A boronic ester derivative and uses thereof

Abstract

Provided is a compound as shown in formula I or a pharmaceutically acceptable salt thereof, and use of the compound in preparation of a drug for preventing and / or treating a PDE-related disorder.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a borate ester derivative and its uses. Background Technology

[0002] Phosphodiesterases (PDEs) are a class of intracellular enzymes that cleave the phosphodiester bonds on the second messenger molecules 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP). Cyclic nucleotides cAMP and cGMP act as second messengers in various cellular pathways. PDE4 exhibits high specificity for cAMP and has four subtypes: PDE4A, PDE4B, PDE4C, and PDE4D. PDE4 participates in physiological and pathological processes related to monocyte and macrophage activation, neutrophil infiltration, vascular smooth muscle proliferation, vasodilation, and myocardial contraction, and influences central nervous system function, cardiovascular function, the inflammatory / immune system, and cell adhesion. PDE4 plays a major regulatory role in the expression of pro-inflammatory 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 severe chronic obstructive pulmonary disease (COPD) to reduce the frequency of sudden exacerbations or prevent COPD symptom exacerbations, and apremilast is approved for the treatment of adults with active psoriatic arthritis. Although PDE4 inhibitors show good pharmacological activity, these PDE4 inhibitors can cause side effects, such as inducing gastrointestinal symptoms like vomiting and diarrhea. Therefore, there is still a need to develop selective PDE4 inhibitors, especially those with affinity for PDE4B and PDE4D.

[0004] The boron-containing (B) drug criborone 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 PDE inhibitors, such as CN102014927A and WO2020070651, have been reported. However, the compound disclosed here has not been reported in any literature, and this class of compounds exhibits specific PDE4 inhibitory effects. Summary of the Invention

[0005] This disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof.

[0006]

[0007] Wherein, ring A is selected from 5- to 6-membered aromatic rings or heteroaromatic rings, wherein the aromatic ring or heteroaromatic ring is optionally surrounded by one or more R A1 Replaced;

[0008] 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 groups optionally selected from one or more halogens, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 Alkyl groups are substituted;

[0009] B represents a boron atom;

[0010] Z is selected from either carbon or nitrogen atoms;

[0011] R 1 Each is independently selected from hydrogen, halogen, deuterium, hydroxyl, 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 groups optionally surrounded by one or more R A2 Replaced;

[0012] 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 groups optionally selected from one or more halogens, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 Alkyl groups are substituted;

[0013] R 2 Selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally surrounded by one or more R... A3 Replaced;

[0014] R A3 Selected from halogens, deuterium, hydroxyl groups, oxo groups, nitro groups, cyano groups, and amino groups;

[0015] R 3 R 4 or R 5 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl, or 3- to 6-membered heterocyclic alkoxy, wherein the alkyl, alkoxy, cycloalkoxy, cycloalkyl, heterocyclic alkyl, or heterocyclic alkoxy is optionally surrounded by one or more R A4 Replaced;

[0016] R A4 Selected from halogens, deuterium, hydroxyl groups, oxo groups, nitro groups, cyano groups, and amino groups;

[0017] R 6 R 7 It forms a 3- to 10-membered carbon ring or a 3- to 10-membered heterocycle with adjacent carbon atoms, wherein the carbon ring or heterocycle is optionally surrounded by one or more R atoms. A5 Replaced;

[0018] 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 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 group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano.

[0019] m is selected from an integer between 0 and 5;

[0020] n is an integer selected from 1 to 3, for example, 1 or 2;

[0021] and and It is located in the intermediate position on ring A;

[0022] It is a single key or does not exist.

[0023] In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof 3 or R 4Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by one or more R A4 Replaced by, R A4 As defined above.

[0024] In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof 3 or R 4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and 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 surrounded by one or more R A4 Replaced by, R A4 As defined above.

[0025] In other embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof 5 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by one or more R A4 What it replaced.

[0026] In other embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof 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 surrounded by one or more R A4 What it replaced.

[0027] Furthermore, some embodiments provide a compound of formula I or a pharmaceutically acceptable salt thereof R. 3 or R 4 Each is independently selected from hydrogen; R 5 Selected from C 1-6 Alkyl or C 1-6 alkoxy group, wherein the alkyl group or alkoxy group is optionally surrounded by 1 to 3 R groups. A4 What it replaced.

[0028] In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof A4 Selected from halogens, such as fluorine.

[0029] In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof A4 Selected from hydroxyl, nitro, cyano, and amino groups.

[0030] On the other hand, some implementation schemes provide the compound shown in Formula I as follows:

[0031]

[0032] Among them, X 1 Selected from -O-, -N(R) 16a )-or-CR 16a R 16b -;

[0033] X 2 Selected from -O- or -CR 17a R 17b -;

[0034] X 3 Selected from key or -CR 18a R 18b -、-CR 18a R 18b CR 18c R 18d -;

[0035] R 16a and R 16b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally halogenated, nitro, cyano, or C. 1-6 Alkyl groups are substituted;

[0036] R 17a and R 17b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally halogenated, nitro, cyano, or C. 1-6 Alkyl groups are substituted;

[0037] R 18a R 18b R 18c and R 18d Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally halogenated, nitro, cyano, or C. 1-6 Alkyl groups are substituted;

[0038] R 8 R 9 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C3-6 The alkyl group, 3- to 6-membered heterocyclic alkyl group, or 3- to 6-membered heterocyclic alkoxy group is substituted with one or more R groups. A6 Replaced;

[0039] Or R 8 R 9 It forms a 3- to 6-membered carbon ring or a 3- to 6-membered heterocycle with adjacent carbon atoms, wherein the carbon ring or heterocycle is optionally surrounded by one or more R atoms. A6 Replaced;

[0040] Or R 8 With R 9 Together they form oxygen (=O);

[0041] R A6 Selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkyl groups;

[0042] Rings A and R 1 ~R 5 B, m, n and Defined in the compound shown in Formula I.

[0043] In some embodiments, X in the compound of formula IA or its pharmaceutically acceptable salt 1 Selected from -O-.

[0044] In some embodiments, X in the compound of formula IA or its pharmaceutically acceptable salt 1 Selected from -O-;X 2 Selected from -O- or -CR 17a R 17b -;R 17a and R 17b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkyl group.

[0045] In some embodiments, X in the compound of formula IA or its pharmaceutically acceptable salt 3 Selected from key or -CR 18a R 18b -, R 18a R 18b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkyl group.

[0046] In some embodiments, X in the compound of formula IA or its pharmaceutically acceptable salt 1 Selected from -O-;X 2Selected from -O- or -CR 17a R 17b -;R 17a and R 17b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy; X 3 Selected from key.

[0047] In some embodiments, X in the compound of formula IA or its pharmaceutically acceptable salt 1 Selected from -O-;X 2 Selected from -O- or -CR 17a R 17b -;R 17a and R 17b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy; X 3 Selected from -CR 18a R 18b -, R 18a R 18b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkyl group.

[0048] On the other hand, some implementation schemes provide the compound shown in Formula IA as

[0049]

[0050] In some embodiments, R in the compound of formula I or formula IA or its pharmaceutically acceptable salt 8 R 9 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by one or more R A6 Replaced; R A6 Selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkyl group.

[0051] In some embodiments, R in the compound of formula IA or its pharmaceutically acceptable salt 8 R 9 The 3- to 6-membered carbon rings or 4- to 6-membered heterocycles formed with adjacent carbon atoms are selected from...

[0052]

[0053] Furthermore, the carbon ring or heterocycle may optionally be surrounded by 1 to 3 R... A6 Replaced; R A6 Selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkyl group.

[0054] In some embodiments, R in the compound of formula IA or its pharmaceutically acceptable salt A6 Selected from deuterium or oxo. In some embodiments, R in the compound of formula IA or a pharmaceutically acceptable salt thereof A6 Selected from halogens, C 1-6 Alkyl or C 1-6 Alkyl group. In some embodiments, R in the compound of formula IA or its pharmaceutically acceptable salt. A6 It is selected from fluorine, chlorine, methyl, ethyl, methoxy, or ethoxy.

[0055] On the other hand, some implementation schemes show the compound of formula I as follows:

[0056]

[0057] Among them, X 4 Selected from nitrogen or carbon atoms;

[0058] R 10 R 11 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 The alkyl group, 3- to 6-membered heterocyclic alkyl group, or 3- to 6-membered heterocyclic alkoxy group is substituted with one or more R groups. A7 Replaced;

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

[0060] Rings A, Z, R 1 ~R 5 B, m, n and Defined in the compound shown in Formula I.

[0061] In some embodiments, R in the compound of formula IB or its pharmaceutically acceptable salt 10 R 11 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by 1 to 3 R groups. A7 Replaced. In some embodiments, R in the compound of formula IB or its pharmaceutically acceptable salt. A7 Selected from halogens, C 1-6 Alkyl or C 1-6 Alkyl group. In some embodiments, R in the compound of formula IB or its pharmaceutically acceptable salt. A7 It 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 its pharmaceutically acceptable salt 4 Selected from nitrogen atoms; Z is selected from nitrogen atoms.

[0063] In some embodiments, the compound represented by Formula I is

[0064]

[0065] Among them, X 5 Selected from nitrogen or carbon atoms;

[0066] R 12 R 13 and R 14 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 The alkyl group, 3- to 6-membered heterocyclic alkyl group, or 3- to 6-membered heterocyclic alkoxy group is substituted with one or more R groups. A8 Replaced;

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

[0068] Rings A, Z, R 1 ~R 5 B, m, n and Defined in the compound shown in Formula I.

[0069] In some embodiments, R in the compound of formula IC or its pharmaceutically acceptable salt 12 R 13 and R 14 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by 1 to 3 R groups. A8Replaced. In some embodiments, R in the compound of formula IC or its pharmaceutically acceptable salt. A8 Selected from halogens, C 1-6 Alkyl or C 1-6 Alkyl group. In some embodiments, R in the compound of formula IC or its pharmaceutically acceptable salt. A8 It is selected from fluorine, chlorine, methyl, ethyl, methoxy, or ethoxy.

[0070] On the other hand, in some embodiments, X in the compound of formula IC or its pharmaceutically acceptable salt 5 Z is selected from nitrogen atoms; Z is selected from carbon atoms.

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

[0072]

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

[0074] In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof 15a R 15b R 15c and R 15d Each element is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl group. In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof 15a R 15b R 15c and R 15d Each is independently selected from fluorine, chlorine, methyl, or ethyl.

[0075] Other embodiments provide that the ring A in the compound of formula I or its pharmaceutically acceptable salt is selected from:

[0076]

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

[0078] In some embodiments, the compounds represented by Formula I or Formula IA are selected from...

[0079]

[0080] In some embodiments, the compounds represented by Formula I or Formula IA are selected from...

[0081]

[0082] In some embodiments, the compounds represented by Formula I or Formula IB are selected from...

[0083]

[0084] In some embodiments, the compounds represented by Formula I or Formula I are selected from...

[0085]

[0086] In some embodiments, the compound represented by Formula I is selected from...

[0087]

[0088] On the other hand, some embodiments provide R in compounds of formula I, IA, IB, or IC or their pharmaceutically acceptable salts. 2 Selected from hydrogen, C 1-6 Alkyl group. In some embodiments, R in the compound of formula I, IA, IB, or IC or a pharmaceutically acceptable salt thereof. 2 Selected from hydrogen, methyl, or ethyl. In some embodiments, R is a compound of formula I, IA, IB, or IC, or a pharmaceutically acceptable salt thereof. 2 Selected from hydrogen.

[0089] On the other hand, some embodiments provide R in compounds of formula I, IA, IB, or IC or their pharmaceutically acceptable salts. 1 Each element is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 The alkoxy group, wherein the alkyl or alkoxy group is optionally substituted with one or more halogens, deuterium, hydroxyl, nitro, cyano, or amino groups. In some embodiments, R in the compound represented by formula I, IA, IB, or IC, or a pharmaceutically acceptable salt thereof 1 Each is independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, or ethoxy.

[0090] Other embodiments provide the compound shown in Formula I as follows:

[0091]

[0092] In some embodiments, the compound represented by Formula I is

[0093]

[0094] Some implementation schemes provide compounds of Formula I selected from...

[0095]

[0096] In some embodiments, the compound represented by Formula I is selected from...

[0097] Typical compounds of Formula I or their pharmaceutically acceptable salts, including but not limited to:

[0098]

[0099]

[0100]

[0101] Typical compounds of Formula I or their pharmaceutically acceptable salts, including but not limited to:

[0102]

[0103]

[0104]

[0105] On the other hand, this disclosure also provides compounds of formula (1) or pharmaceutically acceptable salts thereof.

[0106]

[0107] Among them, R 19a and R 19b Each is independently selected from hydrogen and C. 1-6 Alkyl groups, optionally oxidized by one or more halogens, deuterium, hydroxyl groups, oxo groups, nitro groups, cyano groups, amino groups, or C6 groups. 1-6 Alkoxy groups are substituted, or R 19a and R 19b Together with adjacent atoms, they form a five- or six-membered heterocycle, which is optionally surrounded by one or more R atoms. A9 Replaced by, R A9 Selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkyl groups; cyclic A and R groups 1 ~R 7 B, n, and Z are as defined in the compound shown in Formula I.

[0108] In some embodiments, the compound shown in formula (1) is

[0109] Among them, rings A and R 1 R 3 ~R 5B, 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 shown in Formula IA.

[0110] In some embodiments, the compound represented by formula (1) or its pharmaceutically acceptable salt is

[0111] Among them, rings A and R 1 R 3 ~R 5 B, n, and Z are as defined in the compound shown in Formula I, and R 10 ~R 11 X 4 As defined in the compound shown in Formula IB.

[0112] In some embodiments, the compound shown in formula (1) is

[0113]

[0114] Among them, rings A and R 1 R 3 ~R 5 B, n, and Z are as defined in the compound shown in Formula I, and R 12 ~R 14 X 5 As defined in the compound shown in Formula IB.

[0115] On the other hand, in some embodiments, the compound shown in formula (1) is

[0116] Where R A9 Selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkyl group, o is selected from integers between 0 and 4, cyclic A, R 1 ~R 7 B, n, and Z are as defined in the compound shown in Formula I.

[0117] On the other hand, in some embodiments, the compound shown in formula (1) is

[0118] Where R A9 Selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkyl groups, p is selected from integers between 0 and 6, cyclic A, R 1 ~R 7B, n, and Z are as defined in the compound shown in Formula I.

[0119] This disclosure also provides 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.

[0120]

[0121] Among them, R 19a and R 19b Each is independently selected from hydrogen and C. 1-6 Alkyl groups, optionally oxidized by one or more halogens, deuterium, hydroxyl groups, oxo groups, nitro groups, cyano groups, amino groups, or C6 groups. 1-6 Alkoxy groups are substituted, or R 19a and R 19b Together with adjacent atoms, they form a five- or six-membered heterocycle, which is optionally surrounded by one or more R atoms. A9 Replaced by, R A9 Selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkyl group.

[0122] On the other hand, this disclosure also provides the compound of formula (2) or a pharmaceutically acceptable salt thereof.

[0123] Where R 20a and R 20b Each is independently selected from hydrogen and C. 1-6 Alkyl groups, optionally oxidized by one or more halogens, deuterium, hydroxyl groups, oxo groups, nitro groups, cyano groups, amino groups, or C6 groups. 1-6 Alkoxy groups are substituted, or R 20a and R 20b Together with adjacent atoms, they form a five- or six-membered heterocycle, which is optionally surrounded by one or more R atoms. A10 Replaced by, R A10 Selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkyl group.

[0124] Some implementation schemes provide the compound shown in formula (2) as

[0125] Some implementation schemes provide the compound shown in formula (2) as

[0126] In some embodiments, the compound represented by formula (2) or a pharmaceutically acceptable salt thereof is selected from:

[0127]

[0128] This disclosure also provides a pharmaceutical composition comprising at least one therapeutically effective amount of the aforementioned compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0129] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0130] In some 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 some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0132] This disclosure also provides a method for preventing and / or treating patients with PDE-related conditions by administering to the patient a therapeutically effective amount of a compound as shown in Formula I or Formula IA above, or a pharmaceutically acceptable salt thereof, or a compound or pharmaceutically acceptable salt thereof prepared by the aforementioned method, or the aforementioned pharmaceutical composition.

[0133] In some implementations, the PDE-related conditions are preferably asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism.

[0134] This 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 as shown in Formula I or Formula IA above, or a pharmaceutically acceptable salt thereof, or a compound or pharmaceutically acceptable salt thereof prepared by the aforementioned method, or the aforementioned pharmaceutical composition.

[0135] This disclosure also provides the use of compounds of Formula I or Formula IA, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions, in the preparation of medicaments for the prevention and / or treatment of PDE-related conditions. In some embodiments, the PDE-related conditions are preferably asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism.

[0136] This disclosure also provides the use of compounds of Formula I or Formula IA, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention and / or treatment of asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism.

[0137] On the other hand, the pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic or organic salts.

[0138] The compounds disclosed herein can exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0139] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, 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 desired enantiomer in pure form. 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 salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0140] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be or Or simultaneously include and Two configurations. Bond This indicates that the configuration is not specified, including cis (E) or trans (Z) configurations.

[0141] The compounds and intermediates disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine, lactam-lactamimide isomerization. Examples of lactam-lactamimide equilibria are between A and B as shown below.

[0142]

[0143] All compounds in this disclosure can be classified as type A or type B. All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

[0144] This disclosure also includes compounds identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this 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, etc.

[0145] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). The natural abundance of deuterium in the example compounds can be at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or even higher. This disclosure also includes various deuterated forms of compounds of formula (I). Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated forms of compounds of formula (I) with reference to relevant literature. Commercially available deuterated starting materials can be used to prepare the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0146] "Optional" or "optional" means that the event or situation subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally halogenated or cyano-substituted C..." 1-6 "Alkyl" means that halogens or cyano groups may or may not be present. This description includes cases where alkyl groups are substituted by halogens or cyano groups and cases where alkyl groups are not substituted by halogens or cyano groups.

[0147] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0148] "Pharmaceutical excipients" or "acceptable excipients" include, but are not limited to, any adjuvants, carriers, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0149] The term "effective amount" or "effective therapeutic amount" as used in this disclosure includes an amount sufficient to improve or prevent symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to allow 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 may be the maximum dose or administration regimen that avoids significant side effects or toxicity.

[0150] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms are also included. 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 their various branched isomers. Alkyl groups can be substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point, preferably one or more of the following groups, independently selected from halogens, 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 groups optionally selected from one or more halogens, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 Alkyl groups are substituted.

[0151] The terms "cycloalkyl" or "carbocyclic" refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. The cycloalkyl group can be substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point, preferably one or more of the following groups, independently selected from halogens, 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 groups optionally selected from one or more halogens, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 The cycloalkyl ring is substituted with an alkoxy group. The cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl group; non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, nitro, cyano, amino, C... 1-6 Alkyl, C3-6 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 groups optionally selected from one or more halogens, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 Alkyl groups are substituted.

[0152] The term "heterocyclic alkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 6 ring atoms. Non-limiting examples of "heterocyclic alkyl" include: etc.

[0153] Heterocyclic alkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl groups, oxo groups, nitro groups, cyano groups, and C4 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, phenyl, or 5- to 6-membered heteroaryl, wherein 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 group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano.

[0154] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5- or 6-membered. For example, non-limiting examples include: etc.

[0155] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, 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 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 group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano.

[0156] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, and 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 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 group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano.

[0157] The term "cycloalkoxy" refers to -O- (cycloalkyl), where cycloalkyl is defined as described above. This includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl.

[0158] The term "heterocyclic" refers to a ring composed of atoms other than carbon atoms, including heterocyclic alkyl and heteroaromatic rings.

[0159] The term "hydroxyl group" refers to the -OH group.

[0160] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0161] The term "amino" refers to -CN.

[0162] The term "cyano" refers to -NH2.

[0163] The term "nitro" refers to -NO2.

[0164] The term "oxo" refers to the =O substituent.

[0165] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. Attached Figure Description

[0166] Figure 1 : Comparison of clinical scores of each group of compounds in the disease model.

[0167] Figure 2 Comparison of clinical scores of each group of compounds in the erythema disease model.

[0168] Figure 3 Comparison of clinical scores of different groups of compounds in a psoriasis model.

[0169] Figure 4 Comparison of the inhibitory effects of different compounds on the increase in skin thickness.

[0170] Figure 5 A comparison chart of the effects of different compounds on the percentage of spleen body weight. Detailed Implementation

[0171] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0172] Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[0173] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (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).

[0174] HPLC determination was performed using an Agilent 1100 high-performance liquid chromatograph, a GAS15B DAD UV detector, and a WaterVbridge C18 150*4.6mm 5um column.

[0175] MS measurements were performed using an Agilent 6120 triple quadrupole mass spectrometer with a G1315D DAD detector and a Waters Xbridge C18 4.6*50mm, 5µm column, in positive / negative ion mode, with a mass scan range of 80–1200.

[0176] Preparation HPLC conditions: Waters; Column: Sunfire (Prep C18 OBD 19*250mm 10μm);

[0177] Chiral column separation conditions: Column: Chiralpak IG 5μm 30*250mm; Mobile Phase: Hex:EtOH=35:65at 15mL / min; Temp: 30℃; Wavelength: 254nm.

[0178] The silica gel plates used for thin-layer chromatography are Yantai Huanghai HSGF254 silica gel plates. The silica gel plates used in thin-layer chromatography (TLC) have a size of 0.2mm ± 0.03mm, and the size used for thin-layer chromatography separation and purification of products is 0.4mm-0.5mm.

[0179] Rapid column purification systems use either the Combiflash Rf150 (TELEDYNE ISCO) or Isolara One (Biotage).

[0180] Normal column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh or 300-400 mesh as the carrier, or Changzhou Santai pre-filled ultrapure normal phase silica gel column (40-63μm, 60g, 24g, 40g, 120g or other specifications).

[0181] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Bid Pharmaceuticals.

[0182] Unless otherwise specified in the examples, all reactions can be carried out under a nitrogen atmosphere.

[0183] A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon with a volume of approximately 1 L.

[0184] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0185] Hydrogen was produced by the QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instruments Co., Ltd.

[0186] Nitrogen or hydrogen atmospheres are typically evacuated and then filled with nitrogen or hydrogen gas, and this process is repeated three times.

[0187] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0188] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0189] In the examples, the reaction process was monitored using thin-layer chromatography (TLC). The volume ratio of the developing solvent used in the reaction, the eluent system used for column chromatography to purify the compound, and the developing solvent system for TLC were adjusted according to the different polarities of the compounds. Small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0190] Example 1

[0191]

[0192]

[0193] 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-butyldiphenylchlorosilane (4.0 g, 14.6 mmol) was added dropwise to the reaction system. The mixture was brought to room temperature and stirred until TLC detection showed completion. 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, concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give compound 1b (5.1 g), which was used directly in the next reaction.

[0194] Step 2) Under nitrogen protection, a mixture of compound 1b (5.1 g, 13.6 mmol), pinacol diborate (4.2 g, 16.3 mmol), [1,1'-bis(diphenylphosphine)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 mixture was poured into water and extracted with ethyl acetate (100 mL × 2). The extract was washed with water (30 mL × 2), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give compound 1c (2.0 g), LCMS: m / z 423.2 (M+H). + .

[0195] Step 3) Add trimethylsulfur iodide (20.93 g, 95.10 mmol) and anhydrous tetrahydrofuran (100 mL) sequentially to a 250 mL three-necked flask, stir until dissolved, cool to -10 °C, and slowly add a tetrahydrofuran solution of n-butyllithium (35.19 mL, 2.5 M, 87.97 mmol). Stir at -10 °C for 1 hour, then slowly add a tetrahydrofuran solution of 6-oxabicyclo[3.1.0]hexane (2.00 g, 23.78 mmol). After the addition is complete, heat to room temperature and continue stirring until the reaction is complete as detected by TLC. Quench the reaction solution slowly in water, extract with ethyl acetate (100 mL × 3), dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain compound 1d (400 mg concentrate). The concentrate was used directly for the next synthesis.

[0196] 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 anhydrous tetrahydrofuran (10 mL) in a 25 mL single-necked flask. The mixture was stirred until homogeneous, and the reaction system was purged with nitrogen three times. The temperature was lowered to 0 °C, and diisopropyl azodicarbonate (618.02 mg, 3.06 mmol) was slowly added dropwise. After the addition was complete, the temperature was raised to room temperature and stirred until the reaction was complete as detected by TLC. The reaction solution was quenched with 50 mL of water, extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 1e (60 mg).

[0197] 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).

[0198] Step 5) Add compound 1e (60.00 mg, 1.02 mmol) to a 25 mL single-necked flask, heat to 180 °C, stir until the reaction is complete as detected by TLC, add 10 mL of water to quench the reaction solution, extract with ethyl acetate (20 mL × 3), dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain compound 1f (45 mg).

[0199] 1 H 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).

[0200] Step 6) Add compound 1f (45.00 mg, 0.16 mmol) to a 25 mL single-necked flask at room temperature. 15 ion exchange resin (41.80 mg, 0.64 mmol) was added to toluene (5 mL), stirred until homogeneous, and the reaction system was purged with nitrogen three times. The mixture was 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 1 g (30 mg) of the compound.

[0201] 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).

[0202] Step 7) At room temperature, add 1 g (100.00 mg, 0.35 mmol) of compound 1 g (179.36 mg, 0.71 mmol) of compound pinacol diborate, potassium acetate (104.00 mg, 1.06 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (25.80 mg, 0.035 mmol) to a 25 mL single-necked flask in 50 mL of 1,4-dioxane. Purify the reaction system with nitrogen three times, heat to 90 °C, and stir until the reaction is complete as detected by TLC. Filter, add water (30 mL), extract with ethyl acetate (50 mL × 3), dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography (ethyl acetate / petroleum ether) to obtain compound 1 h (45 mg).

[0203] 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).

[0204] Step 8) At room temperature, 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), and [1,1'-bis(diphenylphosphine)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. The reaction system was purged with nitrogen three times, and the mixture was heated to 90 °C and stirred until the reaction was complete as detected by TLC. The mixture was filtered, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL × 3), 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) + .

[0205] Step 9) At room temperature, 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(diphenylphosphine)ferrocene]palladium dichloride (20.05 mg, 0.023 mmol) were added sequentially to an aqueous solution of 1,4-dioxane (3:1, 8 mL). The reaction system was purged with nitrogen three times, and the mixture was heated to 90 °C and stirred until the reaction was complete as detected by LCMS. The reaction solution was poured into water (20 mL), extracted with ethyl acetate (20 mL × 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).

[0206] LCMS: m / z 576.2 (M+H) + .

[0207] Step 10) Add compound 1k (60mg, 0.10mmol) to a 25mL single-necked flask at room temperature, then add tetrahydrofuran solution of hydrochloric acid (1:1, 4mL), stir at 25°C until the reaction is complete as detected by TLC, concentrate under reduced pressure, and purify by column chromatography (ethyl acetate / petroleum ether) to obtain compound 1l (40mg).

[0208] LCMS: m / z 338.0 (M+H) + .

[0209] Step 11) Add compound 1 (40 mg, 0.12 mmol) to a 25 mL three-necked flask at room temperature, then add tetrahydrofuran (5 mL), cool to 0 °C, and add borane tetrahydrofuran solution (0.47 mL, 1 M, 0.48 mmol) dropwise. After the addition is complete, allow the mixture to warm to room temperature naturally and stir overnight. Add water (0.5 mL) and continue stirring for 0.5 hours. The reaction was confirmed to be complete by LCMS, and compound 1 (1.31 mg) was obtained after preparative liquid chromatography purification.

[0210] LCMS: m / z 366.1 (M+H) + .

[0211] 1H 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).

[0212] Compound 1-1 (shorter retention time) and compound 1-2 (longer retention time) were obtained by chiral separation (Column: Chiralpak IG 5μm 30*250mm; Mobile Phase: Hex:EtOH=35:65at 15mL / min; Temp: 30℃; Wavelength: 254nm).

[0213] Compound 1-1

[0214] LCMS: m / z 366.1 (M+H) + .

[0215] 1 H 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).

[0216] Compounds 1-2

[0217] LCMS: m / z 366.1 (M+H) + .

[0218] 1H 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).

[0219] Example 2

[0220]

[0221] Compound 2 was synthesized according to the method in Example 1.

[0222] LCMS: m / z 326.1(M+H) + .

[0223] 1 H 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).

[0224] Example 3

[0225]

[0226] Compound 3 was synthesized according to the method in Example 1.

[0227] LCMS: m / z 365.1(M+H) + .

[0228] 1H 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).

[0229] Example 4

[0230]

[0231] Compound 4 was synthesized according to the method in Example 1.

[0232] LCMS:m / z 367(M+H) + .

[0233] 1 H 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).

[0234] Example 5

[0235]

[0236] Compound 5 was synthesized according to the method in Example 1.

[0237] LCMS: m / z 367.2(M+H) + .

[0238] 1H 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).

[0239] Example 6

[0240]

[0241] Compound 6 was synthesized according to the method in Example 1.

[0242] LCMS: m / z 340.1(M+H) + .

[0243] 1 H 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).

[0244] Example 7

[0245]

[0246] 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-butyldimethylchlorosilane (14.03 g, 93.08 mmol) was added at 30 °C, and the reaction was carried out at room temperature for 3 hours. The reaction was detected by TLC to be complete. The reaction solution was quenched in water (100 mL), extracted with tert-methyl ether (100 mL x 3), and dried over anhydrous sodium sulfate to give compound 7a (25.00 g).

[0247] 1H 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).

[0248] Step 2) At room temperature, compound 7a (25.00 g, 99.51 mmol), pinacol diborate (27.80 g, 109.46 mmol), potassium acetate (19.53 g, 199.01 mmol), and palladium dichloride bis(triphenylphosphine) (1.55 g, 1.99 mmol) were dissolved in 1,4-dioxane (90 mL). The reaction system was purged with nitrogen three times and stirred at 80 °C for 16 hours. The reaction was confirmed to be complete by LCMS. The reaction solution was extracted with water (200 mL), ethyl acetate (100 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether) to obtain product 7b (11.00 g).

[0249] 1 H 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).

[0250] 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, precipitating a white solid, which was then filtered. The white solid was dissolved in dichloromethane (200 mL), the aqueous phase was separated, the organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was added dropwise at 0 °C to a dichloromethane (100 mL) solution of compound 2-methoxy-pyridine (5.93 g, 54.32 mmol). After the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour. The reaction was confirmed to be complete by TLC. The mixture was concentrated under reduced pressure, and the residue was added to anhydrous diethyl ether, precipitating a white solid, which was then filtered to obtain the target compound 7d (9.5 g).

[0251] 1H 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).

[0252] Step 4) Compound 7d (9.0 g, 27.74 mmol) and ethyl 4,4,4-trifluoro-2-butynedoate (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. The reaction was confirmed to be complete by LCMS. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether) to give compound 7e (3.05 g).

[0253] LCMS: m / z 289.0(M+H) + .

[0254] Step 5) Compound 7e (2.9 g, 10.06 mmol) was dissolved in acetonitrile (20 mL) at room temperature, and N-bromosuccinimide (2.7 g, 15.09 mmol) was added. The mixture was purged with nitrogen three times. The reaction was heated to 70 °C and carried out for 5 hours. The reaction was confirmed to be complete by LCMS. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether) to give compound 7f (1.5 g).

[0255] LCMS: m / z 366.9 (M+1) + .

[0256] 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 proceed at room temperature for 16 hours. The reaction was confirmed to be complete by LCMS. The pH was adjusted to ~7 with 1 N hydrochloric acid, and the methanol was removed by concentration under reduced pressure. The pH was adjusted to ~2 with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate (50 mL × 3). The mixture was washed with water (25 mL × 3), and then with saturated sodium chloride water (25 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7 g (1.3 g).

[0257] LCMS: m / z 339.9 (M+H) + .

[0258] Step 7) 7 g (1.3 g, 3.83 mmol) of compound was dissolved in ethanol (20 mL), and concentrated sulfuric acid (1 mL) was added. The mixture was heated to 90 °C and reacted for 16 hours. The reaction was confirmed to be complete by LCMS. The mixture was concentrated under reduced pressure, and the pH was adjusted to ~9 by adding saturated sodium bicarbonate. Ethyl acetate (50 mL × 3) was added for extraction, followed by washing with water (25 mL × 3), and then washing with saturated sodium chloride water (25 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 7 h (749 mg).

[0259] LCMS: m / z 356.2 (M+H) + .

[0260] Step 8) Compound 7h (300 mg, 1.02 mmol), pinacol diborate (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 mixture was purged with nitrogen three times. The mixture was heated to 100 °C and reacted for 16 hours. The reaction was confirmed to be complete by LCMS. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether) to give compound 7i (300 mg).

[0261] LCMS: m / z 343.1(M+H) + .

[0262] 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(diphenylphosphine)ferrocene]palladium dichloride (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. The reaction was confirmed to be complete by LCMS. The reaction solution was filtered, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 7j (850 mg).

[0263] LCMS: m / z 374(M+H) + .

[0264] Step 10) At room temperature, 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(diphenylphosphine)ferrocene]palladium dichloride (78.65 mg, 0.11 mmol) were mixed in 1,4-dioxane / water (10 mL / 0.02 mL). The reaction system was purged with nitrogen three times and stirred at 90 °C for 16 hours. The reaction was confirmed to be complete by LCMS. The reaction solution was filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give compound 7k (430 mg).

[0265] LCMS: m / z 464(M+H) + .

[0266] Step 11) At room temperature, under nitrogen protection, 1,2-bis(diphenylphosphine)ethane (32.67 mg, 0.082 mmol), (1,5-cyclooctadiene)methoxyiridium(I) dimer (27.17 mg, 0.041 mmol), and 1,2-dichloroethane (3 mL) were added sequentially to a thoroughly dried 100 mL three-necked flask equipped with a thermometer. The mixture was stirred at room temperature for 15 min, then compound 7k (190 mg, 0.410 mmol) was added, and the mixture was stirred at room temperature for 15 min. The mixture was then heated in a 95 °C oil bath with stirring. When the thermometer reading reached 70 °C, pinacol borane (0.416 mL, 2.87 mmol) was added dropwise, and the mixture was stirred for 0.5 h. The reaction was confirmed to be complete by LCMS. The reaction mixture was allowed to cool to room temperature, and the reaction was quenched with 5 mL of methanol. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain compound 7l (120 mg).

[0267] LCMS: m / z 592(M+H) + .

[0268] Step 12) At room temperature, compound 7 (100 mg, 0.17 mmol) was dissolved in tetrahydrofuran (1 mL), and 1 N hydrochloric acid (1 mL) was slowly added dropwise with stirring. The reaction was allowed to proceed for 0.5 hours at room temperature. The reaction was confirmed to be complete by LCMS. The reaction solution was concentrated, diluted with ethyl acetate (5 mL), and the pH was adjusted to approximately 8 with saturated potassium phosphate solution. The solution was extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, concentrated, and purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain 7 (5.54 mg).

[0269] LCMS: m / z 378(M+1) + .

[0270] 1H 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).

[0271] Example 8

[0272]

[0273] Step 1) At room temperature, compound 8a (25.00 g, 178.39 mmol) and N-bromosuccinimide (31.75 g, 178.39 mmol) were added to acetonitrile (200 mL) in a 100 mL single-necked flask and stirred until dissolved. The reaction system was purged with nitrogen three times and stirred at room temperature for 16 hours. The reaction was confirmed to be complete by TLC. The reaction solution was concentrated, diluted with ethyl acetate (100 mL) and poured into a sodium bisulfite aqueous solution (500 mL). The pH was adjusted to about 3, and ethyl acetate (200 mL) was added for extraction. 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).

[0274] 1 H 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).

[0275] Step 2) At room temperature, compound 8b (100.00 mg, 0.46 mmol), 3-bromo-2-methylpropene (61.64 mg, 0.46 mmol), potassium carbonate (94.65 mg, 0.69 mmol), and N,N-dimethylformamide (10 mL) were added to a 100 mL single-necked flask. The reaction system was purged with nitrogen three times and stirred at room temperature for 16 hours. The reaction was confirmed to be complete by TLC. The reaction solution was filtered, concentrated under reduced pressure, and extracted with 100 mL of saturated sodium chloride aqueous solution and 100 mL of ethyl acetate. 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).

[0276] 1H 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).

[0277] 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, along with 2 mL of dichloromethane. The mixture was stirred until dissolved, and the reaction system was purged with nitrogen three times and stirred at room temperature for 16 hours. The reaction was confirmed to be complete by TLC. The reaction solution was then 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 obtain compound 8d (20.0 mg).

[0278] 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).

[0279] Step 4) At room temperature, compound 8d (400.00 mg, 1.46 mmol), boric acid (557.84 mg, 2.2 mmol), potassium acetate (431.18 mg, 4.39 mmol), 1,1-bis(diphenyl)ferrocene palladium dichloride (53.60 mg, 0.073 mmol), and 1,4-dioxane (10 mL) were added to a 50 mL single-necked flask and stirred until dissolved. The reaction system was purged with nitrogen three times and stirred at 110 °C for 16 hours. The reaction was confirmed to be complete by LCMS. The reaction solution was extracted with water (100 mL) and 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 obtain compound 8e (0.26 g).

[0280] LCMS: m / z 321.1(M+H) + .

[0281] Step 5) 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)ferrocene palladium dichloride (54.87 mg, 0.075 mmol) were added to a 25 mL single-necked flask 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. The reaction was confirmed to be complete by LCMS. 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 subjected to column chromatography (ethyl acetate / petroleum ether) to obtain compound 8f (150.00 mg).

[0282] LCMS: m / z 351.9(M+H+2) + .

[0283] Step 6) 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)ferrocene palladium dichloride (13.59 mg, 0.019 mmol) were added to a 100 mL single-necked flask in a mixed solvent of 1,4-dioxane (6 mL) and water (0.12 mL). The mixture was stirred until dissolved, and the reaction system was purged with nitrogen three times and stirred at 110 °C for 16 hours. The reaction was confirmed to be complete by LCMS. The reaction solution was added to 100 mL of water, extracted with ethyl acetate (200 mL x 3), dried and concentrated, and then subjected to column chromatography (ethyl acetate / petroleum ether) to obtain compound 8 g (150.00 mg).

[0284] LCMS: m / z 442.1(M+H) + .

[0285] Step 7) At room temperature, add 1,2-bis(diphenylphosphine)ethane (23.46 mg, 0.059 mmol), (1,5-cyclooctadiene)methoxyiridium(I) dimer (19.51 mg, 0.029 mmol), and then add anhydrous 1,2-dichloroethane (15 mL) to a 50 mL three-necked flask. Then slowly add 8 g of compound (130.00 mg, 0.294 mmol, dissolved in 5 mL of 1,2-dichloroethane). Stir at room temperature for 15 minutes, then heat to 70 °C and begin adding pinacol borane (263.70 mg, 2.061 mmol). After the addition is complete, stir at 70 °C for 1 hour. The reaction was confirmed to be complete by LCMS. The reaction solution was cooled to 0 °C and quenched by adding 20 mL of methanol. The reaction solution was then concentrated and subjected to column chromatography (ethyl acetate / petroleum ether) to obtain compound 8h (120.00 mg).

[0286] LCMS: m / z 570.1(M+H) + .

[0287] Step 8) At room temperature, add the reactant 8h (100.00 mg, 0.17 mmol) and tetrahydrofuran (2 mL) as solvent to a 25 mL round-bottom flask. Cool to 0 °C, add 1 N hydrochloric acid (2 mL) dropwise, and stir at room temperature for 1 hour after the addition is complete. Detect the reaction by LCMS, concentrate the reaction solution under reduced pressure, and extract with ethyl acetate (100 mL × 3). Adjust the pH to 8.0 by adding saturated potassium phosphate solution to the aqueous phase, and extract with ethyl acetate (100 mL × 3). Combine the organic phases, wash with water (100 mL × 3), then wash with saturated brine (100 mL × 3), and dry with anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify by preparative liquid chromatography (Pre-HPLC) to obtain compound 8 (5.46 mg).

[0288] LCMS: m / z 356.1 (M+H) + .

[0289] 1 H 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).

[0290] Example 9

[0291]

[0292] Compound 9 was synthesized according to the method in Example 8.

[0293] LCMS: m / z 354.2(M+H) + .

[0294] 1 H NMR (400MHz, DMSO-d6) δ8.70(s,1H),8.44(d,J=1.8Hz,1H),8.38(d,J=1.8Hz,1H),7.69(s,1H),6.87(d,J=8.3 Hz,1H),6.71(d,J=8.3 Hz,1H),4.27(t,J=8.2 Hz,1H),3.82(t,J=8.9 Hz,1H),3.75(s,3H),3.55-3.42(m,1H),2.54-2.50(m,2H),1.66(t,J=6.5 Hz,2H),1.38-1.23(m,7H),1.17-0.97(m,1H).

[0295] Example 10

[0296]

[0297] Compound 10 was synthesized according to the method of Example 8.

[0298] LCMS: m / z 389.1(M+H) + .

[0299] 1 H NMR (400 MHz, DMSO-d6) δ8.71(s,1H),8.61(d,J=1.5 Hz,1H),8.55(d,J=1.6Hz,1H),8.42(d,J=8.8 Hz,1H),7.99(d,J=8.9 Hz,1H),7.87-7.84(m,1H),7.74(d,J=8.1 Hz,1H),7.46(d,J=8.2 Hz,1H),4.31(t,J=8.3 Hz,1H),4.08(s,3H),3.88(t,J=8.9Hz,1H),3.58-3.55(m,1H),1.34(dd,J=16.2,8.1 Hz, 1H), 1.15 (dd, J = 16.2, 10.4 Hz, 1H).

[0300] Example 11

[0301]

[0302] Compound 11 was synthesized according to the method of Example 9 and chirally isolated to obtain compound 11-1 (with a shorter retention time) and compound 11-2 (with a longer retention time).

[0303] Compound 11-1

[0304] LCMS: m / z 357.2 (M+H) + .

[0305] 1 H NMR (400 MHz, 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=8.8 Hz,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).

[0306] Compound 11-2

[0307] LCMS: m / z 357.2 (M+H) + .

[0308] 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), 4.39-4.23(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).

[0309] Example 12

[0310]

[0311] 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, compound 3-chloro-3-methyl-1-butyne (100 mL, 886 mmol) was added dropwise. The mixture was stirred at 70 °C for 16 hours. After cooling to room temperature, water (1000 mL) and petroleum ether (1000 mL x 3) were added for extraction. The mixture was dried over anhydrous sodium sulfate and filtered. The residue was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate) to give compound 12b (50 g).

[0312] 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).

[0313] Step 2) At room temperature, compound 12b (20.0 g, 74.4 mmol), n-hexane (200 mL), and palladium calcium carbonate (1.95 g, 18.8 mmol) were added sequentially to a 500 mL single-necked flask. The mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. After filtration and concentration under reduced pressure, compound 12c (19 g) was obtained.

[0314] 1 H 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).

[0315] Step 3) At room temperature, 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. The mixture was stirred at 210 °C for 1 hour. After cooling to room temperature, the pH was adjusted to neutral with 1 M HCl solution. The mixture was extracted with ethyl acetate (200 mL x 3) and washed with water (200 mL x 3). The mixture was concentrated under reduced pressure to obtain compound 12d (9.1 g).

[0316] 1H 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).

[0317] Step 4) At room temperature, add compound 12d (5.00 g, 18.5 mmol) and toluene (25 mL) sequentially to a 100 mL single-necked flask. 15 (5.00 g, 15.9 mmol). Stirred at 100 °C for 2 hours under nitrogen protection. Cooled to room temperature and filtered. Concentrated under reduced pressure to give compound 12e (3.89 g).

[0318] 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).

[0319] Step 5) At room temperature, add compound 12e (28.4 g, 105 mmol), dioxane (300 mL), and diboronic acid sequentially to a 500 mL single-necked flask. Pinaryl ester (31.9 g, 126 mmol), potassium acetate (20.6 g, 209 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7.66 g, 10.5 mmol). Stirred at 105 °C for 16 hours under nitrogen protection. Cooled to room temperature and filtered. Concentrated under reduced pressure, the residue was purified by column chromatography (petroleum ether / ethyl acetate) to give compound 12f (28.4 g).

[0320] LCMS: m / z 319(M+H) + .

[0321] Step 6) At room temperature, add compound 12f (6.20 g, 19.5 mmol), 1,4-dioxane (80 mL), and water sequentially to a 250 mL single-necked flask.

[0322] (16 mL), 2,6-dichloropyrazine (2.90 g, 39.0 mmol), potassium carbonate (5.39 g, 39.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.43 g, 1.95 mmol). Stirred at 110 °C for 16 hours under nitrogen protection. Cooled to room temperature and filtered. Concentrated under reduced pressure, the residue was purified by column chromatography (petroleum ether / ethyl acetate) to give 12 g (5.7 g) of the compound.

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

[0324] Step 7) At room temperature, add compound 12 g (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(diphenylphosphine)ferrocene]palladium dichloride (8.41 g, 11.5 mmol) to a 100 mL single-necked flask in a mixture of 1,4-dioxane (250 mL) and water (5 mL). Stir until dissolved, purge with nitrogen three times, and stir at 110 °C for 16 hours. Cool to room temperature, extract with water (500 mL), and ethyl acetate (300 mL x 3), drying over anhydrous sodium sulfate. Concentrate, and purify the residue by column chromatography (petroleum ether / ethyl acetate) to give compound 12 h (37 g).

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

[0326] Step 8) At room temperature, 1,2-bis(diphenylphosphine)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. The mixture was stirred 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 pinacolborane (20.3 g, 159 mmol) was added dropwise. The reaction was carried out 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 mixture was concentrated, and the residue was 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, add reactant 12i (9.00 g, 15.8 mmol) and tetrahydrofuran (30 mL) to a 50 mL single-necked flask. Cool to 0 °C and add 2 M hydrochloric acid (50 mL). Stir at 50 °C for 16 hours. Concentrate under reduced pressure, extract with ethyl acetate (300 mL x 3), dry to anhydrous sodium sulfate, and filter. Concentrate under reduced pressure, and purify the residue by reversed-phase column chromatography (acetonitrile / water / trifluoroacetic acid) to give compound 12 (3.82 g).

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

[0330] Compound 12-1

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

[0332] 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).

[0333] Compound 12-2

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

[0335] 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),3.74-3.60(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] At room temperature, compound 12h (400 mg, 0.91 mmol) was dissolved in anhydrous THF (4 mL). The solution was cooled to -10 °C under N2 protection, and 1,5-cyclooctadiene iridium chloride dimer (21 mg, 0.041 mmol, 4.5% mol) and (S)-1-(diphenylphosphino)-2-[(S)-4-isopropyloxazoline-2-yl]ferrocene (52 mg, 0.11 mmol, 12% mol) were added. The mixture was stirred at room temperature for 15 min, and catechol borane THF solution (1 M, 7.2 mL, 7.2 mmol) was added. The reaction was continued at room temperature for 3 h. After adding concentrated hydrochloric acid (0.2 mL) and continuing the reaction for 2 h, the mixture was filtered, concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (acetonitrile / water / trifluoroacetic acid) to give compound (105 mg). Chiral HPLC confirmed that this compound was the same as the 12-1 obtained by resolution.

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

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

[0342] Biological evaluation

[0343] The following test examples further describe and explain the present disclosure, 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 in patent application WO2020070651A.

[0347] Test Example 1 In vitro PDE4B enzyme activity assay

[0348] 1. Experimental Materials

[0349]

[0350]

[0351] 2. Experimental Procedure

[0352] First, prepare a 10 mM stock solution of the compound in a test tube with 90% DMSO (10% water), and then use it to prepare a series of dilutions with a dilution gradient of 1:5, starting from 100 μM and going down to 0.05 nM.

[0353] Transfer 0.2 μL of the compound solution to each well of a 384-well plate. Transfer 0.2 μL of 100% DMSO to both the negative and positive controls. Then add 10 μL of double-strength PDE4B1 enzyme solution (final concentration 0.04 nM) to each well. For wells with no enzyme activity, replace the enzyme solution with 10 μL of single-strength reaction buffer. Centrifuge at 1000 rpm for 1 min and incubate at room temperature for 15 min. Next, add 10 μL of double-strength FAM-cAMP substrate solution (final substrate concentration 0.1 μM) to each well of the 384-well plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 30 min. After the reaction, add 60 μL of stop solution to each well of the 384-well plate to terminate the reaction, and incubate at room temperature with shaking at 600 rpm in the dark for 60 min.

[0354] After incubation, RLU data were read and inhibition rate was calculated. IC50 was calculated based on the fitted curve of concentration and inhibition rate. 50 The values ​​are: maximum value (for the DMSO control) and minimum value (for the enzyme-free control).

[0355] The embodiments of this disclosure demonstrate the in vitro inhibition of PDE4B1 enzyme activity through the above-mentioned experiments, and the measured IC50 values ​​are as follows: 50 The values ​​are shown in Table 1.

[0356] Table 1

[0357]

[0358] Note: N / A not detected.

[0359] Test Example 2 Inhibitory effect of the compound on the release of pro-inflammatory cytokines from peripheral blood mononuclear cells (PBMCs)

[0360] Thaw frozen PBMCs and assess cell viability and number using trypan blue staining. Wash thawed PBMCs with RPMI 1640 complete medium (RPMI 1640 + 10% FBS + 1% PS), centrifuge, and discard the supernatant. Resuspend PBMCs in RPMI 1640 complete medium and adjust cell density to 2 × 10⁶ cells / cm². 6 cells / mL. 2×10⁻⁶ cells / mL. 5 PBMC cells were cultured in 96-well cell culture plates. Different concentrations of the test compound were added, starting from the highest concentration of 100 μM, and serially diluted 9 times at a ratio of 1:5, with double-duplicate assays. LPS was added to a final concentration of 0.1 ng / mL, for a total volume of 200 μL. Negative and positive controls were set up. The negative control wells contained only LPS and DMSO, while the positive control wells contained cells, LPS, and 1 μg / mL dexamethasone as a positive control. Cells were incubated at 37°C for 24 hours. After incubation, 100 μL of cell culture supernatant was collected, and TNF-α levels were detected by ELISA. 100 μL of CellTiter-Glo was added to the remaining cells in each well, and cell viability was measured. The IC50 value of the compound inhibiting TNF-α release was calculated. 50 value.

[0361] The embodiments of this disclosure demonstrated the inhibition of pro-inflammatory cytokine release from PBMCs in vitro through the above-mentioned experiments, and the measured IC50 values ​​were... 50 The values ​​are shown in Table 2.

[0362] Table 2

[0363]

[0364] Note: N / A not detected.

[0365] Test Example 3 In vitro experiment on the inhibition of IL-23 secretion by dendritic cells (DCs) differentiated from human monocytes by the compound.

[0366] Day 0: Monocytes 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, IL-4 at 50 ng / ml and GM-CSF at 100 ng / ml were added to the medium. Differentiation was carried out in 100 mm diameter culture dishes at a density of 1 × 10⁶ cells / mL under a 37°C incubator and 5% CO₂ concentration. Day 3: Half the volume of complete RPMI medium was replaced with fresh complete RPMI medium, maintaining the IL-4 concentration at 50 ng / ml and the GM-CSF concentration at 100 ng / ml. Day 6: Non-adherent cells (DCs) were collected from the culture dishes and washed with PBS. The washed DCs were then resuspended in complete RPMI medium at a cell density of 1 × 10⁶ cells / mL. Then, 1 × 10⁵ DC cells were added to each well of a 96-well cell culture plate, and pretreated with different concentration gradients of the test compound (or an equivalent concentration of DMSO blank negative control) for 1 hour. Afterward, the DC cells were stimulated with 200 μg / ml of the TLR2 agonist Zymosan for 24 hours. On day 7: After 24 hours of Zymosan stimulation, the supernatant from each well of the 96-well plate was collected, and the concentration of IL-23 was detected by ELISA.

[0367] The inhibitory effect of the disclosed compound on the secretion of IL-23 by human monocyte-differentiated dendritic cells in vitro was determined by the above experiments, and the measured IC50 was [data missing]. 50 The values ​​are shown in Table 3.

[0368] Table 3

[0369]

[0370]

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

[0372] Prepare an ointment with the following components using an appropriate amount of Compound 12-1: 0.1% Compound 12-1, 9% hexanediol, 78.8% white petrolatum, 5% paraffin, 7% glyceryl mono- and distearate, and 0.1% dihydroxybutyltoluene. Stir mechanically until a paste is formed.

[0373] 1) Modeling and drug administration

[0374] Seven-week-old female Balb / c mice were selected. The backs of the mice were shaved one day prior to the experiment, with a shaved area of ​​2cm × 3cm. From day 1 to day 7, 6 hours after applying the test substance to the skin, imiquimod (IMQ) ointment (Aldara (5%)) was continuously applied to the back skin of the mice for 7 days to establish a psoriasis mouse model. The control group received the same dose of petrolatum ointment. The severity of skin inflammation was assessed on days 3, 5, and 7, including measurements of skin thickness, crusting, and erythema, 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 body weight was calculated to assess the degree of immunosuppressive effect of the drug.

[0375] This experiment included 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 overall score for the severity of skin inflammation is a clinical score, which is relatively subjective; a higher score indicates a more severe disease. The degree of increase in skin thickness is an objective evaluation indicator; a greater increase in thickness indicates a more severe disease. The spleen's proportion to body weight is an objective evaluation indicator; a smaller spleen-to-body-weight ratio indicates a stronger immunosuppressive effect of the medication.

[0378] 3) Experimental Results

[0379] 3.1) Clinical score

[0380] At each dose of compound A, compound 1-1, and compound 12-1, clinical scores were significantly reduced at the experimental endpoint. Figures 1-4 From the individual scores, the various dose groups of compounds 1-1 and 12-1 mainly improved the crusting of psoriasis in the model and reduced skin thickness. In the skin thickness score, both low and high doses of compound 12-1 significantly inhibited the increase in skin thickness, while 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 the same dose of compound A. Figure 4 The results showed that compound 12-1 was significantly superior to reference compound A in improving the symptoms of psoriasis. Specific scoring data are shown in Table 4.

[0381] Table 4

[0382]

[0383]

[0384] 3.2) Spleen weight percentage

[0385] Under the influence of IMQ, there was no significant difference in body weight between the model group and each drug-treated group, but the spleen-to-total-volume ratio in the model group increased significantly. Figure 5 The results indicated splenomegaly. Compound A had no significant effect on the spleen's weight percentage, while the three dosage groups of compounds 1-1 and 12-1 significantly reduced the spleen's weight percentage. This suggests that each compound has immunosuppressive effects, and that compound 12-1's effect is dose-dependent. At the same dose (0.03%), compounds 1-1 and 12-1 showed significantly different effects on the spleen's weight percentage compared to compound A, indicating that compounds 1-1 and 12-1 have stronger immunosuppressive effects than compound A. Specific data are shown in Table 5.

[0386] Table 5

[0387]

Claims

1. The compound shown in Formula I or a pharmaceutically acceptable salt thereof, in, The compound represented by Formula I is a compound represented by Formula IA, IB, or IC. 、 、 Ring A is selected from , , , , , , and , where R 15a R 15b R 15c and R 15d Each element is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy group, wherein the alkyl or alkoxy group is optionally substituted with one or more halogens, deuterium, or hydroxyl groups; B represents a boron atom; Z is selected from either carbon or nitrogen atoms; R 1 Each is independently selected from hydrogen and deuterium; R 2 It is hydrogen; R 3 or R 4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by one or more R A4 Replaced; R 5 Selected from C 1-6 Alkyl or C 1-6 alkoxy group, wherein the alkyl group or alkoxy group is optionally surrounded by 1 to 3 R groups. A4 Replaced; R A4 Selected from halogens and deuterium; X 1 -O-; X 2 Selected from -O- or -CR 17a R 17b -; X 3 Selected from key or -CR 18a R 18b -; R 17a and R 17b Each is independently selected from either hydrogen or deuterium; R 18a and R 18b Each is independently selected from either hydrogen or deuterium; R 8 R 9 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by one or more R A6 Replaced; Or R 8 R 9 It forms a 3- to 6-membered carbon ring with adjacent carbon atoms, said carbon ring being optionally bonded by one or more R atoms. A6 Replaced; R A6 Selected from halogens and deuterium; X 4 Selected from nitrogen or carbon atoms; R 10 R 11 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by one or more R A7 Replaced; R A7 Selected from halogens and deuterium; X 5 Selected from nitrogen or carbon atoms; R 12 R 13 and R 14 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by one or more R A8 Replaced; R A8 Selected from halogens and deuterium; m is selected from an integer between 0 and 5; n is 1; and , or and It is located in the intermediate position on ring A; " "Indicates a single key or does not exist." 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 or R 4 It is hydrogen; R 5 Selected from C 1-6 Alkyl or C 1-6 alkoxy group, wherein the alkyl group or alkoxy group is optionally surrounded by 1 to 3 R groups. A4 Replaced by, R A4 As defined in claim 1.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is... or .

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 8 R 9 The 3- to 6-membered carbon rings formed with adjacent carbon atoms are selected from... , , and .

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 4 is a nitrogen atom; Z is a nitrogen atom.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 5 ☐ represents a nitrogen atom; Z represents a carbon atom.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from... , , , , or .

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 15a R 15b R 15c and R 15d Each element is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 alkyl.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R 15a R 15b R 15c and R 15d Each is independently selected from hydrogen, fluorine, chlorine, methyl, or ethyl.

10. The compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-9, wherein the compound represented by formula I is selected from... 、 、 , or ,in, R 1 ~R 5 B, m, as defined in claim 1, R 8 and R 9 As defined in claim 1, R 15a R 15b and R 15d As defined in claim 1.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula I is selected from... 、 、 , or 。 12. The following compounds or their pharmaceutically acceptable salts: or .

13. The following compounds or their pharmaceutically acceptable salts: or .

14. The deuterated form of the compound or its pharmaceutically acceptable salt according to any one of claims 1-13.

15. A pharmaceutical composition comprising at least one therapeutically effective amount of the compound as claimed in any one of claims 1-13 or a pharmaceutically acceptable salt thereof, or the deuterated compound as claimed in claim 14, and a pharmaceutically acceptable excipient.

16. Use of a compound according to any one of claims 1-13, or a deuterated compound according to claim 14, or a pharmaceutical composition according to claim 15 in the preparation of a medicament for the prevention and / or treatment of psoriasis, asthma, obstructive pulmonary disease, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatoid arthritis.

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