6 Alkyl), -S(O)2(C 3-6 Cycloalkyl), -S(O)2(4-8 membered heterocyclic group), -S(O)(C 1-6 alkyl), -S(O)(NR 10 )(C 1-6 alkyl), -S(O)(NR 10 )(NR 10 R 11 )、-P(O)(C 1-6 Alkyl)2, -(C1-4 Alkylene) hydroxyl, -(C 1-4 Alkylene) carboxyl, -(C 1-4 alkylene)NR 10 R 11 、-(C 1-4 alkylene)COO(C 1-4 Alkyl), -(C 1-4 alkylene)CONR 10 R 11 、-(C 1-4 alkylene)NR 10 CONR 10 R 11 、-(C 1-4 Alkylene)SO2NR 10 R 11 、-(C 1-4 alkylene)NR 10 S(O)2NR 10 R 11 、-(C 1-4 Alkylene)S(O)2(C 1-6 Alkyl), -(C 1-4 Alkylene)S(O)(NR 10 )(C 1-6 Alkyl), -(C 1-4 Alkylene)S(O)2(C 3-6 Cycloalkyl), -(C 1-4 Alkylene) S (O) 2 (4-8 membered heterocyclic group), each of the above groups may be further optionally substituted with one or more deuterium, halogen, =O, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SO2(C 1-6 alkyl), -CO(C 1-6 Alkyl), C 3-6 substituted by a cycloalkyl group or a 4-8 membered heterocyclic group;

[0051] Preferably, each R e are independently selected from the group consisting of H, D, halogen, cyano, nitro, hydroxy, oxo (=O), =C(R 12 )2, carboxyl, NR 10 R 11 、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6Cycloalkyloxy, 4-6 membered heterocyclyl, 4-6 membered heterocyclyloxy, phenyl, naphthyl, phenoxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -COO(C 1-4 alkyl), -CO(C 1-4 alkyl), -CO(C 3-6 Cycloalkyl), -CO(4-6 membered heterocyclic group), -CONR 10 R 11 、-NR 10 CONR 10 R 11 、-SO2NR 10 R 11 、-NR 10 S(O)2NR 10 R 11 、-S(O)2(C 1-4 Alkyl), -S(O)2(C 3-6 Cycloalkyl), -S(O)2(4-6 membered heterocyclic), -S(O)(C 1-4 alkyl), -S(O)(NR 10 )(C 1-4 alkyl), -S(O)(NR 10 )(NR 10 R 11 )、-P(O)(C 1-4 Alkyl)2, -(C 1-4 Alkylene) hydroxyl, -(C 1-4 Alkylene) carboxyl, -(C 1-4 alkylene)NR 10 R 11 、-(C 1-4 alkylene)COO(C 1-4 Alkyl), -(C 1-4 alkylene)CONR 10 R 11 、-(C 1-4 alkylene)NR 10 CONR 10 R 11 、-(C 1-4 Alkylene)SO2NR 10 R 11 、-(C 1-4 alkylene)NR 10 S(O)2NR 10 R 11 、-(C 1-4 Alkylene)S(O)2(C 1-4 Alkyl), -(C 1-4 Alkylene)S(O)(NR 10 )(C 1-4 Alkyl), -(C1-4 Alkylene)S(O)2(C 3-6 Cycloalkyl), -(C 1-4 Alkylene) S (O) 2 (4-6 membered heterocyclic group), each of the above groups may be further optionally substituted with one or more deuterium, halogen, =O, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SO2(C 1-6 alkyl), -CO(C 1-6 Alkyl), C 3-6 The cycloalkyl group or the 4- to 6-membered heterocyclic group may be substituted.

[0052] In a preferred embodiment, the R' is selected from the following group: H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene-C 3-8 Cycloalkyl, -C 1-6 Alkylene-C 3-8 Cycloalkoxy, -C 1-6 Alkylene-(4-8 membered heterocyclic group), C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, -S(O)2(C 1-6 Alkyl), -S(O)2(C 1-6 Alkylene)-C 3-8 Cycloalkyl, -S(O)2(C 1-6 Alkylene-(4-8 membered heterocyclic group), -CO(C 1-6 alkyl), -CO(C 1-6 Alkylene)-C 3-8 Cycloalkyl, -CO(C 1-6 Alkylene)-(4-8 membered heterocyclic group), said group may be further optionally substituted by one or more selected from the group consisting of deuterium, halogen, =O, CN, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 substituted by a haloalkoxy substituent;

[0053] Preferably, the R' is selected from the group consisting of H, C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-C 3-6 Cycloalkoxy, -C 1-4 Alkylene-(4-6 membered heterocyclic group), C 3-6Cycloalkyl, 4-6 membered heterocyclic group, -S(O)2(C 1-4 Alkyl), -S(O)2(C 1-4 Alkylene)-C 3-6 Cycloalkyl, -S(O)2(C 1-4 Alkylene-(4-6 membered heterocyclic group), -CO(C 1-4 alkyl), -CO(C 1-4 Alkylene)-C 3-6 Cycloalkyl, -CO(C 1-4 Alkylene)-(4-6 membered heterocyclic group), said group may be further optionally substituted by one or more selected from the group consisting of deuterium, halogen, =O, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 The alkyl group is substituted with a haloalkoxy substituent.

[0054] In a preferred embodiment, the L is selected from the following groups: none, unsubstituted or replaced by one or more R d Substituted C 1-3 Alkylene.

[0055] In another preferred embodiment, the R d Selected from the group consisting of deuterium, oxo (=O), halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, each of the above groups may be optionally further substituted by one or more selected from halogen, C 1-3 Alkyl, C 1-3 substituted with an alkoxy group.

[0056] In a preferred embodiment, the ring A is selected from the following group: C 3-10 Carbocyclic ring, 4-10 membered heterocyclic ring;

[0057] Preferably, the ring A is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, spiro[3.3]heptane, octahydropentane, adamantane, bicyclo[2.2.1]heptane, bicyclo[2.2.2] Octane, cubane, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, tetrahydropyrrole, tetrahydrothiophene, piperidine, piperazine, morpholine, azepane, azepane, 2-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.1]heptane, 6-azabicyclo[3.1.1]heptane, 3,6-diazabicyclo[3.1.1] Heptane, 8-azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane, octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, 2-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-azabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.2 ] octane, 4-azaspiro[2.5]octane, 4,7-diazaspiro[2.5]octane, 3,9-diazabicyclo[3.3.1]nonane, 3-oxa-7,9-diazabicyclo[3.3.1]nonane, 3-thia-7,9-diazabicyclo[3.3.1]nonane, and each of the above groups may further contain one or two intracyclic unsaturated double bonds at any possible position, provided that the entire ring system does not have aromaticity.

[0058] In a preferred embodiment, the ring B is selected from the following group: C 6-10 Aromatic ring, 5-14 membered heteroaromatic ring;

[0059] Preferably, the ring B is selected from the following group: a benzene ring, a naphthalene ring, a 5-10 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from O, S and N.

[0060] In another preferred embodiment, each R 5 are independently selected from the group consisting of H, D, halogen, cyano, oxo (=O), =C(R 12 )2, hydroxyl, NR 10 R 11 , carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 4-6 membered heterocyclic group, -S(O)2C 1-4 Alkyl, -COC 1-6 Alkyl, -CONR10 R 11 The above groups may be optionally further substituted by one or more selected from halogen, oxo (=O), C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 The alkyl group is substituted with a haloalkoxy group.

[0061] In another preferred embodiment, each R 5 are independently selected from the group consisting of H, D, F, Cl, Br, cyano, hydroxy, carboxyl, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxymethyl, trifluoromethoxymethyl, ethoxymethyl, 2,2,2-trifluoroethoxymethyl, CF3, CHF2, CH2F, 2,2,2-trifluoroethyl, 2-fluoroisopropyl, 3,3,3-trifluoroisopropyl, methoxy, trifluoromethoxy, ethoxy, 2-methoxyethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, 2-fluoroisopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, 1-fluorocyclopropyloxy, cyclobutyloxy, oxetanyl, azetidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, thiomorpholinyl,

[0062] In another preferred embodiment, each R 6 Independently selected from the group consisting of H, D, halogen, cyano, hydroxyl, NR 10 R 11 , carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, SF6, C 6-10 Aryl, 5-10 membered heteroaryl, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, -COO(C 1-6 alkyl), -CONR 10 R 11 、-NR 10 CONR 10 R 11 、-SO2NR 10 R 11 、-NR 10 S(O)2NR 10 R 11 、-S(O)2(C 1-6 Alkyl), -S(O)2(C 3-6 Cycloalkyl), -S(O)2(4-6 membered heterocyclic), -S(O)(C1-6 alkyl), -S(O)(NR 10 )(C 1-6 alkyl), -S(O)(NR 10 )(NR 10 R 11 )、-P(O)(C 1-6 Alkyl)2, -(C 1-4 Alkylene) carboxyl, -(C 1-4 alkylene)NR 10 R 11 、-(C 1-4 alkylene)COO(C 1-4 Alkyl), -(C 1-4 alkylene)CONR 10 R 11 、-(C 1-4 alkylene)NR 10 CONR 10 R 11 、-(C 1-4 Alkylene)SO2NR 10 R 11 、-(C 1-4 alkylene)NR 10 S(O)2NR 10 R 11 、-(C 1-4 Alkylene)S(O)2(C 1-6 Alkyl), -(C 1-4 Alkylene)S(O)(NR 10 )(C 1-6 Alkyl), -(C 1-4 Alkylene)S(O)2(C 3-6 Cycloalkyl), -(C 1-4 Alkylene) S (O) 2 (4-6 membered heterocyclic group), each of the above groups may be optionally further substituted by one or more selected from deuterium, halogen, =O, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SO2(C 1-4 alkyl), -CO(C 1-4 Alkyl), C 3-6 The cycloalkyl group or the 4- to 6-membered heterocyclic group may be substituted.

[0063] In another preferred embodiment, each R 6Independently selected from the group consisting of H, D, F, Cl, Br, cyano, hydroxy, amino, methylamino, dimethylamino, ethylamino, propylamino, isopropylamino, -CONHCH3, -CON(CH3)2-NHAc, -NHSO2Me, carboxyl, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxymethyl, trifluoromethoxymethyl, ethoxymethyl, 2,2,2-trifluoroethoxymethyl, cyclopropyloxymethyl, CF3, CHF2 , CH2F, 2,2,2-trifluoroethyl, 2-fluoroisopropyl, 3,3,3-trifluoroisopropyl, methoxy, trifluoromethoxy, ethoxy, 2-methoxyethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, 2-fluoroisopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, 1-fluorocyclopropyloxy, cyclobutyloxy, oxetanyl, azetidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, thiomorpholinyl, Phenyl, naphthyl, furyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, isoxazolyl, oxazolyl.

[0064] In another preferred embodiment, the two R 6 The groups and the atoms they are part of together form the C 4-6 Carbocyclic or 4-6 membered heterocyclic rings, wherein the carbocyclic and heterocyclic rings may be further optionally substituted by one or more selected from deuterium, halogen, =O, =C(R 12 )2, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SO2(C 1-4 alkyl), -CO(C 1-4 Alkyl), C 3-6 The cycloalkyl group or the 4- to 6-membered heterocyclic group may be substituted.

[0065] In a preferred embodiment, the compound has a structure represented by formula (II),

[0066]

[0067] Among them, m, n, s, t, L, R 1 、R 2 、R 4 、R 5 、R 6 , R', X, Y, Ring A and Ring B are as defined above.

[0068] In a preferred embodiment, the compound is selected from the following group:

[0069]

[0070]

[0071]

[0072] In a second aspect of the present invention, a pharmaceutical composition is provided, characterized in that the composition comprises:

[0073] (i) the compound according to the first aspect of the present invention, its stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; and

[0074] (ii) pharmaceutically acceptable carriers, adjuvants or vehicles.

[0075] In a third aspect of the present invention, there is provided a use of the compound according to the first aspect of the present invention, its stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition according to the second aspect of the present invention, characterized in that it is used for preparing a PDE4B inhibitor; or for preparing a drug for treating and / or preventing a disease associated with PDE4B;

[0076] Preferably, the PDE4B-related disease is a respiratory disease, a gastrointestinal disease, an inflammatory disease of the joints, skin or eyes, or a peripheral or central nervous system disease;

[0077] More preferably, the disease associated with PDE4B is selected from the group consisting of chronic obstructive pulmonary disease, asthma, chronic bronchitis, idiopathic pulmonary fibrosis, allergic rhinitis, adult respiratory distress syndrome, chronic sinusitis, ulcerative colitis, Crohn's disease, Crohn's disease, overactive bladder, atopic dermatitis, psoriasis, vitiligo, urticaria, rheumatoid arthritis, osteoarthritis, gouty arthritis, spondylitis, depression, acute and chronic anxiety states, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain, brain damage caused by stroke, hypoxia or craniocerebral trauma.

[0078] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0079] After extensive and lengthy research and extensive screening, the inventors have developed, for the first time, a compound represented by Formula (I), its stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs. The compound of the present invention is a selective PDE4B inhibitor and can be used to prepare a medicament for treating and / or preventing diseases associated with PDE4B. Based on this, the inventors have completed the present invention.

[0080]

[0081] the term

[0082] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0083] As used herein, the term "alkyl" refers to a monovalent straight-chain or branched saturated hydrocarbon group consisting of carbon and hydrogen atoms, for example, "C 1-6 "Alkyl" means an alkyl group having 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl groups.

[0084] As used herein, the term "alkylene" refers to a group obtained by removing a hydrogen atom from an alkyl group as described above, for example, methylene (-CH2-), ethylene (-CH2CH2-), and the like.

[0085] As used herein, the term "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond, for example, "C 2-6 The term "alkenyl" refers to an alkenyl group having 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.

[0086] As used herein, the term "alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. 2-6 The term "alkynyl" refers to an alkynyl group having 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.

[0087] As used herein, the terms "carbocycle" and "carbocyclyl" refer to saturated or unsaturated carbocyclic groups composed of carbon and hydrogen atoms, such as monocyclic, bicyclic, or tricyclic rings, wherein the ring structure as a whole is not aromatic but may contain one or more unsaturated structures. The rings may be further substituted with one or more substituents. When the carbocyclyl contains two or more rings, the rings may further form fused rings, bridged rings, spirocycles, or any combination thereof.

[0088] As used herein, the term "cycloalkyl" refers to a monovalent saturated carbocyclic group composed of carbon and hydrogen atoms, such as "C 3-8 "Cycloalkyl" refers to a cycloalkyl group containing 3 to 8 (e.g., 3, 4, 5, 6, 7 or 8) carbon atoms, preferably C 3-6 Cycloalkyl. A cycloalkyl group may be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like, or a bicyclic or polycyclic ring, such as a fused ring, a bridged ring, or a spiro ring, or a combination of any of these.

[0089] As used herein, the term "cycloalkenyl" refers to an unsaturated cyclic hydrocarbon group having at least one double bond, such as "C 3-8 "Cycloalkenyl" refers to a cycloalkenyl group having 3 to 8 (e.g., 3, 4, 5, 6, 7 or 8) carbon atoms, preferably C 3-6 Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclohexadienyl, and the like.

[0090] As used herein, the term "alkoxy" refers to a group of the formula -OR z group, where R z Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, tert-butoxy, and the like.

[0091] As used herein, the term "cycloalkyloxy" or "cycloalkoxy" refers to a radical of the formula -OR v group, where R v is a cycloalkyl group as defined herein.

[0092] As used herein, the term "heteroaryloxy" refers to a radical of the formula -OR u group, where R u is a heteroaryl group as defined herein.

[0093] As used herein, the term "aryloxy" refers to a radical of the formula -OR t group, where R t is an aryl group as defined herein.

[0094] As used herein, the term "halogen" refers to halogen and its isotopes, including but not limited to F, 18 F.32 Cl, Br, I.

[0095] As used herein, the term "amino" refers to -NH2.

[0096] As used herein, the term "carboxyl" refers to -COOH.

[0097] As used herein, the term "oxo" refers to a =0 moiety.

[0098] As used herein, the term "haloalkyl" refers to a group in which one or more hydrogen atoms in the alkyl group described above are replaced by the same or different halogen atoms. 1-6 "Alkyl" is preferably a halogenated C 1-4 Examples of alkyl and halogenated alkyl groups include, but are not limited to, -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl groups (eg, -CF3-, -CF2CF3), and the like.

[0099] As used herein, the term "haloalkoxy" refers to an alkoxy group as described above in which one or more hydrogen atoms are replaced by the same or different halogen atoms. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, and 2,2,2-trifluoroethoxy.

[0100] As used herein, the term "sulfone" refers to a group of the formula -S(O)2-.

[0101] As used herein, the term "alkylsulfonyl" refers to a group of the formula -S(O)2-alkyl. Alkylsulfonyl is preferably -S(O)2-(C 1-6 Alkyl), such as -S(O)2-CH3, -S(O)2-CH2CH3, etc.

[0102] As used herein, the terms "heterocycle" and "heterocyclyl" refer to fully saturated or partially saturated monocyclic, bicyclic or polycyclic cyclic groups containing one or more heteroatoms selected from N, S or O on the ring backbone. When describing the number of ring backbones, it is intended to include the case where the number of backbone atoms is any integer in the range. For example, "3-8 membered heterocyclyl" refers to a group having 3-8 ring members (3, 4, 5, 6, 7 or 8). Among them, the nitrogen atom or sulfur atom can be oxidized, and the nitrogen atom can also be quaternized. The heterocyclic group can be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule. Monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxanyl, and tetrahydro-1,1-dioxythiophene. Polycyclic heterocyclic groups include, but are not limited to, spirocyclic, fused, and bridged heterocyclic groups; the spirocyclic, fused, and bridged heterocyclic groups are optionally linked to other groups via single bonds, or further linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups via any two or more atoms on the ring.

[0103] As used herein, the term "aryl" refers to an aromatic cyclic hydrocarbon group (including monocyclic, bicyclic or polycyclic groups), for example, "C 6-12 "Aryl" refers to an aromatic cyclic hydrocarbon group with 6-12 (6, 7, 8, 9, 10, 11 or 12) ring carbon atoms. Among them, it contains two or more aromatic rings (such as bicyclic rings, etc.), and the aromatic rings of the aryl group can be connected by a single bond (such as biphenyl) or fused (such as naphthalene, anthracene, etc.). Examples of aryl groups (especially monocyclic and bicyclic groups) include but are not limited to: phenyl, biphenyl or naphthyl. The aryl group can be fused with the heterocyclic group through a single bond or any two adjacent ring carbon atoms, for example: benzotetrahydrofuranyl, chromanyl, benzodioxanyl, wait.

[0104] As used herein, the term "heteroaryl" refers to an aromatic cyclic group (including monocyclic, bicyclic or polycyclic groups) whose ring backbone contains 1, 2, 3 or 4 heteroatoms selected from N, S or O, for example, "5-12 membered heteroaryl" refers to a monocyclic, bicyclic or tricyclic group having 5 to 12 (5, 6, 7, 8, 9, 10, 11 or 12) ring atoms. Examples of heteroaryl groups include, but are not limited to, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, furanyl, pyranyl, pyridinyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, aza Base, diazepine Acridinium, etc.

[0105] As used herein, the term "polysubstituted" means comprising two or more substitutions.

[0106] When each group loses one H atom, it is a subunit of the corresponding group, and it is a divalent group. For example, when an alkyl group loses one H atom, it becomes an alkylene group (for example, methylene, ethylene, propylene, isopropylene (such as ), butylene (such as ), pentylene (such as ), hexamethylene (such as ), heptylene (such as ) etc.); cycloalkyl corresponds to cycloalkylene (such as: etc.); heterocyclic groups correspond to heterocyclic groups (such as: ), alkoxy corresponds to alkyleneoxy (such as: -CH2O-, -CH2CH2O-, -OCH2CH2CH2-), heteroalkyl corresponds to heteroalkylene (such as: -CH2-O-CH2CH2-, -CH2-O-(CH2)2CH2-, -CH2CH2-O-CH2CH2-, -CH2-O-CH2CH2CH2-, -CH2-S-CH2CH2-, -CH2-S-(CH2)2CH2-, -CH2CH2-S-CH2CH2-, -CH2-S-CH2CH2CH2-, -CH2-NH-CH2CH2-, -CH2-NH-(CH2)2CH2-, -CH2CH2-NH-CH2CH2-, -CH2-NH-CH2CH2CH2-), etc.

[0107] In the present invention, the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl and other groups include substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl and the like unless otherwise specified, and the substituents include but are not limited to halogen, hydroxyl, cyano, acyl, sulfone, ester, sulfoxide, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl and the like.

[0108] As used herein, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Specific substituents are those described above or as appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from the specified group at any substitutable position on the group, and the substituents may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.

[0109] Unless otherwise specified, the groups of the present invention may be substituted by a substituent selected from the group consisting of: D, halogen, cyano, nitro, hydroxy, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-12 membered heterocyclyl, C3-C 12 Cycloalkyl, 5-10 membered heteroaryl and C6-C 10 Aryl.

[0110] As used herein, "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0111] The term "plurality" herein refers to a positive integer of 2, 3, 4, 5 or more.

[0112] Active ingredient

[0113] As used herein, "compound of the present invention" refers to the compound represented by formula (I), and also includes its stereoisomers, tautomers, optical isomers, pharmaceutically acceptable salts, crystalline forms, isotopic derivatives, prodrugs, metabolites, solvates or hydrates thereof.

[0114] Unless otherwise indicated, the structural formulas described herein are intended to include all stereoisomers (e.g., cis-trans isomers, enantiomers, diastereomers, and conformational isomers): R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, cis-trans isomers of cycloalkanes, etc. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or conformational isomers are all within the scope of the present invention.

[0115] The compounds of the present invention may contain cis- and trans-isomers, one or more chiral carbon atoms, and thus may produce stereoisomeric forms such as cis- and trans-isomers, chiral isomers, enantiomers, diastereomers, and other combinations thereof. Cis- and trans-isomerism refers to the diastereoisomerism that occurs due to restrictions on the free rotation of the compound molecule, resulting in different spatial arrangements of the various groups. These restrictions are generally caused by the presence of functional groups in the organic compound structure that cannot rotate freely, such as C=C double bonds, C=N double bonds, C=S double bonds, N=N double bonds, heterocycles, or cycloalkanes. Organic molecules containing such isomers, such as alkenes, azo compounds, and alicyclic hydrocarbons, are considered cis- and trans-isomers. The cis form refers to the presence of ligands of the same type in adjacent positions, typically designated "cis" or "cis-"; the trans form refers to the presence of ligands of the same type in diagonal positions, typically designated "trans" or "trans-". Each chiral carbon atom can be defined as either (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the present invention may be prepared using racemates, cis-trans isomers, chiral isomers, diastereomers, or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0116] Conventional techniques for preparing / isolating individual optical isomers (i.e., cis-trans and chiral isomers) include chiral synthesis from appropriate cis-trans or optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography.

[0117] If a synthesis of a specific stereoisomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, followed by separation of the resulting stereomixture and removal of the chiral auxiliary to obtain a pure cis-trans monomer, chiral monomer, or mixed stereoisomer. If the molecule contains a cis-trans isomeric center, pure cis- or trans-forms can be obtained by purification via column chromatography (normal-phase silica gel or reverse-phase high-performance liquid chromatography). Furthermore, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with a suitable optically active acid or base, and then separated by conventional means such as fractional crystallization or chromatography to obtain the pure enantiomers.

[0118] The present invention also includes isotopically labeled compounds (i.e., isotopic derivatives) that are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number. Examples of isotopes in the isotopic derivatives of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H.3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. The isotopic derivatives of the compounds of the present invention are all within the scope of protection of the present invention. 3 H-labeled compounds and 14 C-labeled compounds are useful in drug and substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 The preparation and detection of C) labeled compounds are relatively easy and are the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2 H, due to its excellent metabolic stability, has advantages in certain therapeutics, such as increasing half-life in vivo or reducing dosage, and therefore, may be preferred in certain situations. Isotopically labeled compounds can be prepared using conventional methods by replacing readily available isotopically labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

[0119] As used herein, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0120] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without the side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, and naphthalene disulfonate. These salts can be prepared by methods known in the art.

[0121] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. The salt derived from organic base includes but is not limited to following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

[0122] Metabolites of the compound represented by formula (I) and pharmaceutically acceptable salts thereof, as well as prodrugs that can be converted into the compound represented by formula (I) and pharmaceutically acceptable salts thereof in vivo, are also included in the scope of protection of the present invention.

[0123] As used herein, the term "solvate" refers to a complex in which the compound represented by formula (I) is coordinated with solvent molecules to form a specific ratio.

[0124] As used herein, the term "hydrate" refers to a complex formed by the compound represented by formula (I) coordinated with water molecules to form a specific ratio.

[0125] As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to expand their scope. Generally, the term "substituted" refers to the replacement of a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are substituted with multiple substituents of a specified structure, the substituents may be the same or different at each position. As used herein, the term "substituted" includes all permissible organic group substitutions. Broadly speaking, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic groups. Herein, for example, heteroatoms such as nitrogen may be substituted with hydrogen or any of the permissible organic groups described above to supplement their valences. Furthermore, the present invention is not intended to limit the permissible organic groups in any way. The present invention recognizes that combinations of substituents and variable groups are advantageous for the treatment of diseases by forming stable compounds. The term "stable" herein refers to compounds that are stable and maintain the structural integrity of the compound over a sufficient period of time for testing, preferably for a sufficient period of time for efficacy, and is used herein for such purposes.

[0126] Pharmaceutical compositions and methods of administration

[0127] Since the compounds of the present invention can selectively inhibit PDE4B and are used to treat respiratory diseases, gastrointestinal diseases, inflammatory diseases of the joints, skin or eyes, and peripheral or central nervous system diseases, the compounds of the present invention and their stereoisomers, optical isomers, pharmaceutically acceptable salts, crystalline forms, isotopic derivatives, prodrugs, metabolites, solvates or hydrates thereof, as well as pharmaceutical compositions containing the compounds of the present invention as the main active ingredient, can be used to prevent and / or treat (stabilize, alleviate or cure) PDE4B-related diseases (respiratory diseases, gastrointestinal diseases, inflammatory diseases of the joints, skin or eyes, peripheral or central nervous system diseases, etc.).

[0128] The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention and a pharmaceutically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-200 mg per dose. Preferably, "one dose" is one capsule or tablet.

[0129] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0130] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration methods include, but are not limited to, oral administration and parenteral administration (intravenous, intramuscular, or subcutaneous).

[0131] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0132] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0133] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0134] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0135] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0136] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0137] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0138] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0139] When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds. One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds can be used simultaneously, separately, or sequentially with the compound of the present invention to prevent and / or treat diseases associated with PDE4B.

[0140] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1-2000 mg, preferably 20-500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0141] The main advantages of the present invention are:

[0142] The compound of the present invention has good PDE4B inhibitory activity, weak inhibitory activity on PDE4D, high selectivity, and small potential toxic and side effects.

[0143] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are percentages by weight and parts by weight.

[0144] In the following examples, the characterization methods used are as follows.

[0145] H NMR spectroscopy ( 1 H NMR):

[0146] The NMR spectra of the reaction products and intermediates (1 H NMR spectra were obtained on a Bruker AVANCE III HD400 / 500 in Germany. Sample preparation is as follows: In a clean, dry glass NMR tube, completely dissolve an appropriate amount of sample in approximately 0.5 mL of a deuterated solvent. Most compounds have good solubility in DMSO-d6, making it the preferred deuterated solvent. DMSO-d6 readily solidifies at relatively low room temperatures and requires a hair dryer to dissolve it before loading. Other suitable deuterated reagents, such as CDCl3 and CD3OD, can also be used depending on testing needs. Tetramethylsilane (TMS) was used as the internal standard for testing at room temperature, with a chemical shift of 0 ppm.

[0147] Example 1: Preparation of (5R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-((2-phenylcyclopropyl)methoxy)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxidation

[0148]

[0149] Step 1: Dissolve 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (3 g, 14.49 mmol) in acetonitrile (15 mL). Add triethylamine (7.33 g, 10.07 mL, 72.44 mmol) and 1-aminocyclobutylmethanol hydrochloride (2.19 g, 15.94 mmol) sequentially. Stir the reaction mixture at 75°C for 12 hours. Cool the reaction mixture to room temperature and concentrate. The crude product is purified by silica gel chromatography to afford [1-[(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino]cyclobutyl]methanol (2.50 g, crude) as a pale yellow solid.

[0150] Step 2: To a solution of [1-[(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino]cyclobutyl]methanol (5.20 g, 19.13 mmol) in dichloromethane (50 mL) were added (S)-(-)-1,1'-bi-2-naphthol (547.86 mg, 1.91 mmol) and tetraisopropyl titanate (271.92 mg, 286.23 μL, 956.73 μmol). The mixture was stirred at 25°C for 0.5 hour, followed by the addition of water (344.61 mg, 344.61 μL, 19.13 mmol). Stirring was continued for 1 hour, followed by the addition of tert-butyl hydroperoxide (2.07 g, 2.20 mL, 22.96 mmol). The mixture was stirred at room temperature for 2 h and then concentrated. The crude product was purified by silica gel chromatography to give (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (4.60 g, yield: 83.54%).

[0151] Step 3: tert-Butyldimethylsilyl chloride (1.08 g, 6.96 mmol) was added to a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (1 g, 3.48 mmol) and 1H-imidazole (947.67 mg, 13.92 mmol) in N,N-dimethylformamide (10 mL) and allowed to react at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the crude product was purified by silica gel chromatography to afford (R)-4-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)-2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (1.20 g, yield: 85.77%).

[0152] Step 4: Add trans-(2-phenylcyclopropyl)methanol (73.73 mg, 497.48 μmol), (R)-4-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)-2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (200 mg, 497.48 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (28.78 mg, 49.75 μmol), tris(dibenzylideneacetone)palladium (45.56 mg, 49.75 μmol) and potassium carbonate (206.27 mg, 1.49 mmol) to the reaction flask, and add 1,4-dioxane (5 mL) under nitrogen protection. Seal the system and replace it with nitrogen three times. Heat the reaction system at 80°C and stir for 4 hours. After cooling to room temperature, the reaction solution was concentrated and the crude product was purified by silica gel chromatography to give (5R)-4-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)-2-((2-phenylcyclopropyl)methoxy)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (120 mg, yield: 46.95%) as a yellow solid.

[0153] Step 5: (5R)-4-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)-2-((2-phenylcyclopropyl)methoxy)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg, 194.64 μmol) was dissolved in N,N-dimethylformamide (1 mL), and cesium fluoride (147.83 mg, 973.20 μmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated to remove the solvent, and the crude product was purified by silica gel chromatography and reverse preparative chromatography to afford (5R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-((2-phenylcyclopropyl)methoxy)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (8.15 mg, yield: 10.48%, purity: 98.43%) as a light yellow solid. ESI-MS[M+H]+:found 400.2. 1 HNMR (400MHz, DMSO-d6) δ8.00 (s, 1H), 7.24 (t, J = 7.5Hz, 2H), 7.17-7.05 (m, 3H), 4.88 ( s,1H),4.25(ddd,J=11.4,6.8,3.3Hz,1H),4.17(ddd,J=11.4,7.2,3.1Hz,1H),3.76-3. 65(m,2H),3.53-3.41(m,1H),3.30-3.23(m,1H),3.05-2.90(m,2H),2.37-2.12(m,4H) ,1.97(dt,J=9.2,5.2Hz,1H),1.83-1.67(m,2H),1.61-1.52(m,1H),1.06-0.94(m,2H).

[0154] Example 2: Preparation of (5R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(methyl((2-(pyridin-2-yl)cyclopropyl)methyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxidation

[0155]

[0156] Step 1: Under nitrogen, ethyl diazoacetate (5.71 g, 47.56 mmol) was added to a solution of 2-vinylpyridine (5.15 g, 47.56 mmol) in toluene (50 mL), and the mixture was stirred at 110° C. for 16 hours. After cooling to room temperature, the mixture was concentrated, and the crude product was purified by silica gel chromatography to give trans-ethyl 2-(pyridin-2-yl)cyclopropanecarboxylate (3.20 g, yield: 35.19%) as a brown oil.

[0157] Step 2: Trans-ethyl 2-(pyridin-2-yl)cyclopropanecarboxylate (100 mg, 522.93 μmol) and ethanolic methylamine solution (27%, 2.70 mL, 65.72 mmol) were dissolved in ethanol (5 mL) and reacted at 100° C. in a sealed tube for 16 hours. After cooling to room temperature, the mixture was concentrated and the crude product was purified by silica gel chromatography to obtain N-methyl-2-(pyridin-2-yl)cyclopropane-1-carboxamide (80 mg, crude) as a light yellow oil.

[0158] Step 3: To a solution of N-methyl-2-(pyridin-2-yl)cyclopropane-1-carboxamide (80 mg, 453.98 μmol) in tetrahydrofuran (2 mL) was added lithium aluminum hydride (907.96 μL, 907.99 μmol, 1 M in tetrahydrofuran) at 0°C under nitrogen. The mixture was reacted at 70°C for 2 hours. After cooling to room temperature, the mixture was cooled to 0°C and quenched with 1 M sodium hydroxide solution. The mixture was filtered and concentrated to give N-methyl-1-(2-(pyridin-2-yl)cyclopropyl)methanamine (70 mg, crude product), which was used directly in the next reaction.

[0159] Step 4: Dissolve N-methyl-1-(2-(pyridin-2-yl)cyclopropyl)methanamine (100 mg, 616.37 μmol), (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (88.68 mg, 308.19 μmol) and N,N-diisopropylethylamine (241.39 mg, 1.85 mmol) in 1,4-dioxane (5 mL) and react at 100 °C for 3 hours. The mixture was concentrated, and the crude product was purified by silica gel chromatography followed by reverse preparative purification to give (5R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(methyl((2-(pyridin-2-yl)cyclopropyl)methyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (52.32 mg, yield: 20.53%, purity: 99.8%). ESI-MS: 414.3 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ8.36(dd,J=4.8,1.6Hz,1H),7.61(tt,J=7.6,1.6Hz,1H),7.26(d,J=8.0Hz,1H),7. 31-7.14(m,1H),7.10(dd,J=7.6,4.8Hz,1H),4.84(t,J=5.6Hz,1H),3.82-3.73(m,1H),3.73-3.61(m,2H), 3.61-3.45(m,1H),3.44-3.34(m,1H),3.25-3.15(m,1H),3.12(s,3H),2.97-2.79(m,2H),2.42-2.25(m,2H ),2.19-2.01(m,3H),1.81-1.63(m,2H),1.62-1.50(m,1H),1.13(dt,J=8.8,4.0Hz,1H),1.03-0.90(m,1H).

[0160] Examples 3-85 can be prepared by selecting appropriate raw materials according to the synthesis method of Example 2, and their structures are shown in Table 1.

[0161] Table 1. Structural formula, chemical name and mass spectrometry data of Examples 3-85

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182] The NMR data of some of the compounds in the examples are as follows:

[0183]

[0184]

[0185] Example 86: PDE4B / 4D enzyme activity inhibition experiment

[0186] The inhibitory activity of the compounds provided herein against PDE4B and PDE4D can be assayed using the PDELight™ HTS cAMP Phosphodiesterase Assay Kit (Lonza, LT07-600). The specific procedure is as follows: First, prepare a 10 mM stock solution of the test compound in DMSO and serially dilute it using Assay Buffer (50 mM Tris-HCl, pH 7.5; 1.3 mM MgCl2; 0.01% Brij-35) to obtain a working solution. PDE4B and PDE4D enzymes are each diluted to 160 pM using Assay Buffer, performed on ice throughout. Simultaneously, cAMP (Sigma, A9501) is diluted to the appropriate concentration using Assay Buffer. 4 μL of PDE4B or PDE4D working solution and 4 μL of compound working solution were added to each well of a 384-well plate (PerkinElmer, 6007680). The plates were incubated at room temperature with shaking for 5 minutes. 4 μL of cAMP was then added per well. The plates were incubated at room temperature with shaking for another 60 minutes. 4 μL of Stop Solution was then added per well, followed by 8 μL of AMP-Detection Agent per well. After incubation at room temperature for 15 minutes, bioluminescence was detected using a microplate reader (PerkinElmer, Ensight). The experimental results were entered into GraphPad Prism software, and the IC values ​​of each compound were calculated by fitting. 50 , the specific test results are shown in Table 2.

[0187] Table 2. Test results of some example compounds

[0188]

[0189]

[0190] Among them: "NT" is the abbreviation of "Not Tested", which means it has not been tested yet;

[0191] "A" stands for IC 50 ≤100nM, “B” means 100nM <IC 50 ≤1uM, “C” means 1uM <IC 50 ≤10uM, “D” means 10uM <IC 50 .

[0192] From the above test results, it can be seen that the compounds of the present invention have good inhibitory activity against PDE4B, while their PDE4D inhibitory activity is relatively weak, thus having good activity and selectivity, and are a class of very potential PDE4B selective inhibitors.

[0193] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound represented by formula (I), its stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, in, m is 0, 1, or 2; n is 2 or 3; s and t are each independently 0, 1, 2, 3 or 4; X and Y are each independently N or CR, and X and Y are not CR at the same time; Each R is independently selected from the group consisting of H, D, halogen, cyano, hydroxy, NR 10 R 11 , carboxyl, -S(O)2C 1-6 Alkyl, -CONR 10 R 11 、-S(O)2(NR 10 R 11 )、-COO(C 1-6 alkyl), -P(O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkyloxy, C 2-6 Alkynyl, 4-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; wherein the hydrogen atoms on the above groups may be optionally further replaced by one or more R a Substituted, the R a Selected from the group consisting of D, halogen, cyano, hydroxy, amino, carboxyl, C 1-6 Alkylsulfone, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkyloxy, 4-8 membered heterocyclic group; R 1 and R 2 Each independently selected from the group consisting of H, D, halogen, cyano, hydroxyl, NR 10 R 11 、C 1-6 Alkyl, C 1-6 Alkoxy, -S(O)2C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyloxy, 4-8 membered heterocyclic group; Alternatively, R attached to the same carbon atom 1 、R 2 The carbon atoms connected thereto together form a 3-7 membered carbocyclic ring or a 4-7 membered heterocyclic ring, wherein the carbocyclic ring and the heterocyclic ring may be optionally further substituted by one or more selected from deuterium, halogen, =O, CN, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 substituted by a haloalkoxy substituent; Alternatively, two R atoms connected to two adjacent carbon atoms 1 Together with the two carbon atoms where they are located, they form a 3-7 membered carbocyclic ring or a 4-7 membered heterocyclic ring, wherein the carbocyclic ring and the heterocyclic ring may be optionally further substituted with one or more selected from deuterium, halogen, =O, CN, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 substituted by a haloalkoxy substituent; Alternatively, two R atoms connected to two adjacent carbon atoms 1 Directly bond, and together with the two carbon atoms where they are located, form a carbon-carbon double bond; R 3 Selected from the group consisting of H, unsubstituted or substituted with one or more R b Substituted C 1-6 alkyl, and the R b Selected from the group consisting of D, halogen, cyano, hydroxyl, NR 10 R 11 , carboxyl, -CONR 10 R 11 、-S(O)2(C 1-6 Alkyl), -S(O)2(NR 10 R 11 )、-COO(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-15 membered heteroaryl; R 4 Select from the following group: C 1-10 Alkyl, C 3-10 Carbocyclic group, 4-14 membered heterocyclic group, C 6-10 Aryl, 5-15 membered heteroaryl, the alkyl, carbocyclic, heterocyclic, aryl, heteroaryl may be further optionally substituted by one or more independent R e replace; Each R e are independently selected from the group consisting of H, D, halogen, cyano, nitro, hydroxy, oxo (=O), =C(R 12 )2, carboxyl, NR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyloxy, 4-10 membered heterocyclyl, 4-10 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -COO(C 1-6 alkyl), -CO(C 1-6 alkyl), -CO(C 3-10 Cycloalkyl), -CO(4-10 membered heterocyclic group), -CONR 10 R 11 、-NR 10 CONR 10 R 11 、-SO2NR 10 R 11 、-NR 10 S(O)2NR 10 R 11 、-S(O)2(C 1-6 Alkyl), -S(O)2(C 3-10 Cycloalkyl), -S(O)2(4-10 membered heterocyclic group), -S(O)(C 1-6 alkyl), -S(O)(NR 10 )(C 1-6 alkyl), -S(O)(NR 10 )(NR 10 R 11 )、-P(O)(C 1-6 Alkyl)2, -(C 1-4 Alkylene) hydroxyl, -(C 1-4 Alkylene) carboxyl, -(C 1-4 alkylene)NR 10 R 11 、-(C 1-4 alkylene)COO(C 1-4 Alkyl), -(C 1-4 alkylene)CONR 10 R 11 、-(C 1-4 alkylene)NR 10 CONR 10 R 11 、-(C 1-4 Alkylene)SO2NR 10 R 11 、-(C 1-4 alkylene)NR 10 S(O)2NR 10 R 11 、-(C 1-4 Alkylene)S(O)2(C 1-6 Alkyl), -(C 1-4 Alkylene)S(O)(NR 10 )(C 1-6 Alkyl), -(C 1-4 Alkylene)S(O)2(C 3-10 Cycloalkyl), -(C 1-4 Alkylene) S (O) 2 (4-10 membered heterocyclic group), each of the above groups may be further optionally substituted with one or more deuterium, halogen, =O, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SO2(C 1-6 alkyl), -CO(C 1-6 Alkyl), C 3-6 substituted by a cycloalkyl group or a 4-10 membered heterocyclic group; Z is selected from the following group: -S-, -O-, -NR', -CR m R m '; wherein the R m and R m 'Selected from the following group: H, D, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, the above groups may be optionally further substituted with one or more selected from halogen, C 1-3 Alkyl, C 1-3 substituted by an alkoxy substituent; Said R' is selected from the following group: H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -C 1-6 Alkylene-C 3-10 Cycloalkoxy, -C 1-6 Alkylene-(4-10 membered heterocyclic group), C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, -S(O)2(C 1-6 Alkyl), -S(O)2(C 1-6 Alkylene)-C 3-10 Cycloalkyl, -S(O)2(C 1-6 Alkylene-(4-10 membered heterocyclic group), -CO(C 1-6 alkyl), -CO(C 1-6 Alkylene)-C 3-10 Cycloalkyl, -CO(C 1-6 Alkylene)-(4-10 membered heterocyclic group), said group may be further optionally substituted by one or more selected from the group consisting of deuterium, halogen, =O, CN, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 substituted by a haloalkoxy substituent; L is selected from the group consisting of none, unsubstituted or replaced by one or more R d Substituted C 1-6 Alkylene; wherein, the R d Selected from the group consisting of deuterium, oxo (=O), halogen, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocyclic group, each of the above groups may be optionally further substituted by one or more selected from halogen, C 1-3 Alkyl, C 1-3 substituted with an alkoxy group; Ring A is selected from the group consisting of: C 3-10 Carbocyclic ring, 4-14 membered heterocyclic ring; Ring B is selected from the group consisting of: C 6-14 Aromatic ring, 5-15 membered heteroaromatic ring; Each R 5 Independently selected from the group consisting of H, D, halogen, cyano, oxo (=O), =C(R 12 )2, hydroxyl, NR 10 R 11 , carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-8 membered heterocyclic group, -S(O)2C 1-6 Alkyl, -COC 1-6 Alkyl, -CONR 10 R 11 The above groups may be optionally further substituted by one or more selected from halogen, oxo (=O), C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 substituted with a haloalkoxy group; Each R 6 Independently selected from the group consisting of H, D, halogen, cyano, hydroxy, NR 10 R 11 , carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, SF5, C 6-10 Aryl, 5-15 membered heteroaryl, C 6-10 Aryloxy, 5-15 membered heteroaryloxy, -COO(C 1-6 alkyl), -CONR 10 R 11 、-NR 10 CONR 10 R 11 、-SO2NR 10 R 11 、-NR 10 S(O)2NR 10 R 11 、-S(O)2(C 1-6 Alkyl), -S(O)2(C 3-10 Cycloalkyl), -S(O)2(4-10 membered heterocyclic group), -S(O)(C 1-6 alkyl), -S(O)(NR 10 )(C 1-6 alkyl), -S(O)(NR 10 )(NR 10 R 11 )、-P(O)(C 1-6 Alkyl)2, -(C 1-4 Alkylene) carboxyl, -(C 1-4 alkylene)NR 10 R 11 、-(C 1-4 alkylene)COO(C 1-4 Alkyl), -(C 1-4 alkylene)CONR 10 R 11 、-(C 1-4 alkylene)NR 10 CONR 10 R 11 、-(C 1-4 Alkylene)SO2NR 10 R 11 、-(C 1-4 alkylene)NR 10 S(O)2NR 10 R 11 、-(C 1-4 Alkylene)S(O)2(C 1-6 Alkyl), -(C 1-4 Alkylene)S(O)(NR 10 )(C 1-6 Alkyl), -(C 1-4 Alkylene)S(O)2(C 3-10 Cycloalkyl), -(C 1-4 Alkylene) S (O) 2 (4-10 membered heterocyclic group), each of the above groups may be optionally further substituted by one or more selected from deuterium, halogen, =O, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SO2(C 1-6 alkyl), -CO(C 1-6 Alkyl), C 3-6 substituted by a cycloalkyl group or a 4-10 membered heterocyclic group; Alternatively, two R atoms attached to two adjacent atoms 6 The groups and the atoms they are located on together form the C 4-8 Carbocyclic or 4-8 membered heterocyclic rings, wherein the carbocyclic and heterocyclic rings may be further optionally substituted by one or more selected from deuterium, halogen, =O, =C(R 12 )2, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SO2(C 1-6 alkyl), -CO(C 1-6 Alkyl), C 3-6 substituted by a cycloalkyl group or a 4-10 membered heterocyclic group; Each R 10 , each R 11 Independently selected from the group consisting of H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, -S(O)2(C 1-6 alkyl), -CO(C 1-6 alkyl), which may be further optionally substituted by one or more radicals selected from deuterium, halogen, =O, CN, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-10 Cycloalkyl, C 3-10 Halogenated cycloalkyl, 4-10 membered heterocyclic group, -S(O)2(C 1-6 alkyl), -CONH2, -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl)2 is substituted by a substituent; Alternatively, R attached to the same nitrogen atom 10 and R 11 Together with the nitrogen atom, a 4-10 membered heterocyclic ring is formed, wherein the heterocyclic ring may be optionally further substituted with one or more selected from deuterium, halogen, =O, CN, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SO2(C 1-6 alkyl), -CO(C 1-6 alkyl) substituent; Each R 12 are independently selected where present: hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 alkyl halide; Or, two R 12 Together with the carbon atoms they are located on, they form a C 3-6 Carbocyclic or 4-6 membered heterocyclic ring, wherein the carbocyclic ring and the heterocyclic ring may be further optionally substituted by one or more selected from halogen, C 1-4 Alkoxy, C 1-4 substituted by a haloalkoxy substituent; The carbocyclic or heterocyclic group may be saturated or partially unsaturated, but does not include an aromatic ring; The heterocyclic and heteroaryl groups each independently contain 1, 2, 3 or 4 heteroatoms selected from N, S or O.

2. The compound according to claim 1, wherein The R 4 Select from the following group: C 1-6 Alkyl, C 3-10 Saturated carbocyclic group, C 4-10 Unsaturated carbocyclic group, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl; Preferably, the R 4 Select from the following group: C 1-6 Alkyl, C 3-8 Saturated carbocyclic group, C 4-8 Unsaturated carbocyclic group, 4-8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl; More preferably, the R 4 Select from the following group: C 1-6 Alkyl, C 3-8 Cycloalkyl, C 4-8 cycloalkenyl, 4-6 membered heterocyclyl, aryl, naphthyl, 5-10 membered heteroaryl.

3. The compound according to claim 1, wherein Said R' is selected from the following group: H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene-C 3-8 Cycloalkyl, -C 1-6 Alkylene-C 3-8 Cycloalkoxy, -C 1-6 Alkylene-(4-8 membered heterocyclic group), C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, -S(O)2(C 1-6 Alkyl), -S(O)2(C 1-6 Alkylene)-C 3-8 Cycloalkyl, -S(O)2(C 1-6 Alkylene-(4-8 membered heterocyclic group), -CO(C 1-6 alkyl), -CO(C 1-6 Alkylene)-C 3-8 Cycloalkyl, -CO(C 1-6 Alkylene)-(4-8 membered heterocyclic group), said group may be further optionally substituted by one or more selected from the group consisting of deuterium, halogen, =O, CN, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 substituted by a haloalkoxy substituent; Preferably, the R' is selected from the group consisting of H, C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-C 3-6 Cycloalkoxy, -C 1-4 Alkylene-(4-6 membered heterocyclic group), C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, -S(O)2(C 1-4 Alkyl), -S(O)2(C 1-4 Alkylene)-C 3-6 Cycloalkyl, -S(O)2(C 1-4 Alkylene-(4-6 membered heterocyclic group), -CO(C 1-4 alkyl), -CO(C 1-4 Alkylene)-C 3-6 Cycloalkyl, -CO(C 1-4 Alkylene)-(4-6 membered heterocyclic group), said group may be further optionally substituted by one or more selected from the group consisting of deuterium, halogen, =O, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 The alkyl group is substituted with a haloalkoxy substituent.

4. The compound according to claim 1, wherein The L is selected from the following group: none, unsubstituted or replaced by one or more R d Substituted C 1-3 Alkylene.

5. The compound according to claim 1, wherein The ring A is selected from the following group: C 3-10 Carbocyclic ring, 4-10 membered heterocyclic ring; Preferably, the ring A is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, spiro[3.3]heptane, octahydropentane, adamantane, bicyclo[2.2.1]heptane, bicyclo[2.2.2] Octane, cubane, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, tetrahydropyrrole, tetrahydrothiophene, piperidine, piperazine, morpholine, azepane, azepane, 2-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.1]heptane, 6-azabicyclo[3.1.1]heptane, 3,6-diazabicyclo[3.1.1] Heptane, 8-azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane, octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, 2-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-azabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.2 ] octane, 4-azaspiro[2.5]octane, 4,7-diazaspiro[2.5]octane, 3,9-diazabicyclo[3.3.1]nonane, 3-oxa-7,9-diazabicyclo[3.3.1]nonane, 3-thia-7,9-diazabicyclo[3.3.1]nonane, and each of the above groups may further contain one or two intracyclic unsaturated double bonds at any possible position, provided that the entire ring system does not have aromaticity.

6. The compound according to claim 1, wherein The ring B is selected from the following group: C 6-10 Aromatic ring, 5-14 membered heteroaromatic ring; Preferably, the ring B is selected from the following group: a benzene ring, a naphthalene ring, a 5-10 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from O, S and N.

7. The compound according to claim 1, wherein The compound has a structure shown in formula (II), Among them, m, n, s, t, L, R 1 、R 2 、R 4 、R 5 、R 6 , R', X, Y, ring A and ring B are as defined in claim 1.

8. The compound according to claim 1, wherein The compound is selected from the group consisting of:

9. A pharmaceutical composition, characterized in that The composition comprises: (i) a compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof; and (ii) pharmaceutically acceptable carriers, adjuvants or vehicles.

10. Use of the compound according to any one of claims 1 to 8, its stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition according to claim 9, wherein: For use in the preparation of PDE4B inhibitors; or for use in the preparation of drugs for treating and / or preventing diseases associated with PDE4B; Preferably, the PDE4B-related disease is a respiratory disease, a gastrointestinal disease, an inflammatory disease of the joints, skin or eyes, or a peripheral or central nervous system disease; More preferably, the disease associated with PDE4B is selected from the group consisting of chronic obstructive pulmonary disease, asthma, chronic bronchitis, idiopathic pulmonary fibrosis, allergic rhinitis, adult respiratory distress syndrome, chronic sinusitis, ulcerative colitis, Crohn's disease, Crohn's disease, overactive bladder, atopic dermatitis, psoriasis, vitiligo, urticaria, rheumatoid arthritis, osteoarthritis, gouty arthritis, spondylitis, depression, acute and chronic anxiety states, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain, brain damage caused by stroke, hypoxia or craniocerebral trauma.

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