DERIVATIVES OF BORATE AND METHODS OF PREPARING THIS COMPOUND

Abstract

The invention relates to a compound with the formula I or its pharmaceutical salt, and a pharmaceutical composition containing such a compound and a method for preparing such a compound.

Description

A borate derivative and its use Technical Field

[0001] The present invention relates to the field of medicine and relates to a borate derivative and its use. Background Art

[0002] Phosphodiesterases (PDEs) are a class of intracellular enzymes that cleave the phosphodiester bonds of the second messenger molecules 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP). The cyclic nucleotides cAMP and cGMP act as second messengers in various cellular pathways. Among them, PDE4 is highly specific for cAMP and has four isoforms: PDE4A, PDE4B, PDE4C, and PDE4D. PDE4 is involved in physiological and pathological processes such as monocyte and macrophage activation, neutrophil infiltration, vascular smooth muscle proliferation, vasodilation, and myocardial contraction, affecting central nervous system function, cardiovascular function, inflammation / immune system, and cell adhesion. PDE4 plays a major role in regulating the expression of pro- and anti-inflammatory mediators. PDE4 inhibitors can inhibit the release of harmful mediators from inflammatory cells.

[0003] Many PDE4 inhibitors have been discovered in recent years. For example, roflumilast is approved for the treatment of severe chronic obstructive pulmonary disease (COPD) to reduce the number of flare-ups or prevent worsening of COPD symptoms, and apremilast is approved for the treatment of adults with active psoriatic arthritis. Although PDE4 inhibitors exhibit promising pharmacological activity, they can also cause side effects, such as induced gastrointestinal symptoms like vomiting and diarrhea. There is a continued need for the development of selective PDE4 inhibitors, particularly those with affinity for both PDE4B and PDE4D.

[0004] The boron (B)-containing drug crisaborole was approved by the FDA on December 14, 2016, as a topical treatment for mild to moderate atopic dermatitis. The boron atom facilitates skin penetration and binds to the bimetallic center of phosphodiesterase 4 (PDE4). Other boron-containing small molecules that inhibit PDEs have been reported, such as CN102014927A and WO2020070651. However, the compounds disclosed herein have not been previously reported in any literature, and these compounds exhibit specific PDE4 inhibition.

[0005] Summary of the Invention

[0006] The present disclosure provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof

[0007]

[0008] wherein Ring A is selected from a 5- to 6-membered aromatic ring or heteroaromatic ring, wherein the aromatic ring or heteroaromatic ring is optionally substituted by one or more R A1 replaced by;

[0009] R A1 Selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy or 3 to 6 membered heterocycloalkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy or 3 to 6 membered heterocycloalkoxy is optionally substituted by one or more radicals selected from halogen, deuterium, hydroxy, nitro, cyano, amino, C 1-6 substituted with alkoxy;

[0010] B is a boron atom;

[0011] Z is selected from a carbon atom or a nitrogen atom;

[0012] R 1 are each independently selected from hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy or 3 to 6 membered heterocycloalkoxy is optionally substituted with one or more R A2 replaced by;

[0013] R A2 Selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy or 3 to 6 membered heterocycloalkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy or 3 to 6 membered heterocycloalkoxy is optionally substituted by one or more radicals selected from halogen, deuterium, hydroxy, nitro, cyano, amino, C 1-6 substituted with alkoxy;

[0014] R 2is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally replaced by one or more R A3 replaced by;

[0015] R A3 Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino;

[0016] R 3 、R 4 or R 5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl or 3 to 6 membered heterocycloalkoxy, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, heterocycloalkyl or heterocycloalkoxy is optionally substituted by one or more R A4 replaced by;

[0017] R A4 Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino;

[0018] R 6 、R 7 Together with adjacent carbon atoms, they form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by one or more R A5 replaced by;

[0019] R A5 Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano;

[0020] m is selected from an integer between 0 and 5;

[0021] n is an integer selected from 1 to 3, for example 1 or 2;

[0022] and and In the meta position on ring A;

[0023] Is a single key or does not exist.

[0024] In some embodiments, R 3 or R 4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, the alkyl, alkoxy is optionally substituted by one or more R A4 Replaced by R A4 As defined above.

[0025] In some embodiments, R 3 or R 4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl or 3 to 6 membered heterocycloalkoxy, wherein the cycloalkoxy, cycloalkyl, heterocycloalkyl or heterocycloalkoxy is optionally substituted by one or more R A4 Replaced by R A4 As defined above.

[0026] In other embodiments, R 5 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, the alkyl, alkoxy is optionally substituted by one or more R A4 replaced.

[0027] In other embodiments, R 5 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl or 3 to 6 membered heterocycloalkoxy, wherein the cycloalkoxy, cycloalkyl, heterocycloalkyl or heterocycloalkoxy is optionally substituted by one or more R A4 replaced.

[0028] Furthermore, some embodiments provide a compound of formula I or a pharmaceutically acceptable salt thereof R 3 or R 4 are each independently selected from hydrogen; R 5 Selected from C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl, alkoxy is optionally substituted by 1 to 3 R A4 replaced.

[0029] In some embodiments, R A4 is selected from halogen, such as fluorine.

[0030] In some embodiments, R A4 Selected from hydroxyl, nitro, cyano, and amino.

[0031] On the other hand, some embodiments provide compounds of formula I are

[0032]

[0033] Among them, X 1 Selected from -O-, -N(R 16a )-or-CR 16a R 16b -;

[0034] X 2 Selected from -O- or -CR 17a R 17b -;

[0035] X 3 Select from bond or -CR 18a R 18b -、-CR 18a R 18b CR 18c R 18d -;

[0036] R 16a and R 16b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, the alkyl or alkoxy group is optionally substituted by halogen, nitro, cyano or C 1-6 substituted with alkoxy;

[0037] R 17a and R 17b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, the alkyl or alkoxy group is optionally substituted by halogen, nitro, cyano or C 1-6 substituted with alkoxy;

[0038] R 18a 、R 18b 、R 18c and R 18d are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, the alkyl or alkoxy group is optionally substituted by halogen, nitro, cyano or C 1-6 substituted with alkoxy;

[0039] R 8 、R 9are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl or 3 to 6 membered heterocycloalkoxy, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R A6 replaced by;

[0040] or R 8 、R 9 Together with adjacent carbon atoms, they form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by one or more R A6 replaced by;

[0041] or R 8 With R 9 Together they form oxo (=O);

[0042] R A6 Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 alkoxy;

[0043] Ring A, R 1 ~R 5 , B, m, n and As defined in the compound represented by formula I.

[0044] In some embodiments, X in the compound of Formula IA or a pharmaceutically acceptable salt thereof is 1 Selected from -O-.

[0045] In some embodiments, X in the compound of Formula IA or a pharmaceutically acceptable salt thereof is 1 Selected from -O-;X 2 Selected from -O- or -CR 17a R 17b -;R 17a and R 17b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy.

[0046] In some embodiments, X in the compound of Formula IA or a pharmaceutically acceptable salt thereof is 3 Select from bond or -CR 18a R 18b -, R 18a 、R 18b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy.

[0047] In some embodiments, X in the compound of Formula IA or a pharmaceutically acceptable salt thereof is 1 Selected from -O-;X 2 Selected from -O- or -CR 17a R 17b -;R 17a and R 17b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy; X 3 Select from keys.

[0048] In some embodiments, X in the compound of Formula IA or a pharmaceutically acceptable salt thereof is 1 Selected from -O-;X 2 Selected from -O- or -CR 17a R 17b -;R 17a and R 17b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy; X 3 Selected from-CR 18a R 18b -, R 18a 、R 18b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy.

[0049] On the other hand, some embodiments provide compounds of formula IA are

[0050]

[0051] In some embodiments, R 8 、R 9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, the alkyl or alkoxy is optionally substituted by one or more R A6 Replaced by; R A6 Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy.

[0052] In some embodiments, R 8 、R 9 The 3 to 6 membered carbocyclic ring or 4 to 6 membered heterocyclic ring formed with adjacent carbon atoms is selected from

[0053] Further, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 3 R A6 Replaced by; R A6 Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy.

[0054] In some embodiments, R A6 In some embodiments, R A6 Selected from halogen, C 1-6 Alkyl or C 1-6 In some embodiments, R A6 is selected from fluorine, chlorine, methyl, ethyl, methoxy or ethoxy.

[0055] On the other hand, in some embodiments, the compound of formula I is

[0056]

[0057] Among them, X 4 is selected from a nitrogen atom or a carbon atom;

[0058] R 10 、R 11 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl or 3 to 6 membered heterocycloalkoxy, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R A7 replaced by;

[0059] R A7 Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 alkoxy;

[0060] Ring A, Z, R 1 ~R 5 , B, m, n and As defined in the compound represented by formula I.

[0061] In some embodiments, R 10 、R 11are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, the alkyl or alkoxy group is optionally substituted by 1 to 3 R A7 In some embodiments, R A7 Selected from halogen, C 1-6 Alkyl or C 1-6 In some embodiments, R A7 is selected from fluorine, chlorine, methyl, ethyl, methoxy or ethoxy.

[0062] On the other hand, in some embodiments, X in the compound of Formula IB or a pharmaceutically acceptable salt thereof is 4 is selected from nitrogen atoms; Z is selected from nitrogen atoms.

[0063] In some embodiments, the compound of formula I is

[0064]

[0065] Among them, X 5 is selected from a nitrogen atom or a carbon atom;

[0066] R 12 、R 13 and R 14 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl or 3 to 6 membered heterocycloalkoxy, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R A8 replaced by;

[0067] R A8 Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 alkoxy;

[0068] Ring A, Z, R 1 ~R 5 , B, m, n and As defined in the compound represented by formula I.

[0069] In some embodiments, R 12 、R 13 and R 14 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C1-6 Alkoxy, the alkyl or alkoxy group is optionally substituted by 1 to 3 R A8 In some embodiments, R A8 Selected from halogen, C 1-6 Alkyl or C 1-6 In some embodiments, R in the compound of Formula IC or a pharmaceutically acceptable salt thereof A8 is selected from fluorine, chlorine, methyl, ethyl, methoxy or ethoxy.

[0070] On the other hand, in some embodiments, X in the compound represented by Formula IC or a pharmaceutically acceptable salt thereof is 5 is selected from nitrogen atoms; Z is selected from carbon atoms.

[0071] On the other hand, in some embodiments, the compound of formula I or its pharmaceutically acceptable salt, wherein ring A is selected from

[0072]

[0073] where R 15a 、R 15b 、R 15c and R 15d Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally substituted by one or more halogen, deuterium, hydroxy, nitro, cyano, or amino.

[0074] In some embodiments, R 15a 、R 15b 、R 15c and R 15d Each independently selected from hydrogen, deuterium, halogen, C 1-6 In some embodiments, R in the compound of Formula I or a pharmaceutically acceptable salt thereof is 15a 、R 15b 、R 15c and R 15d Each is independently selected from fluoro, chloro, methyl or ethyl.

[0075] Other embodiments provide compounds of Formula I or pharmaceutically acceptable salts thereof wherein Ring A is selected from:

[0076]

[0077] In some embodiments, in the compound of Formula I or a pharmaceutically acceptable salt thereof, n is selected from 1 or 2.

[0078] In some embodiments, the compound represented by Formula I or Formula IA is selected from

[0079]

[0080]

[0081] In some embodiments, the compound represented by Formula I or Formula IA is selected from

[0082]

[0083] In some embodiments, the compound represented by Formula I or Formula IB is selected from

[0084]

[0085] In some embodiments, the compound represented by Formula I or Formula IC is selected from

[0086]

[0087] In some embodiments, the compound of formula I is selected from

[0088]

[0089] On the other hand, some embodiments provide compounds of Formula I, Formula IA, Formula IB, or Formula IC, or pharmaceutically acceptable salts thereof, wherein R 2 Selected from hydrogen, C 1-6 In some embodiments, R in the compound represented by Formula I, Formula IA, Formula IB, or Formula IC or a pharmaceutically acceptable salt thereof is 2 In some embodiments, R in the compound of Formula I, Formula IA, Formula IB, or Formula IC or a pharmaceutically acceptable salt thereof is selected from hydrogen, methyl, or ethyl. 2 Selected from hydrogen.

[0090] On the other hand, some embodiments provide compounds of Formula I, Formula IA, Formula IB, or Formula IC, or pharmaceutically acceptable salts thereof, wherein R 1 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally substituted by one or more halogen, deuterium, hydroxyl, nitro, cyano, or amino groups. In some embodiments, R 1 Each is independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, methoxy or ethoxy.

[0091] Other embodiments provide compounds of formula I as

[0092]

[0093] In some embodiments, the compound of formula I is

[0094]

[0095] Some embodiments provide compounds of formula I selected from

[0096]

[0097] In some embodiments, the compound of formula I is selected from

[0098]

[0099] Typical compounds represented by Formula I or pharmaceutically acceptable salts thereof include but are not limited to:

[0100]

[0101]

[0102]

[0103] Typical compounds represented by Formula I or pharmaceutically acceptable salts thereof include but are not limited to:

[0104]

[0105]

[0106]

[0107] On the other hand, the present disclosure also provides a compound represented by formula (1) or a pharmaceutically acceptable salt thereof,

[0108]

[0109] Among them, R 19a and R 19b are each independently selected from hydrogen, C 1-6 Alkyl, said alkyl being optionally substituted with one or more halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 Alkoxy substituted, or R 19a and R 19b Together with adjacent atoms, they form a five-membered or six-membered heterocyclic ring, which is optionally substituted by one or more R A9 Replaced by R A9 Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy; Ring A, R 1 ~R 7 , B, n, and Z are as defined in the compound represented by formula I.

[0110] In some embodiments, the compound represented by formula (1) is

[0111] Among them, ring A, R 1 、R 3 ~R 5 , B, n are as defined in the compound shown in formula I, R 8 ~R 9 、X 1 、X 2 、X 3 As defined in the compound of formula IA.

[0112] In some embodiments, the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is

[0113] Among them, ring A, R 1 、R 3 ~R 5 , B, n, Z are as defined in the compound shown in formula I, R 10 ~R 11 、X 4 As defined in the compound of formula IB.

[0114] In some embodiments, the compound represented by formula (1) is

[0115] , where ring A, R 1 、R 3 ~R 5 , B, n, Z are as defined in the compound shown in formula I, R 12 ~R 14 、X 5 As defined in the compound of formula IB.

[0116] On the other hand, in some embodiments, the compound represented by formula (1) is

[0117] where R A9 Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, o is selected from an integer between 0 and 4, ring A, R 1 ~R 7 , B, n, and Z are as defined in the compound represented by formula I.

[0118] On the other hand, in some embodiments, the compound represented by formula (1) is

[0119] where R A9 Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C1-6 Alkyl, C 1-6 Alkoxy, p is selected from an integer between 0 and 6, ring A, R 1 ~R 7 , B, n, and Z are as defined in the compound represented by formula I.

[0120] The present disclosure also provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, comprising the steps of converting a compound of formula (1) into a compound of formula I or a pharmaceutically acceptable salt thereof,

[0121]

[0122] Among them, R 19a and R 19b are each independently selected from hydrogen, C 1-6 Alkyl, said alkyl being optionally substituted with one or more halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 Alkoxy substituted, or R 19a and R 19b Together with adjacent atoms, they form a five-membered or six-membered heterocyclic ring, which is optionally substituted by one or more R A9 Replaced by R A9 Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy.

[0123] On the other hand, the present disclosure also provides a compound represented by formula (2) or a pharmaceutically acceptable salt thereof,

[0124] where R 20a and R 20b are each independently selected from hydrogen, C 1-6 Alkyl, said alkyl being optionally substituted with one or more halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 Alkoxy substituted, or R 20a and R 20b Together with adjacent atoms, they form a five-membered or six-membered heterocyclic ring, which is optionally substituted by one or more R A10 Replaced by R A10 Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy.

[0125] Some embodiments provide compounds represented by formula (2)

[0126] Some embodiments provide compounds represented by formula (2)

[0127] In some embodiments, the compound represented by formula (2) or a pharmaceutically acceptable salt thereof is selected from:

[0128]

[0129] The present disclosure also provides a pharmaceutical composition comprising at least one therapeutically effective amount of the compound represented by the aforementioned formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0130] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0131] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.

[0132] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0133] The present disclosure also provides a method for preventing and / or treating a patient suffering from a PDE-related disorder, comprising administering to the patient a therapeutically effective amount of a compound as represented by the aforementioned Formula I or Formula IA, or a pharmaceutically acceptable salt thereof, or a compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, prepared by the aforementioned method.

[0134] In some embodiments, the PDE-related disorder is preferably asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism.

[0135] The present disclosure also provides a method for preventing and / or treating patients suffering from asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism, by administering to the patient a therapeutically effective amount of a compound represented by Formula I or Formula IA, or a pharmaceutically acceptable salt thereof, or a compound or pharmaceutically acceptable salt thereof, or the pharmaceutical composition prepared by the aforementioned method.

[0136] The present disclosure also provides the use of a compound as shown in Formula I or Formula IA, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating a PDE-related condition. In some embodiments, the PDE-related condition is preferably asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism.

[0137] The present disclosure also provides the use of a compound represented by the aforementioned Formula I or Formula IA, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis, or rheumatism.

[0138] In another aspect, the pharmaceutically acceptable salts of the compounds described in the present disclosure are selected from inorganic salts or organic salts.

[0139] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0140] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0141] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or or include both and Two configurations. indicates unspecified configuration, including cis (E) or trans (Z) configuration.

[0142] Compounds and intermediates of the present disclosure can also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. The lactam-lactim equilibrium example is between A and B as shown below.

[0143]

[0144] All compounds in this disclosure can be drawn as either Form A or Form B. All tautomeric forms are within the scope of this disclosure. The naming of the compounds does not exclude any tautomers.

[0145] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H.11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0146] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position should be understood to have deuterium (that is, at least 10% deuterium incorporation) at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). In the example, the compound has a natural abundance greater than deuterium that can be at least 1000 times greater than the deuterium of an abundance, at least 2000 times greater than the deuterium of an abundance, at least 3000 times greater than the deuterium of an abundance, at least 4000 times greater than the deuterium of an abundance, at least 5000 times greater than the deuterium of an abundance, at least 6000 times greater than the deuterium of an abundance or more. The disclosure also includes various deuterated forms of formula (I) compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of formula (I) compounds with reference to relevant literature. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds of formula (I), or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0147] "Optionally" 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, "optionally substituted C 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes both the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0148] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0149] "Pharmaceutically acceptable excipients" or "acceptable excipients" include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the U.S. Food and Drug Administration as acceptable for use by humans or domestic animals.

[0150] As used herein, an "effective amount" or "therapeutically effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also refers to an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0151] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched chain isomers thereof. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy or 3 to 6 membered heterocycloalkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy or 3 to 6 membered heterocycloalkoxy is optionally substituted by one or more radicals selected from halogen, deuterium, hydroxy, nitro, cyano, amino, C 1-6 Alkoxy substituted.

[0152] The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls. Cycloalkyls may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 Alkyl, C 3-6Cycloalkyl, 3 to 6 membered heterocycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy or 3 to 6 membered heterocycloalkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy or 3 to 6 membered heterocycloalkoxy is optionally substituted by one or more radicals selected from halogen, deuterium, hydroxy, nitro, cyano, amino, C 1-6 The cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring connected to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy or 3 to 6 membered heterocycloalkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy or 3 to 6 membered heterocycloalkoxy is optionally substituted by one or more radicals selected from halogen, deuterium, hydroxy, nitro, cyano, amino, C 1-6 Alkoxy substituted.

[0153] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 6 ring atoms. Non-limiting examples of "heterocycloalkyl" include: etc.

[0154] Heterocycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro and cyano.

[0155] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5-membered or 6-membered. For example, non-limiting examples include: etc.

[0156] Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro and cyano.

[0157] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, phenyl or 5 to 6 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro and cyano.

[0158] The term "cycloalkoxy" refers to -O-(cycloalkyl), wherein cycloalkyl is as defined above, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl.

[0159] The term "heterocycle" refers to a ring having atoms other than carbon atoms, and includes heterocycloalkyl and heteroaryl rings.

[0160] The term "hydroxy" refers to an -OH group.

[0161] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0162] The term "amino" refers to -CN.

[0163] The term "cyano" refers to -NH2.

[0164] The term "nitro" refers to -NO2.

[0165] The term "oxo" refers to a =0 substituent.

[0166] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort. BRIEF DESCRIPTION OF THE DRAWINGS

[0167] Figure 1: Comparison of clinical scores of each group of compounds in disease models.

[0168] Figure 2: Comparison of clinical scores of each group of compounds in the erythema disease model.

[0169] Figure 3: Comparison of clinical scores of each group of compounds in the psoriasis model.

[0170] Figure 4: Comparison of the inhibitory effects of various groups of compounds on skin thickness increase.

[0171] Figure 5: Comparison of the effects of each group of compounds on the proportion of spleen body weight. DETAILED DESCRIPTION

[0172] The present disclosure is further described below with reference to examples, but these examples are not intended to limit the scope of the present disclosure.

[0173] Experimental methods in the examples of this disclosure that do not specify specific conditions are generally based on conventional conditions or the conditions recommended by the raw material or product manufacturers. Reagents without specific sources are conventional reagents purchased from the market.

[0174] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (Methanol-d4). The internal standard was tetramethylsilane (TMS).

[0175] HPLC determination used Agilent1100 high pressure liquid chromatograph, GAS15B DAD UV detector, Water Vbridge C18 150*4.6mm 5um chromatographic column.

[0176] MS was determined using an Agilent 6120 triple quadrupole mass spectrometer, a G1315D DAD detector, and a Waters Xbridge C18 4.6*50mm, 5um column. The samples were scanned in positive / negative ion mode with a mass scan range of 80-1200.

[0177] Preparative HPLC conditions: Waters; Column: Sunfire (Prep C18 OBD 19*250mm 10μm);

[0178] Chiral column separation conditions: Column: Chiralpak IG 5 μm 30*250 mm; Mobile Phase: Hex:EtOH=35:65 at 15 mL / min; Temp: 30° C.; Wavelength: 254 nm).

[0179] The thin layer chromatography silica gel plate used was Yantai Huanghai HSGF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) was 0.2 mm ± 0.03 mm. The specification used for thin layer chromatography separation and purification products was 0.4 mm - 0.5 mm.

[0180] The flash column purification system used was Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

[0181] Forward column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh or 300-400 mesh silica gel as the carrier, or uses Changzhou Santai pre-packed ultra-pure normal phase silica gel column (40-63μm, 60g, 24g, 40g, 120g or other specifications).

[0182] The known starting materials in the present disclosure can be synthesized by methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Bid Pharmaceuticals, etc.

[0183] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0184] Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a capacity of about 1L.

[0185] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0186] Hydrogen was produced by a QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instrument Co., Ltd.

[0187] The nitrogen atmosphere or hydrogen atmosphere is usually evacuated and filled with nitrogen or hydrogen, and the operation is repeated three times.

[0188] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0189] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0190] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the column chromatography eluent system used to purify the compound, and the developing solvent system for thin layer chromatography, the volume ratio of the solvent were adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could be added for adjustment.

[0191] Example 1

[0192]

[0193]

[0194] Step 1) Compound 1a (2.0 g, 14.6 mmol) and triethylamine (1.8 g, 17.8 mmol) were dissolved in N'N-dimethylformamide (30 mL), and the solution was cooled to 0°C. Under nitrogen protection, tert-butyldiphenylsilyl chloride (4.0 g, 14.6 mmol) was added dropwise to the reaction system. The mixture was warmed to room temperature and stirred until the reaction was complete as detected by TLC. The reaction solution was poured into water and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with water (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified on a silica gel column (ethyl acetate / petroleum ether) to obtain compound 1b (5.1 g), which was used directly in the next reaction.

[0195] Step 2) Under nitrogen protection, a mixture of compound 1b (5.1 g, 13.6 mmol), bipyralidoborane (4.2 g, 16.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (512 mg, 0.7 mmol), potassium acetate (2.0 g, 20.4 mmol) and dioxane (100 mL) was heated to 80 ° C and stirred overnight. The reaction solution was poured into water and extracted with ethyl acetate (100 mL × 2). Washed with water (30 mL × 2), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column (petroleum ether / ethyl acetate) to give compound 1c (2.0 g), LCMS: m / z 423.2 (M+H) + .

[0196] Step 3) trimethylsulfide iodide (20.93 g, 95.10 mmol) and anhydrous tetrahydrofuran (100 mL) were added to a 250 mL three-necked flask in sequence, stirred until dissolved, cooled to -10 ° C, and a solution of n-butyllithium in tetrahydrofuran (35.19 mL, 2.5 M, 87.97 mmol) was slowly added dropwise. Stirred at -10 ° C for 1 hour, 6-oxabicyclo[3.1.0]hexane in tetrahydrofuran (2.00 g, 23.78 mmol) was then slowly added dropwise. After the addition was complete, the mixture was warmed to room temperature and stirred until the reaction was complete as determined by TLC. The reaction solution was slowly poured into water to quench, extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 1d (400 mg concentrate), which was used directly in the next step of synthesis.

[0197] Step 4) Compound 5 (100.00 mg, 1.02 mmol), 5-bromo-2-methoxyphenol (206.87 mg, 1.02 mmol), and triphenylphosphine (801.12 mg, 3.06 mmol) were added sequentially to a 25 mL single-necked flask in anhydrous tetrahydrofuran (10 mL). The mixture was stirred and uniformly stirred. The reaction system was purged with nitrogen three times, cooled to 0°C, and diisopropyl azodicarboxylate (618.02 mg, 3.06 mmol) was slowly added dropwise. After completion of the addition, the mixture was warmed to room temperature and stirred until the reaction was complete as determined by TLC. The reaction mixture was quenched by the addition of 50 mL of water, extracted with ethyl acetate (100 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate / petroleum ether) to afford compound 1e (60 mg).

[0198] 1 H NMR (400MHz, DMSO-d6) δ7.17(d,J=2.3Hz,1H),7.08(dd,J=8.6,2.3Hz,1H),6.92(dd,J=8.6,4.2Hz,1H),5.05(d,J=1.5H z,2H),5.01(t,J=4.3Hz,1H),3.74(s,3H),2.47-2.36(m,1H),2.35-2.21(m,1H),2.05-1.90(m,1H),1.86-1.59(m,3H).

[0199] Step 5) Compound 1e (60.00 mg, 1.02 mmol) was added to a 25 mL single-necked flask, heated to 180°C, and stirred until the reaction was complete as detected by TLC. The reaction solution was quenched by adding 10 mL of water, extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 1f (45 mg).

[0200] 1H NMR (400MHz, CDCl3) δ7.06(d,J=8.7Hz,1H),6.63(d,J=8.7Hz,1H),5.19(s,1H),3.87(s,3H),3.55(s,2H),2.33-2.28(m,4H),1.9-1.79(m,2H).

[0201] Step 6) Compound 1f (45.00 mg, 0.16 mmol) was added to a 25 mL single-necked bottle at room temperature. 15 Ion exchange resin (41.80 mg, 0.64 mmol) was dissolved in toluene (5 mL) and stirred evenly. The reaction system was replaced with nitrogen three times, heated to 90°C and stirred until the reaction was complete as detected by TLC. The mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 1g (30 mg).

[0202] 1 H NMR (400MHz, DMSO-d6) δ6.93(d,J=8.7Hz,1H),6.79(d,J=8.7Hz,1H),3.74(s,3H),3.16(s,2H),2.04-1.90(m,2H),1.86-1.66(m,6H).

[0203] Step 7) Compound 1g (100.00 mg, 0.35 mmol), diboronic acid pinacol ester (179.36 mg, 0.71 mmol), potassium acetate (104.00 mg, 1.06 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (25.80 mg, 0.035 mmol) were added sequentially to a 25 mL single-necked flask at room temperature in 1,4-dioxane (50 mL). The reaction system was purged with nitrogen three times and the temperature was raised to 90°C with stirring until the reaction was complete as determined by TLC. The mixture was filtered, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate / petroleum ether) to afford compound 1h (45 mg).

[0204] 1 H NMR(400MHz, CDCl3) δ7.24(d,J=2.9Hz,1H),6.72(d,J=8.1Hz,1H),3.86(s,3H),3. 34(s,2H),2.17-2.10(m,2H),1.97-1.85(m,2H),1.80-1.66(m,4H),1.30(s,12H).

[0205] Step 8) Compound 1h (45.00 mg, 0.14 mmol), compound 3-bromo-5-iodopyridine (38.69 mg, 0.14 mmol), potassium carbonate (153.50 mg, 0.27 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (41.00 mg, 0.014 mmol) in an aqueous solution of 1,4-dioxane (3:1, 8 mL) were added sequentially to a 25 mL single-necked flask at room temperature. The reaction system was purged with nitrogen three times, heated to 90°C, and stirred until the reaction was complete as determined by TLC. The mixture was filtered, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 1i (30 mg). LCMS: m / z 360.0 (M+H) + .

[0206] Step 9) Compound 1i (100 mg, 0.28 mmol), compound 1c (176.02 mg, 0.42 mmol), potassium carbonate (76.75 mg, 0.56 mmol), potassium acetate (40.87 mg, 0.42 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (20.05 mg, 0.023 mmol) in a 1,4-dioxane aqueous solution (3:1, 8 mL) were added sequentially to a 25 mL single-necked flask at room temperature. The reaction system was purged with nitrogen three times, heated to 90°C, and stirred until the reaction was complete as determined by LCMS. The reaction solution was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 1k (60 mg).

[0207] LCMS: m / z 576.2 (M+H) + .

[0208] Step 10) Compound 1k (60 mg, 0.10 mmol) was added to a 25 mL single-necked flask at room temperature, followed by a solution of hydrochloric acid in tetrahydrofuran (1:1, 4 mL). The mixture was stirred at 25°C until the reaction was complete as detected by TLC. The mixture was concentrated under reduced pressure and purified by column chromatography (ethyl acetate / petroleum ether) to give compound 1l (40 mg).

[0209] LCMS: m / z 338.0 (M+H) + .

[0210] Step 11) Compound 11 (40 mg, 0.12 mmol) was added to a 25 mL three-necked flask at room temperature, followed by tetrahydrofuran (5 mL). The temperature was cooled to 0°C, and a borane tetrahydrofuran solution (0.47 mL, 1 M, 0.48 mmol) was added dropwise. After addition, the mixture was naturally warmed to room temperature and stirred overnight. Water (0.5 mL) was added and stirring continued for 0.5 h. The reaction was complete by LCMS. Compound 1 (1.31 mg) was obtained after purification by preparative liquid chromatography.

[0211] LCMS: m / z 366.1 (M+H) + .

[0212] 1 H NMR(400MHz,MeOD)δ8.40(d,J=26.6Hz,2H),7.79(s,1H),6.91(q,J=8.4Hz,2H),4.58(s,3H),4.17-3.95(m,1H),3.89-3.85 (m,3H),3.83-3.78(m,1H),2.16-2.01(m,2H),1.93-1.88(m,2H),1.84-1.68(m,5H),1.37-1.22(m,1H),1.19-1.09(m,1H).

[0213] Chiral separation (Column: Chiralpak IG 5μm 30*250mm; Mobile Phase: Hex:EtOH=35:65at 15mL / min; Temp: 30℃; Wavelength: 254nm) was used to obtain compound 1-1 (shorter retention time) and compound 1-2 (longer retention time).

[0214] Compound 1-1

[0215] LCMS: m / z 366.1 (M+H) + .

[0216] 1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.53(d,J=2.0Hz,1H),8.43(d,J=1.9H z,1H),7.77(s,1H),6.96-6.89(m,2H),4.27(t,J=8.2Hz,1H),3.83(t,J=8.9 Hz,1H),3.79(s,3H),3.55-3.43(m,1H),3.30(s,2H),2.03-1.89(m,2H),1.7 6-1.69(m,6H),1.31(dd,J=16.2,8.2Hz,1H),1.11(dd,J=16.2,10.2Hz,1H).

[0217] Compound 1-2

[0218] LCMS: m / z 366.1 (M+H) + .

[0219] 1 H NMR(400MHz, DMSO-d6)δ8.68(s,1H),8.51(d,J=1.9Hz,1H),8.41(d,J=1.7Hz, 1H),7.75(s,1H),6.97-6.81(m,2H),4.25(t,J=8.2Hz,1H),3.81(t,J=8.9Hz, 1H),3.77(s,3H),3.55-3.40(m,1H),3.29-3.23(m,2H),1.95-1.91(m,2H),1. 74-1.67(m,6H),1.29(dd,J=16.1,8.1Hz,1H),1.09(dd,J=16.2,10.2Hz,1H).

[0220] Example 2

[0221]

[0222] Compound 2 was synthesized according to the method of Example 1.

[0223] LCMS: m / z 326.1 (M+H) + .

[0224] 1H NMR (400MHz, CD3OD) δ8.77(s,1H),8.66(s,1H),8.56(s,1H),7.06-7.01(m,2H),5.02(d,J=6.4Hz,1H),3.90(s,3H) ,3.88(s,2H),3.47(d,J=8.5Hz,1H),3.32(s,1H),3.01(dd,J=15.4,8.2Hz,1H),1.48(d,J=6.2Hz,3H),1.36(m,2H).

[0225] Example 3

[0226]

[0227] Compound 3 was synthesized according to the method of Example 1.

[0228] LCMS: m / z 365.1 (M+H) + .

[0229] 1 H NMR(400MHz, DMSO-d6)δ8.63(s,1H),7.37-7.26(m,3H),7.21(d,J=7.4Hz,1H),6.87(dd,J=19.4,8.4Hz,2H),4.28-4.20(m,1H),3.82-3.74 (m,4H),3.51-3.40(m,1H),3.28(s,2H),2.03-1.89(m,2H),1.84-1.63(m,6H),1.28(dd,J=16.2,8.1Hz,1H),1.05(dd,J=16.2,9.8Hz,1H).

[0230] Example 4

[0231]

[0232] Compound 4 was synthesized according to the method of Example 1.

[0233] LCMS: m / z 367 (M+H) + .

[0234] 1H NMR (400MHz, DMSO-d6) δ8.86(s,1H),8.64(s,1H),8.44(s,1H),7.41(d,J=8.4Hz,1H),6.97(d,J=7.2Hz,1H),4.31(t,J=10.8Hz,1H),4.03- 3.94(m,1H),3.82(s,3H),3.77-3.65(m,1H),3.53(d,J=6.4Hz,2H),1.97(s,2H),1.78-1.75(m,6H),1.32-1.30(m,1H),1.22-1.12(m,1H).

[0235] Example 5

[0236]

[0237] Compound 5 was synthesized according to the method of Example 1.

[0238] LCMS: m / z 367.2 (M+H) + .

[0239] 1 H NMR(400MHz,DMSO-d6)δ9.10(d,J=2.0Hz,1H),8.77(s,1H),7.86(d,J=1.9H z,1H),7.34(d,J=8.5Hz,1H),6.99(d,J=8.5Hz,1H),4.33-4.27(m,1H),3.8 9(t,J=8.9Hz,1H),3.83(s,3H),3.57-3.46(m,3H),2.01-1.94(m,2H),1.84 -1.68(m,6H),1.34(dd,J=16.3,8.3Hz,1H),1.16(dd,J=16.4,10.4Hz,1H).

[0240] Example 6

[0241]

[0242] Compound 6 was synthesized according to the method of Example 1.

[0243] LCMS: m / z 340.1 (M+H) + .

[0244] 1H NMR (400MHz, DMSO-d6) δ8.70(s,1H),8.52(d,J=2.1Hz,1H),8.44(d,J=2.0Hz,1H),7.77(t,J=2.0Hz,1H),6.98-6.90(m,2H),4.37 -4.21(m,1H),3.86-3.82(m,1H),3.80(s,3H),3.57-3.42(m,1H),3.15(s,2H),1.42(s,6H),1.34-1.28(m,1H),1.14-1.08(m,1H).

[0245] Example 7

[0246]

[0247] Step 1) Compound 1a (15.00 g, 109.51 mmol) and imidazole (6.71 g, 98.555 mmol) were dissolved in N,N-dimethyl sulfoxide (100 mL). Tert-butyldimethylsilyl chloride (14.03 g, 93.08 mmol) was added at 30°C and allowed to react at room temperature for 3 hours. TLC confirmed the reaction was complete. The reaction solution was quenched by addition of water (100 mL), extracted with tert-methyl ether (100 mL x 3), and dried over anhydrous sodium sulfate to obtain compound 7a (25.00 g).

[0248] 1 H NMR (400MHz, CDCl3) δ5.98(dd,J=3.5,1.7Hz,1H),5.55(dd,J=3.1,1.5Hz,1H),4.23(t,J=1.7Hz,2H),0.95(s,9H),0.12(s,6H).

[0249] Step 2) Compound 7a (25.00 g, 99.51 mmol), pinacol diboron (27.80 g, 109.46 mmol), potassium acetate (19.53 g, 199.01 mmol), and bistriphenylphosphine palladium dichloride (1.55 g, 1.99 mmol) were dissolved in 1,4-dioxane (90 mL) at room temperature. The reaction system was purged with nitrogen three times and stirred at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was added with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether) to afford product 7b (11.00 g).

[0250] 1H NMR (400MHz, DMSO-d6) δ5.85-5.80(m,1H),5.73-5.71(m,1H),4.17(t,J=1.9Hz,2H),1.20(s,12H),0.87(s,9H),0.03(s,6H).

[0251] Step 3) Compound 7c (10.0 g, 35.04 mmol) was dissolved in 1,4-dioxane (14 mL), cooled to 0°C, and perchloric acid (5.14 mL, 59.57 mmol, 70% wt.) was added dropwise. The mixture was stirred at 0°C for 0.5 hours, and ice water (140 mL) was added to precipitate a white solid, which was then filtered. The white solid was dissolved in dichloromethane (200 mL). The aqueous phase was separated, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was added dropwise to a solution of 2-methoxy-pyridine (5.93 g, 54.32 mmol) in dichloromethane (100 mL) at 0°C. After the addition was complete, the mixture was allowed to react at room temperature for 1 hour. TLC confirmed the reaction was complete. The mixture was concentrated under reduced pressure, and anhydrous ether was added to the residue to precipitate a white solid, which was then filtered to yield the target compound 7d (9.5 g).

[0252] 1 H NMR(400MHz, DMSO-d6)δ8.55(dd,J=6.5,1.5Hz,1H),8.28-8.24(m,1H),7.72(dd,J=6.6,3.1H z,1H),7.53-7.45(m,1H),6.74(s,2H),4.26(s,3H),2.50(dd,J=4.0,2.1Hz,6H),2.17(s,3H).

[0253] Step 4) Compound 7d (9.0 g, 27.74 mmol) and ethyl 4,4,4-trifluoro-2-butynoate (4.61 g, 27.74 mmol) were dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (7.7 g, 55.48 mmol) was added. The mixture was stirred at room temperature for 16 hours. LCMS confirmed the reaction was complete. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether) to afford compound 7e (3.05 g).

[0254] LCMS: m / z 289.0 (M+H) + .

[0255] Step 5) Dissolve compound 7e (2.9 g, 10.06 mmol) in acetonitrile (20 mL) at room temperature and add N-bromosuccinimide (2.7 g, 15.09 mmol). Replace the atmosphere with nitrogen three times. Heat to 70°C and react for 5 hours. LCMS confirms the reaction is complete. Concentrate under reduced pressure, and purify the residue by column chromatography (ethyl acetate / petroleum ether) to afford compound 7f (1.5 g).

[0256] LCMS: m / z 366.9 (M+1) + .

[0257] Step 6) Compound 7f (1.5 g, 4.09 mmol) was dissolved in methanol (10 mL), and a solution of potassium hydroxide (917 mg, 16.34 mmol) in water (5 mL) was added dropwise. The reaction was allowed to react at room temperature for 16 hours. LCMS confirmed the reaction was complete. 1N hydrochloric acid was added to adjust the pH to ~7, and the methanol was removed by concentration under reduced pressure. 1N hydrochloric acid was added to adjust the pH to ~2, and the mixture was extracted with ethyl acetate (50 mL x 3). The mixture was washed with water (25 mL x 3), then with saturated sodium chloride solution (25 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 7g (1.3 g).

[0258] LCMS: m / z 339.9 (M+H) + .

[0259] Step 7) Compound 7g (1.3 g, 3.83 mmol) was dissolved in ethanol (20 mL) and concentrated sulfuric acid (1 mL) was added. The temperature was raised to 90°C and the reaction was allowed to react for 16 hours. LCMS confirmed the reaction was complete. The solution was concentrated under reduced pressure, and the pH was adjusted to ~9 by adding saturated sodium bicarbonate. The product was extracted with ethyl acetate (50 mL × 3), washed with water (25 mL × 3), and then with saturated sodium chloride (25 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 7h (749 mg).

[0260] LCMS: m / z 356.2 (M+H) + .

[0261] Step 8) Compound 7h (300 mg, 1.02 mmol), pinacol diboron (387 mg, 1.53 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (75 mg, 0.102 mmol), and potassium acetate (299 mg, 3.05 mmol) were mixed in 1,4-dioxane (5 mL) and the atmosphere was purged with nitrogen three times. The temperature was raised to 100°C and the reaction was allowed to react for 16 hours. LCMS confirmed the reaction was complete. The product was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether) to afford compound 7i (300 mg).

[0262] LCMS: m / z 343.1 (M+H) + .

[0263] Step 9) Compound 7i (0.9 g, 2.63 mmol), 3,5-dibromopyridine (0.612 mL, 5.26 mmol), potassium carbonate (0.55 g, 3.95 mmol), and 1,1'-bis(diphenylphosphino)ferrocene[1,1'-dichloropalladium] (0.10 g, 0.13 mmol) were mixed in 1,4-dioxane / water (10 mL / 0.2 mL). The reaction system was purged with nitrogen three times and stirred at 90°C for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was filtered, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether) to afford compound 7j (850 mg).

[0264] LCMS: m / z 374 (M+H) + .

[0265] Step 10) Compound 7j (800 mg, 2.15 mmol), compound 6b (833.67 mg, 2.79 mmol), potassium acetate (316.46 mg, 3.23 mmol), potassium carbonate (594.23 mg, 4.3 mmol), and 1,1'-bis(diphenylphosphino)ferrocene[1,1'-dichloropalladium] (78.65 mg, 0.11 mmol) were mixed in 1,4-dioxane / water (10 mL / 0.02 mL) at room temperature. The reaction system was purged with nitrogen three times and stirred at 90°C for 16 hours. The reaction was complete by LCMS. The reaction solution was filtered, concentrated, and purified on a silica gel column (ethyl acetate / petroleum ether) to afford compound 7k (430 mg).

[0266] LCMS: m / z 464 (M+H) + .

[0267] Step 11) At room temperature, to a thoroughly dried 100 mL three-necked flask equipped with a thermometer, 1,2-bis(diphenylphosphino)ethane (32.67 mg, 0.082 mmol) and (1,5-cyclooctadiene)methoxyiridium(I) dimer (27.17 mg, 0.041 mmol) in 1,2-dichloroethane (3 mL) were added sequentially under nitrogen protection. The mixture was stirred at room temperature for 15 min. Compound 7k (190 mg, 0.410 mmol) was added and stirred at room temperature for 15 min. The mixture was heated in a 95°C oil bath with stirring. When the thermometer read 70°C, pinacol borane (0.416 mL, 2.87 mmol) was added dropwise and stirred for 0.5 h. The reaction was complete by LCMS. The reaction solution was allowed to cool to room temperature, quenched by the addition of 5 mL of methanol, concentrated under reduced pressure, and purified on a silica gel column (ethyl acetate / petroleum ether) to afford compound 7l (120 mg).

[0268] LCMS: m / z 592 (M+H) + .

[0269] Step 12) Compound 71 (100 mg, 0.17 mmol) was dissolved in tetrahydrofuran (1 mL) at room temperature, and 1N hydrochloric acid (1 mL) was slowly added dropwise with stirring. The mixture was allowed to react at room temperature for 0.5 h. LCMS confirmed the reaction was complete. The reaction solution was concentrated, diluted with ethyl acetate (5 mL), and the pH was adjusted to approximately 8 with a saturated aqueous solution of potassium phosphate. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to afford 7 (5.54 mg).

[0270] LCMS: m / z 378 (M+1) + .

[0271] 1 H NMR (400MHz, DMSO-d6) δ8.72(d,J=2.0Hz,1H),8.70(s,1H),8.57(m,1H),7.99(s,1H),7.62(d,J=7.6Hz,1H),7.19(s,1H),6.78(d, J=8.0Hz,1H),4.34-4.28(t,J=8.6Hz,1H),4.20(s,3H),3.89(t,J=8.8Hz,1H),3.62-3.51(m,1H),1.34(m,1H),1.19-1.12(m,1H).

[0272] Example 8

[0273]

[0274] Step 1) To a 100 mL single-necked flask at room temperature, compound 8a (25.00 g, 178.39 mmol) and N-bromosuccinimide (31.75 g, 178.39 mmol) in acetonitrile (200 mL) were added and stirred until dissolved. The reaction system was purged with nitrogen three times and stirred at room temperature for 16 hours. TLC confirmed the reaction was complete. The reaction solution was concentrated, diluted with ethyl acetate (100 mL), and poured into an aqueous sodium bisulfite solution (500 mL). The pH was adjusted to approximately 3, and extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 8b (24.00 g).

[0275] 1H NMR (400MHz, DMSO-d6) δ9.12(s,1H),8.94(s,1H),6.87(d,J=8.9Hz,1H),6.45(d,J=8.9Hz,1H),3.76(s,3H).

[0276] Step 2) Compound 8b (100.00 mg, 0.46 mmol), 3-bromo-2-methylpropene (61.64 mg, 0.46 mmol), and potassium carbonate (94.65 mg, 0.69 mmol) in N,N-dimethylformamide (10 mL) were added to a 100 mL single-necked flask at room temperature. The reaction system was purged with nitrogen three times and stirred at room temperature for 16 hours. The reaction was complete by TLC. The reaction solution was filtered and concentrated under reduced pressure. A saturated aqueous sodium chloride solution (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 8c (25.00 mg).

[0277] 1 H NMR (400MHz, DMSO-d6) δ9.03(s,1H),6.94(d,J=8.8Hz,1H),6.67(d,J=8.9Hz,1H),5.07(s,1H),4.91(s,1H),4.36(s,2H),3.76(s,3H),1.82(s,3H).

[0278] Step 3) At room temperature, compound 8c (50.00 mg, 0.18 mmol) and iodine (9.29 mg, 0.037 mmol) were added to a 100 mL single-necked flask in dichloromethane (2 mL) and stirred until dissolved. The reaction system was purged with nitrogen three times and stirred at room temperature for 16 hours. TLC confirmed the reaction was complete. The reaction solution was added to a saturated sodium thiosulfate solution (25 mL), extracted with ethyl acetate (30 mL x 3), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether) to give compound 8d (20.0 mg).

[0279] 1 H NMR (400MHz, DMSO-d6) δ7.83(d,J=8.9Hz,1H),7.37(d,J=8.9Hz,1H),4.80(s,2H),4.53(s,3H),2.08(s,6H).

[0280] Step 4) To a 50 mL single-necked flask at room temperature, compound 8d (400.00 mg, 1.46 mmol), boronic acid (557.84 mg, 2.2 mmol), potassium acetate (431.18 mg, 4.39 mmol), and 1,1-bis(diphenyl)ferrocenepalladium dichloride (53.60 mg, 0.073 mmol) in 1,4-dioxane (10 mL) were added and stirred until dissolved. The reaction system was purged with nitrogen three times and stirred at 110°C for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was added with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether) to afford compound 8e (0.26 g).

[0281] LCMS: m / z 321.1 (M+H) + .

[0282] Step 5) To a 25 mL single-necked flask at room temperature, compound 8e (240.00 mg, 0.750 mmol), 3,5-dibromopyridine (355.12 mg, 1.5 mmol), potassium carbonate (207.18 mg, 1.5 mmol), and 1,1-bis(diphenyl)ferrocenepalladium dichloride (54.87 mg, 0.075 mmol) were added in a mixed solvent of 1,4-dioxane (6 mL) and water (2 mL). The mixture was stirred until dissolved. The reaction system was purged with nitrogen three times and stirred at 90°C for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was added to 100 mL of water and extracted with ethyl acetate (100 mL x 3). The organic phase was dried and concentrated, and then purified by column chromatography (ethyl acetate / petroleum ether) to afford compound 8f (150.00 mg).

[0283] LCMS: m / z 351.9 (M+H+2) + .

[0284] Step 6) To a 100 mL single-necked flask at room temperature, compound 8f (130.00 mg, 0.37 mmol), compound 7b (143.95 mg, 0.48 mmol), potassium carbonate (102.60 mg, 0.74 mmol), potassium acetate (54.65 mg, 0.56 mmol), and 1,1-bis(diphenyl)ferrocenepalladium dichloride (13.59 mg, 0.019 mmol) were added in a mixed solvent of 1,4-dioxane (6 mL) and water (0.12 mL). The mixture was stirred until dissolved. The reaction system was purged with nitrogen three times and stirred at 110°C for 16 hours. LCMS analysis confirmed the reaction was complete. The reaction solution was added to 100 mL of water and extracted with ethyl acetate (200 mL x 3). The organic phase was dried and concentrated, and then purified by column chromatography (ethyl acetate / petroleum ether) to afford compound 8g (150.00 mg).

[0285] LCMS: m / z 442.1 (M+H) + .

[0286] Step 7) At room temperature, 1,2-bis(diphenylphosphino)ethane (23.46 mg, 0.059 mmol) and (1,5-cyclooctadiene)methoxyiridium(I) dimer (19.51 mg, 0.029 mmol) were added to a 50 mL three-necked flask. Anhydrous 1,2-dichloroethane (15 mL) was then added, followed by the slow addition of compound 8g (130.00 mg, 0.294 mmol, dissolved in 5 mL of 1,2-dichloroethane). The mixture was stirred at room temperature for 15 minutes, and then the temperature was raised to 70°C. After the addition was complete, pinacol borane (263.70 mg, 2.061 mmol) was added dropwise. After the addition was complete, the mixture was stirred at 70°C for 1 hour. LCMS analysis indicated that the reaction was complete. The reaction solution was cooled to 0°C and quenched with 20 mL of methanol. The reaction solution was then concentrated and purified by column chromatography (ethyl acetate / petroleum ether) to afford compound 8h (120.00 mg).

[0287] LCMS: m / z 570.1 (M+H) + .

[0288] Step 8) At room temperature, the reactant 8h (100.00 mg, 0.17 mmol) and the solvent tetrahydrofuran (2 mL) were added to a 25 mL eggplant flask. The temperature was lowered to 0°C, and 1N hydrochloric acid (2 mL) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1 hour. The reaction was detected by LCMS, and the reaction solution was concentrated under reduced pressure and extracted with ethyl acetate (100 mL × 3). Saturated potassium phosphate aqueous solution was added to the aqueous phase to adjust the pH to 8.0, and ethyl acetate (100 mL × 3) was added for extraction. The organic phases were combined, washed with water (100 mL × 3), saturated brine (100 mL × 3), washed, and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and purified by preparative liquid chromatography (Pre-HPLC) to obtain compound 8 (5.46 mg).

[0289] LCMS: m / z 356.1 (M+H) + .

[0290] 1H NMR (400MHz, DMSO-d6) δ8.69(s,1H),8.53(s,1H),8.39(s,1H),7.75(s,1H),6.87(d,J=8.4Hz,1H),6.70(d,J=8.5Hz,1H),4.2 7(t,J=8.1Hz,1H),3.92(s,2H),3.82(t,J=8.9Hz,1H),3.78(s,3H),3.51-3.46(m,1H),1.34-1.28(m,7H),1.14-1.07(m,1H).

[0291] Example 9

[0292]

[0293] Compound 9 was synthesized according to the method of Example 8.

[0294] LCMS: m / z 354.2 (M+H) + .

[0295] 1 H NMR (400MHz, DMSO-d6) δ8.70 (s, 1H), 8.44 (d, J = 1.8 Hz, 1H), 8.38 (d, J =1.8Hz,1H),7.69(s,1H),6.87(d,J=8.3Hz,1H),6.71(d,J=8.3Hz,1H),4.27(t,J=8.2Hz,1H),3.82(t,J=8.9Hz,1H ),3.75(s,3H),3.55-3.42(m,1H),2.54-2.50(m,2H),1.66(t,J=6.5Hz,2H),1.38-1.23(m,7H),1.17-0.97(m,1H).

[0296] Example 10

[0297]

[0298] Compound 10 was synthesized according to the method of Example 8.

[0299] LCMS: m / z 389.1 (M+H) + .

[0300] 1H NMR(400MHz, DMSO-d6)δ8.71(s,1H),8.61(d,J=1.5Hz,1H),8.55(d,J=1.6Hz,1H), 8.42(d,J=8.8Hz,1H),7.99(d,J=8.9Hz,1H),7.87-7.84(m,1H),7.74(d,J=8.1Hz, 1H),7.46(d,J=8.2Hz,1H),4.31(t,J=8.3Hz,1H),4.08(s,3H),3.88(t,J=8.9Hz,1 H),3.58-3.55(m,1H),1.34(dd,J=16.2,8.1Hz,1H),1.15(dd,J=16.2,10.4Hz,1H).

[0301] Example 11

[0302]

[0303] Compound 11 was synthesized by referring to the method of Example 9 and chirally separated to obtain compound 11-1 (shorter retention time) and compound 11-2 (longer retention time).

[0304] Compound 11-1

[0305] LCMS: m / z 357.2 (M+H) + .

[0306] 1 H NMR (400MHz, DMSO-d6) δ8.93(s,1H),8.64(s,1H),8.42(s,1H),7.37(d,J=8.8Hz,1H),6.76(d,J=8.8Hz,1H), 4.34-4.26(m,1H),4.07-3.97(m,3H),3.80(s,3H),3.73-3.62(m,1H),1.36-1.27(m,7H),1.25-1.14(m,1H).

[0307] Compound 11-2

[0308] LCMS: m / z 357.2 (M+H) + .

[0309] 1H NMR (400MHz, DMSO-d6) δ8.93(s,1H),8.64(s,1H),8.42(s,1H),7.37(d,J=8.8Hz,1H),6.76(d,J=8.8Hz,1H), 4.39-4.23(m,1H),4.06-3.93(m,3H),3.80(s,3H),3.73-3.62(m,1H),1.33-1.23(m,7H),1.21-1.15(m,1H).

[0310] Example 12

[0311]

[0312] Step 1) At room temperature, compound 12a (100 g, 492 mmol), DMF (1000 mL), potassium iodide (92.6 g, 837 mmol), cuprous iodide (3.13 g, 9.85 mmol), and potassium carbonate (136 g, 985 mmol) were added sequentially to a 2000 mL single-necked flask. Under nitrogen protection, 3-chloro-3-methyl-1-butyne (100 mL, 886 mmol) was added dropwise. Stir at 70°C for 16 hours. Cool to room temperature, add water (1000 mL), and extract with petroleum ether (1000 mL x 3). Dry over anhydrous sodium sulfate and filter. Concentrate under reduced pressure, and the residue is purified by column chromatography (petroleum ether / ethyl acetate) to obtain compound 12b (50 g).

[0313] 1 H NMR (400MHz, CDCl3) δ7.57(d,J=2.4Hz,1H),7.15(dd,J=8.8,2.4Hz,1H),6.76(d,J=8.8Hz,1H),3.79(s,3H),2.58(s,1H),1.65(s,6H).

[0314] Step 2) To a 500 mL single-necked flask at room temperature were added compound 12b (20.0 g, 74.4 mmol), n-hexane (200 mL), and palladium calcium carbonate (1.95 g, 18.8 mmol). Stir under a hydrogen atmosphere at room temperature for 16 hours. Filter and concentrate under reduced pressure to obtain compound 12c (19 g).

[0315] 1H NMR (400MHz, CDCl3) δ7.15 (d, J=2.4Hz, 1H), 7.09 (dd, J=8.8, 2.4Hz, 1H), 6.73 (d, J=8.8Hz, 1H), 6.12 (dd, J=17.6, 10.8Hz, 1H), 5.14 (dd, J=20.0, 9.2Hz, 2H), 3.79 (s, 3H), 1.46 (s, 6H).

[0316] Step 3) Compound 12c (10.0 g, 36.9 mmol) and diethylaniline (10 mL, 62.5 mmol) were added sequentially to a 50 mL single-necked flask at room temperature. Stir at 210°C for 1 hour. Cool to room temperature, adjust the pH to neutral with 1 M HCl solution, extract with ethyl acetate (200 mL x 3), and wash with water (200 mL x 3). Concentrate under reduced pressure to obtain compound 12d (9.1 g).

[0317] 1 H NMR (400MHz, DMSO-d6) δ8.97(s,1H),6.97(d,J=8.8Hz,1H),6.77(d,J=8.8Hz,1H) ,5.14-5.01(m,1H),3.78(s,3H),3.40(d,J=6.8Hz,2H),1.74(s,3H),1.63(s,3H).

[0318] Step 4) Compound 12d (5.00 g, 18.5 mmol), toluene (25 mL) were added sequentially to a 100 mL single-necked bottle at room temperature. 15 (5.00 g, 15.9 mmol). Stir at 100°C for 2 hours under nitrogen protection. Cool to room temperature, filter, and concentrate under reduced pressure to obtain compound 12e (3.89 g).

[0319] 1 H NMR (400MHz, DMSO-d6) δ7.04(d,J=8.8Hz,1H),6.75(d,J=8.8Hz,1H),3.71(s,3H),2.63(t,J=6.8Hz,2H),1.78(t,J=6.8Hz,2H),1.26(s,6H).

[0320] Step 5) To a 500 mL single-necked flask at room temperature were added compound 12e (28.4 g, 105 mmol), dioxane (300 mL), pinacol diboron (31.9 g, 126 mmol), potassium acetate (20.6 g, 209 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7.66 g, 10.5 mmol). Stir at 105°C for 16 hours under nitrogen. Cool to room temperature and filter. Concentrate under reduced pressure, and the residue is purified by column chromatography (petroleum ether / ethyl acetate) to afford compound 12f (28.4 g).

[0321] LCMS: m / z 319 (M+H) + .

[0322] Step 6) Compound 12f (6.20 g, 19.5 mmol), 1,4-dioxane (80 mL), water (16 mL), 2,6-dichloropyrazine (2.90 g, 39.0 mmol), potassium carbonate (5.39 g, 39.0 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.43 g, 1.95 mmol) were added sequentially to a 250 mL single-necked flask at room temperature. Under nitrogen protection, the mixture was stirred at 110°C for 16 hours. The mixture was cooled to room temperature and filtered. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate) to give compound 12g (5.7 g).

[0323] LCMS: m / z 305 (M+H) + .

[0324] Step 7) To a 100 mL single-necked flask at room temperature, compound 12g (35.0 g, 115 mmol), compound 1c (44.5 g, 149 mmol), potassium carbonate (23.8 g, 172 mmol), potassium acetate (16.9 g, 172 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (8.41 g, 11.5 mmol) were added in a mixed solvent of 1,4-dioxane (250 mL) and water (5 mL). Stir until dissolved, replace the atmosphere with nitrogen three times, and stir at 110°C for 16 hours. Cool to room temperature, add water (500 mL), extract with ethyl acetate (300 mL x 3), and dry over anhydrous sodium sulfate. Concentrate, and the residue is purified by column chromatography (petroleum ether / ethyl acetate) to afford compound 12h (37 g).

[0325] LCMS: m / z 441.1 (M+H) + .

[0326] Step 8) At room temperature, 1,2-bis(diphenylphosphino)ethane (1.81 g, 4.54 mmol), (1,5-cyclooctadiene)methoxyiridium(I) dimer (1.50 g, 2.27 mmol), and anhydrous 1,2-dichloroethane (100 mL) were added to a 250 mL three-necked flask. Stir at room temperature for 10 minutes, and compound 12h (10.0 g, 22.7 mmol) was added. The temperature was raised to 70°C, and pinacol borane (20.3 g, 159 mmol) was added dropwise. The reaction was continued at 95°C for 4 hours. The temperature was lowered to 0°C, and methanol (50 mL) was added dropwise to quench the reaction. The residue was concentrated, and purified by column chromatography (petroleum ether / ethyl acetate) to give compound 12i (1.4 g).

[0327] LCMS: m / z 569.3 (M+H) + .

[0328] Step 9) At room temperature, reactant 12i (9.00 g, 15.8 mmol) and tetrahydrofuran (30 mL) were added to a 50 mL single-necked flask. The mixture was cooled to 0°C and 2 M hydrochloric acid (50 mL) was added. The mixture was stirred at 50°C for 16 hours. The mixture was concentrated under reduced pressure, extracted with ethyl acetate (300 mL x 3), dried over anhydrous sodium sulfate, and filtered. The residue was concentrated under reduced pressure and purified by reverse phase column chromatography (acetonitrile / water / trifluoroacetic acid) to afford compound 12 (3.82 g).

[0329] Compound 12-1 (shorter retention time) and compound 12-2 (longer retention time) were obtained by chiral separation (Column: Chiralpak IG 5μm 30*250mm; Mobile Phase: Hex:EtOH=35:65 at 15mL / min; Temp: 30°C; Wavelength: 254nm).

[0330] Compound 12-1

[0331] LCMS: m / z 355.0 (M+H) + .

[0332] 1H NMR (400MHz, DMSO-d6) δ8.62(s,1H),8.48(s,1H),6.98(d,J=8.4Hz,1H),6.90(d,J=8.4Hz,1H),4.29(dd,J=8.8,7.6Hz,1H),3.96(dd ,J=8.8,6.8Hz,1H),3.77(s,3H),3.74-3.62(m,1H),2.93-2.67(m,2H),1.68(t,J=6.8Hz,2H),1.38-1.24(m,7H),1.21-1.08(m,1H).

[0333] Compound 12-2

[0334] LCMS: m / z 355.0 (M+H) + .

[0335] 1 H NMR (400MHz, DMSO-d6) δ8.62(s,1H),8.48(s,1H),6.98(d,J=8.4Hz,1H),6.90(d,J=8.4Hz,1H),4.29(dd,J=8.8,7.6Hz,1H),3.96(dd ,J=8.8,6.8Hz,1H),3.77(s,3H),3.74-3.60(m,1H),2.89-2.67(m,2H),1.68(t,J=6.8Hz,2H),1.36-1.25(m,7H),1.21-1.07(m,1H).

[0336] Example 13

[0337]

[0338]

[0339] Compound 12h (400 mg, 0.91 mmol) was dissolved in anhydrous THF (4 mL) at room temperature and cooled to -10°C under N2 protection. 1,5-Cyclooctadiene iridium chloride dimer (21 mg, 0.041 mmol, 4.5% mol) and (S)-1-(diphenylphosphino)-2-[(S)-4-isopropyloxazolin-2-yl]ferrocene (52 mg, 0.11 mmol, 12% mol) were added. The mixture was stirred at room temperature for 15 minutes, and a solution of catecholborane in THF (1 M, 7.2 mL, 7.2 mmol) was added. The reaction was continued at room temperature for 3 hours. Concentrated hydrochloric acid (0.2 mL) was added and the reaction was continued for 2 hours. The mixture was then filtered and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (acetonitrile / water / trifluoroacetic acid) to obtain compound 12h (105 mg). Chiral HPLC confirmed that the resolved compound was identical to compound 12-1.

[0340] LCMS: m / z 355.0 (M+H) + .

[0341] 1 H NMR (400MHz, DMSO-d6) δ8.62(s,1H),8.48(s,1H),6.98(d,J=8.4Hz,1H),6.90(d,J=8.4Hz,1H),4.29(dd,J=8.8,7.6Hz,1H),3.96(dd ,J=8.8,6.8Hz,1H),3.77(s,3H),3.74-3.62(m,1H),2.93-2.67(m,2H),1.68(t,J=6.8Hz,2H),1.38-1.24(m,7H),1.21-1.08(m,1H).

[0342] Biological evaluation

[0343] The present disclosure is further described and explained below in conjunction with test examples, but these test examples are not intended to limit the scope of the present disclosure.

[0344] The structure of compound A is

[0345]

[0346] Compound A was prepared using the method disclosed in "Example 4 on page 181 of the specification of patent application WO2020070651A".

[0347] Test Example 1 In vitro PDE4B enzyme activity detection experiment

[0348] 1. Experimental Materials

[0349]

[0350]

[0351] 2. Experimental Procedure

[0352] A 10 mM stock solution of the compound was prepared in 90% DMSO (10% water) in a test tube and used to prepare a 1:5 dilution series starting from 100 uM and going down to 0.05 nM.

[0353] Transfer 0.2 μl of compound solution to a 384-well reaction plate. Transfer 0.2 μl of 100% DMSO to each negative and positive control. Then, add 10 μl of a 2x PDE4B1 enzyme solution (final concentration 0.04 nM) to each well. For the no-enzyme control wells, replace the enzyme solution with 10 μl of 1x reaction buffer. Centrifuge at 1000 rpm for 1 minute and incubate at room temperature for 15 minutes. Next, add 10 μl of a 2x FAM-cAMP substrate solution (final concentration 0.1 μM) to each well of the 384-well reaction plate. Centrifuge at 1000 rpm for 1 minute and incubate at 25°C for 30 minutes. After the reaction is complete, add 60 μl of stop solution to each well of the 384-well plate and incubate at room temperature for 60 minutes on a shaker at 600 rpm in the dark.

[0354] After the incubation, read the RLU data and calculate the inhibition rate. The IC is calculated based on the concentration and inhibition rate fitting curve. 50 The maximum value refers to the reading of the DMSO control, and the minimum value refers to the reading of the no enzyme activity control.

[0355] The examples disclosed herein were used to determine the inhibition of PDE4B1 enzyme activity in vitro using the above assays. The IC 50 See Table 1 for values.

[0356] Table 1

[0357]

[0358] Note: N / A not tested

[0359] Test Example 2 Inhibitory Effect of Compounds on the Release of Proinflammatory Cytokines from Peripheral Blood Mononuclear Cells (PBMCs)

[0360] Thaw frozen PBMCs and detect cell viability and number using trypan blue staining. Wash the thawed PBMCs with RPMI1640 complete medium (RPMI1640 + 10% FBS + 1% PS), centrifuge and discard the supernatant. Resuspend the PBMCs in RPMI1640 complete medium and adjust the cell density to 2×10 6 cells / mL. 2×10 5PBMC cells were cultured in 96-well cell culture plates, and different concentrations of the test compound were added. Starting from the maximum concentration of 100 μM of the compound, 9 concentration gradient dilutions were made at a ratio of 1:5, and double-well detection was performed. LPS was added at a final concentration of 0.1 ng / mL, and the total volume was 200 μL. Negative and positive controls were set up. Only LPS and a final concentration of DMSO were added to the negative control wells. In addition to cells and LPS, 1 μg / mL of dexamethasone was added to the positive control wells as a positive control. The cells were incubated in a 37-degree incubator for 24 hours. After incubation, 100 μL of cell culture supernatant was collected and the level of TNF-α was detected by ELISA. 100 μL of CellTiter-Glo was added to the remaining cells in each well to detect the cell viability level. Calculate the IC value of the compound for inhibiting TNF-α release 50 value.

[0361] The inhibition of PBMC pro-inflammatory cytokine release in vitro by the disclosed embodiments was determined by the above test, and the measured IC 50 See Table 2 for values.

[0362] Table 2

[0363]

[0364] Note: N / A not tested

[0365] Test Example 3: In vitro inhibition of IL-23 secretion by DCs differentiated from human monocytes

[0366] Day 0: Mononuclear cells were isolated and purified from fresh human peripheral blood and resuspended in complete RPMI-1640 medium (RPMI-1640 + 10% FBS + 1% PS + 55 μM 2-Mercaptoethanol). For DC differentiation, 50 ng / ml IL-4 and 100 ng / ml GM-CSF were added to the culture medium. The cells were cultured at a density of 1×106 cells / mL in a 100 mm diameter dish in an incubator at 37°C with 5% CO2. Day 3: Half the volume of complete RPMI medium was replaced with fresh complete RPMI medium, maintaining IL-4 concentrations of 50 ng / ml and GM-CSF concentrations of 100 ng / ml. Day 6: Unattached cells (DCs) were harvested from the dish and washed with PBS. The washed DCs were then resuspended in complete RPMI medium at a density of 1×106 cells / mL. 1×105 DCs were then added to each well of a 96-well cell culture plate. The cells were pretreated with varying concentrations of the test compound (or a DMSO blank negative control at the same concentration) for 1 hour. The DCs were then stimulated with 200 μg / ml of the TLR2 agonist Zymosan for 24 hours. Day 7: Following 24 hours of Zymosan stimulation of the DCs, the supernatants from each well of the 96-well plate were collected and IL-23 concentrations were measured by ELISA.

[0367] The inhibition of the compounds disclosed herein on the secretion of IL-23 by DC cells differentiated from human monocytes in vitro was determined by the above test, and the measured IC 50 See Table 3 for values.

[0368] Table 3

[0369] No. PBMC IC 50 (nM) Number PBMC IC 50 (nM) Compound 1-10.12 Compound 12-10.018

[0370] Roflumilast 12.91 Compound A0.61

[0371] Test Example 4 Imiquimod-induced psoriasis inhibition experiment

[0372] Take an appropriate amount of compound 12-1 to prepare an ointment with the following ingredients: 0.1% compound 12-1, 9% hexylene glycol, 78.8% white vaseline, 5% paraffin, 7% mono- and di-stearate glyceryl, 0.1% dihydroxybutyltoluene, and stir mechanically until the ointment is formed.

[0373] 1) Modeling and drug administration

[0374] Seven-week-old female Balb / c mice were selected. The day before the experiment, the back of the mice was shaved (2 cm x 3 cm). Six hours after the test substance was applied to the skin, imiquimod (IMQ) ointment (Aldara (5%)) was applied to the back skin of the mice for 7 consecutive days to establish a psoriasis mouse model. A control group received the same dose of petrolatum ointment. The severity of skin inflammation was assessed on days 3, 5, and 7, including skin thickness, crusting, and erythema, and scored on a 5-point scale (0-4). The total score was used to assess the severity of skin inflammation. On day 7, the spleen was weighed, and the percentage of spleen to body weight was calculated to assess the degree of immunosuppressive effect of the drug.

[0375] This experiment set up a normal control group, a model control group, low-, medium- and high-dose groups of compound 12-1 (0.01%, 0.03% and 0.1%), a 0.03% compound 1-1 group and a 0.03% reference compound A group.

[0376] 2) Evaluation indicators

[0377] The total score for skin inflammation is a clinical score, which is relatively subjective; higher scores indicate more severe disease. Skin thickness is an objective evaluation indicator; greater thickness indicates more severe disease. Spleen weight ratio is also an objective evaluation indicator; a smaller spleen weight ratio indicates a stronger immunosuppressive effect of the drug.

[0378] 3) Experimental results

[0379] 3.1) Clinical scoring

[0380] Each dose of compound A, compound 1-1 and compound 12-1 significantly reduced the clinical score at the end of the experiment. (Figure 1-Figure 4). From the perspective of single score, each dose group of compound 1-1 and compound 12-1 mainly improved the psoriasis scab of the model and reduced skin thickness. In the skin thickness score, both the low and high dose groups of compound 12-1 significantly inhibited the increase in skin thickness, and compound A had no significant effect. The inhibitory effect of 0.03% of compound 12-1 on the increase in skin thickness was significantly higher than that of compound A at the same dose (Figure 4). The results show that compound 12-1 is significantly better than reference compound A in improving the manifestations of psoriasis. The specific scoring data are shown in Table 4.

[0381] Table 4

[0382]

[0383]

[0384] 3.2) Spleen body weight ratio

[0385] Under the action of IMQ, there was no significant difference in the body weight of animals in the model group and each drug-treated group, while the spleen in the model group increased significantly (Figure 5), indicating splenomegaly. Compound A had no significant effect on the proportion of spleen body weight, while the three dose groups of compound 1-1 and compound 12-1 significantly reduced the proportion of spleen body weight. This suggests that each compound has an immunosuppressive effect, and the effect of compound 12-1 is dose-response. At the same dose (0.03%), the effects of compound 1-1 and compound 12-1 on the proportion of spleen body weight were significantly different from those of compound A. The results suggest that the immune effects of compound 1-1 and compound 12-1 are stronger than those of compound A. Specific data are shown in Table 5

[0386] Table 5

[0387]

Claims

1. The compound of formula I or a pharmaceutically acceptable salt thereof Wherein, Ring A is selected from 5- to 6-membered aryl or heteroaryl rings, which aryl or heteroaryl rings are optionally substituted by one or more R A1 ; R A1 selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 alkoxy; B is a boron atom; Z is selected from a carbon atom or a nitrogen atom; R 1 Each independently selected from hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy is optionally substituted by one or more R A2 ; R A2 Selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 alkoxy; R 2 selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R A3 substituents; R A3 selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino; R 3 、R 4 or R 5 each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl or 3- to 6-membered heteroalkoxy, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, heteroalkyl or heteroalkoxy is optionally substituted with one or more R A4 ; R A4 selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino; R 6 and R 7 form a 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring with an adjacent carbon atom, said carbocyclic or heterocyclic ring being optionally substituted by one or more R A5 substituents; R A5 selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, phenyl or 5- to 6-membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, phenyl or 5- to 6-membered heteroaryl is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano; m is selected from an integer between 0 and 5; n is selected from an integer of 1 to 3, for example 1 or 2; and With Is in the meta position on ring A; Is a single bond or does not exist.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 or R 4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, the alkyl and alkoxy being optionally substituted by one or more R A4 as defined in claim 1. A4 as defined in claim 1.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 or R 4 each independently is selected from hydrogen, deuterium, halogen, amino, hydroxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl or 3- to 6-membered heterocycloalkyloxy, and the cycloalkyloxy, cycloalkyl, heterocycloalkyl or heterocycloalkyloxy is optionally substituted by one or more R A4 as defined in claim 1. A4 ​ 4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein R 5 is selected from hydrogen, deuterium, halogen, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, and the alkyl and alkoxy are optionally substituted by one or more R A4 , where R A4 is as defined in claim 1.

5. The compound or its pharmaceutically acceptable salt according to any one of claims 1-3, wherein R 5 is selected from hydrogen, deuterium, halogen, amino, hydroxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl or 3- to 6-membered heterocycloalkoxy, said cycloalkoxy, cycloalkyl, heterocycloalkyl or heterocycloalkoxy being optionally substituted by one or more R A4 as defined in claim 1. A4 as defined in claim 1.

6. The compound according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein R 3 or R 4 each independently is selected from hydrogen; R 5 is selected from C 1-6 alkyl or C 1-6 alkoxy, the alkyl and alkoxy being optionally substituted by 1 to 3 R A4 , R A4 being as defined in claim 1.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein the compound of formula I is Wherein, X 1 Selected from -O-, -N(R 16a )- or -CR 16a R 16b -; X 2 selected from -O- or -CR 17a R 17b -; X 3 selected from a bond or -CR 18a R 18b -, -CR 18a R 18b CR 18c R 18d -; R 16a and R 16b each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, said alkyl or alkoxy optionally substituted by halogen, nitro, cyano or C 1-6 alkoxy; R 17a and R 17b each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, said alkyl or alkoxy optionally substituted by halogen, nitro, cyano or C 1-6 alkoxy; R 18a 、R 18b 、R 18c and R 18d are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, wherein the alkyl or alkoxy is optionally substituted by halogen, nitro, cyano or C 1-6 alkoxy; R 8 and R 9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl or 3- to 6-membered heteroalkoxy, and the alkyl, alkoxy, cycloalkoxy, cycloalkyl or heteroalkyl is optionally substituted by one or more R A6 ; or R 8 、R 9 forms a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring with an adjacent carbon atom, and the carbocyclic ring or heterocyclic ring is optionally substituted by one or more R A6 ; or R 8 and R 9 together form oxo(=O); R A6 selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy; Ring A, R 1 ~R 5 , B, m, n and As defined in claim 1.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 7, wherein X 1 is selected from -O-; X 2 is selected from -O- or -CR 17a R 17b -; R 17a and R 17b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy.

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 7 or 8, wherein the compound of formula I is 10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 7-9, wherein R 8 and R 9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, and the alkyl or alkoxy is optionally substituted by one or more R A6 ; R A6 is as defined in claim 7.

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 7-9, wherein R 8 , R 9 The 3- to 6-membered carbocyclic ring or 4- to 6-membered heterocyclic ring formed with adjacent carbon atoms is selected from Further, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 3 R A6 ; R A6 is as defined in claim 7.

12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein the compound of formula I is Wherein, X 4 selected from a nitrogen atom or a carbon atom; R 10 and R 11 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl or 3- to 6-membered heteroalkoxy, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl or heteroalkyl is optionally substituted by one or more R A7 ; R A7 selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy; Rings A, Z, R 1 ~R 5 , B, m, n and As defined in claim 1.

13. The compound or a pharmaceutically acceptable salt thereof according to claim 12, wherein R 10 and R 11 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, the alkyl or alkoxy being optionally substituted by 1 to 3 R A7 as defined in claim 12, R A7 being as defined in claim 12.

14. The compound or a pharmaceutically acceptable salt thereof according to claim 12 or 13, wherein R A7 is selected from halogen, C 1-6 alkyl or C 1-6 alkoxy, preferably fluorine, chlorine, methyl, ethyl, methoxy or ethoxy.

15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 12-14, wherein X 4 is selected from a nitrogen atom; Z is selected from a nitrogen atom.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein the compound of formula I is Wherein, X 5 selected from a nitrogen atom or a carbon atom; R 12 , R 13 and R 14 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 substituted by cycloalkyl, 3- to 6-membered heterocycloalkyl or 3- to 6-membered heterocycloalkoxy, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R A8 replaced by; R A8 selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy; Rings A, Z, R 1 ~R 5 , B, m, n and As defined in claim 1.

17. The compound or a pharmaceutically acceptable salt thereof according to claim 16, wherein R 12 , R 13 and R 14 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, wherein the alkyl or alkoxy is optionally substituted by 1 to 3 R A8 ; R A8 is as defined in claim 16.

18. The compound or a pharmaceutically acceptable salt thereof according to claim 16 or 17, wherein R A8 is selected from halogen, C 1-6 alkyl or C 1-6 alkoxy, preferably fluoro, chloro, methyl, ethyl, methoxy or ethoxy.

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 16 - 18, wherein X 5 is selected from a nitrogen atom; Z is selected from a carbon atom.

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-19, wherein ring A is selected from wherein R 15a , R 15b , R 15c and R 15d are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, and the alkyl or alkoxy is optionally substituted by one or more halogen, deuterium, hydroxy, nitro, cyano, amino; further, ring A is preferably 21. The compound or a pharmaceutically acceptable salt thereof according to claim 20, wherein R 15a , R 15b , R 15c and R 15d are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, preferably hydrogen, fluorine, chlorine, methyl or ethyl.

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-21, wherein n is selected from 1 or 2.

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-22, wherein R 2 is selected from hydrogen, C 1-6 alkyl, preferably hydrogen, methyl or ethyl, more preferably hydrogen.

24. The compound or its pharmaceutically acceptable salt according to any one of claims 1-23, wherein R 1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, the alkyl or alkoxy being optionally substituted by one or more halogen, deuterium, hydroxy, nitro, cyano, amino, preferably R 1 is independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, methoxy or ethoxy.

25. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-24, wherein the compound of formula I is selected from Wherein, R 1 ~R 5 , B, m, as defined in claim 1, R 8 and R 9 as defined in claim 7, R 15a , R 15b and R 15d as defined in claim 20, further, the compound of formula I is preferably 26. The compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from: Furthermore, the compound of formula I is preferably:

27. The isotope substitute of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-26, preferably, the isotope substitute is a deuterated compound.

28. A method for preparing the compound of formula I or a pharmaceutically acceptable salt thereof, comprising the step of converting the compound of formula (1) into the compound of formula I or a pharmaceutically acceptable salt thereof, Wherein, R 19a and R 19b are each independently selected from hydrogen, C 1-6 alkyl, said alkyl being optionally substituted by one or more halogens, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 alkoxy, or R 19a and R 19b together with adjacent atoms form a five- or six-membered heterocycle, said heterocycle being optionally substituted by one or more R A9 , R A9 being selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy; Ring A, R 1 ~R 7 、B、n、Z are as defined in claim 1.

29. The compound of formula (1) or a pharmaceutically acceptable salt thereof, Wherein, R 19a and R 19b are each independently selected from hydrogen, C 1-6 alkyl, wherein the alkyl is optionally substituted with one or more halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 alkoxy, or R 19a and R 19b together with adjacent atoms form a 5- or 6-membered heterocycle, which heterocycle is optionally substituted with one or more R A9 , R A9 is selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy; Ring A, R 1 ~R 7 、B、n、Z are as defined in claim 1.

30. A pharmaceutical composition comprising at least one therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-26, or the isotope substitute of claim 27, and a pharmaceutically acceptable excipient.

31. Use of the compound according to any one of claims 1-26, or the isotope substitute of claim 27, the compound of formula I or a pharmaceutically acceptable salt thereof prepared by the method of claim 28 or the compound of claim 29 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30 in the preparation of a drug for preventing and / or treating PDE-related diseases.

32. Use of the compound according to any one of claims 1-26, or the isotope substitute of claim 27, the compound of formula I or a pharmaceutically acceptable salt thereof prepared by the method of claim 28 or the compound of claim 29 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30 in the preparation of a drug for preventing and / or treating asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis or rheumatism.