Tetrazolyl derivatives and uses thereof

Abstract

The present disclosure relates to tetrazole derivatives and uses thereof. Specifically, the present disclosure provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 and A are as defined herein.

Description

Technical Field

[0001] The present invention belongs to the field of medicine and relates to a tetrazole derivative and a use thereof. Background Art

[0002] Phosphodiesterases (PDEs) are a class of intracellular enzymes that cleave 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. Among them, PDE4 is highly specific for cAMP and has four subtypes: PDE4A, PDE4B, PDE4C, and PDE4D. PDE4 is involved in promoting physiological and pathological processes such as monocyte and macrophage activation, neutrophil infiltration, vascular smooth muscle proliferation, vasodilation, and myocardial contraction, and has an impact on central nervous system function, cardiovascular function, inflammation / immune system, cell adhesion, etc. PDE4 plays a major regulatory role in the expression of pro-inflammatory and anti-inflammatory mediators, and 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 use in severe chronic obstructive pulmonary disease (COPD) to reduce the number of sudden attacks or prevent worsening of COPD symptoms, and apremilast is approved for the treatment of adults with active psoriatic arthritis. Although PDE4 inhibitors show good pharmacological activity, these PDE inhibitors can cause side effects, such as induced gastrointestinal symptoms such as vomiting and diarrhea. There is still a need to develop selective PDE4 inhibitors, especially selective PDE4 inhibitors with affinity for PDE4B and PDE4D.

[0004] In addition, various heterocyclic structures such as oxazole compounds have been reported, such as WO03 / 072102, WO98 / 15274, WO2007058338, etc. However, the tetrazole compound disclosed in the present invention is not disclosed in any document. Summary of the invention

[0005] The present disclosure provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof

[0006]

[0007] Among them, R 1is selected from aryl or heteroaryl, the aryl or heteroaryl is optionally substituted by one or more selected from deuterium, halogen, hydroxyl, alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy, and / or the aryl or heteroaryl is fused with cycloalkyl or heterocycloalkyl, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy or fused ring is optionally substituted by one or more selected from deuterium, halogen, hydroxyl, alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy or fused ring 3a replaced by;

[0008] R 3a Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, optionally substituted by one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano;

[0009] R 2 is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more selected from deuterium, halogen, hydroxy, alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy, cycloalkenyloxy, -SR', -S(O)2R', -NR'(R"), -COR', -COOR' or -CONR'(R"), wherein the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy or cycloalkenyloxy is optionally substituted by one or more R 3b replaced by;

[0010] R' or R" is independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano;

[0011] R 3b Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C3-8 Cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, optionally substituted by one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano;

[0012] A is a divalent group represented by formula (i) or (ii):

[0013] Formula (i) is -Y 1 -X 1 -

[0014] Formula (ii) is -Y 2 -C(=O)-

[0015] Where X 1 is selected from alkenylene or alkylene, wherein the alkenylene or alkylene is optionally substituted by one or more selected from deuterium, halogen, hydroxyl, alkyl or alkoxy, 1 selected from a bond, -C(=O)-, -C(=O)N(R 4 )-、-N(R 5 )C(=O)-、-S(O) n -、-S(O) m N(R 4 )-or-N(R 5 )S(O) m -, R 4 or R 5 is independently selected from hydrogen, deuterium or alkyl, and n and m are each independently selected from an integer from 0 to 2;

[0016] Y 2 is selected from a piperazinylene group or a divalent group represented by formula (iii) or (v):

[0017] Formula (iii) is -C(=O)-B 1 -N(R 6 )-

[0018] Formula (v) is -B 2 -N(R 7 )-

[0019] Among them B 1 and B 2 are each independently selected from alkenylene or alkylene, the alkenylene or alkylene being optionally substituted by one or more selected from deuterium, halogen, hydroxyl, alkyl or alkoxy, R 6 or R7 are independently selected from hydrogen, deuterium or alkyl.

[0020] In some embodiments, R 1 Selected from C 6-8 aryl or 5 to 8 membered heteroaryl, the aryl or heteroaryl being optionally substituted by one or more selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy or C 3-6 The alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy or fused ring is optionally substituted by one or more R 3a Replaced by R 3a As defined above.

[0021] Some embodiments provide a compound of formula I or a pharmaceutically acceptable salt thereof:

[0022]

[0023] Among them, R 8 , R 9 , R 10 , R 11 or R 12 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy or C 3-6 substituted by cycloalkenyloxy, or R 8 , R 9 Together with adjacent carbon atoms, they form a 3-10 cycloalkyl group or a 3-10 heterocycloalkyl group, wherein the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, cycloalkyl or heterocycloalkyl group is optionally substituted by one or more R 3a Replaced by R 3a As defined in the compound represented by formula I.

[0024] In some embodiments, R 10 Selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl or C1-6 Alkoxy, the alkyl or alkoxy group is optionally substituted by 1 to 3 R 3a Replaced by R 3a As defined in the compound represented by formula I.

[0025] In some embodiments, in the compound of Formula II or a pharmaceutically acceptable salt thereof, R 10 Selected from C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy or C 3-6 Cycloalkenyloxy, wherein the alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 3 R 3a Replaced by R 3a As defined in the compound represented by formula I.

[0026] In some embodiments, R 8 Selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl or alkoxy group is optionally substituted by 1 to 3 R 3a Replaced by R 3a As defined in the compound of formula I. In other embodiments, in the compound of formula II or a pharmaceutically acceptable salt thereof, R 8 Selected from hydrogen or deuterium.

[0027] In another embodiment, in some embodiments, R 12 Selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl or alkoxy group is optionally substituted by 1 to 3 R 3a Replaced by R 3a As defined in the compound of formula I. Further, in the compound of formula II, R 12 Selected from hydrogen or deuterium.

[0028] In some embodiments, R 9 Selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl or alkoxy group is optionally substituted by 1 to 3 R 3a Replaced by R 3a As defined in the compound represented by formula I.

[0029] In some embodiments, in the compound of Formula II or a pharmaceutically acceptable salt thereof, R 9 Selected from C2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy or C 3-6 Cycloalkenyloxy, wherein the alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 3 R 3a Replaced by R 3a As defined in the compound represented by formula I.

[0030] In some embodiments, R 8 , R 9 Together with the adjacent carbon atoms, a 3 to 10 heterocycloalkyl group is formed, wherein the heterocycloalkyl group is optionally substituted by 1 to 3 R 3a Replaced by R 3a As defined in the compound represented by formula I.

[0031] In some embodiments, R 8 , R 9 Together with the adjacent carbon atoms, a 3 to 10 heterocycloalkyl group is formed, wherein the heterocycloalkyl group is optionally substituted by 1 to 3 R 3a Replaced by; R 10 Selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl or alkoxy group is optionally substituted by 1 to 3 R 3a Replaced by R 3a As defined in the compound represented by formula I.

[0032] In other embodiments, R 8 , R 9 Together with the adjacent carbon atoms, a 3 to 10 heterocycloalkyl group is formed, wherein the heterocycloalkyl group is optionally substituted by 1 to 3 R 3a Replaced by; R 10 Selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, the alkyl or alkoxy group is optionally substituted by 1 to 3 R 3a Replaced by; R 11 or R 12 Selected from hydrogen, R 3a As defined in the compound represented by formula I.

[0033] On the other hand, the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof

[0034]

[0035] Among them, X1 Selected from C 2-6 Alkenylene or C 1-6 Alkylene, the alkenylene or alkylene is optionally substituted by one or more selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy substituted, Y 1 selected from a bond, -C(=O)-, -C(=O)N(R 4 )-、-N(R 5 )C(=O)-、-S(O) n -、-S(O) m N(R 4 )-or-N(R 5 )S(O) m -, R 4 or R 5 are independently selected from hydrogen, deuterium or alkyl, n and m are each independently selected from an integer from 0 to 2, R 8 , R 9 , R 10 , R 11 or R 12 As defined in the compound of formula II, R 2 As defined in the compound represented by formula I.

[0036] In some embodiments, in the compound represented by Formula I, Formula II, or Formula IIIa or a pharmaceutically acceptable salt thereof, X 1 Selected from C 1-6 Alkylene, the alkylene is optionally substituted by one or more selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

[0037] In some embodiments, Y in the compound represented by Formula I, Formula II or Formula IIIa or a pharmaceutically acceptable salt thereof is 1 Select from keys.

[0038] In some embodiments, Y in the compound represented by Formula I, Formula II or Formula IIIa or a pharmaceutically acceptable salt thereof is 1 Selected from -C(=O)N(R 4 )-、-N(R 5 )C(=O)-、-S(O) n -、-S(O) m N(R 4 )-or-N(R 5 )S(O) m -, R 4 or R 5 are independently selected from hydrogen, deuterium or C 1-6 Alkyl, n and m are each independently selected from integers from 0 to 2 (including 0, 1, 2).

[0039] In some embodiments, in the compound represented by Formula I, Formula II, or Formula IIIa or a pharmaceutically acceptable salt thereof, X 1 Selected from C 1-6 Alkylene, the alkylene is optionally substituted by one or more selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy substituted; Y 1 Selected from -C(=O)N(R 4 )-or-N(R 5 )C(=O)-,R 4 or R 5 are independently selected from hydrogen.

[0040] On the other hand, some embodiments provide a compound of formula I or a pharmaceutically acceptable salt thereof:

[0041]

[0042] where Y 2 is selected from a piperazinylene group or a divalent group represented by formula (iii) or (v):

[0043] Formula (iii) is -C(=O)-B 1 -N(R 6 )-

[0044] Formula (v) is -B 2 -N(R 7 )-

[0045] Among them B 1 and B 2 Each independently selected from C 2-6 Alkenylene or C 1-6 Alkylene, the alkenylene or alkylene is optionally substituted by one or more selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy substituted, R 6 or R 7 are independently selected from hydrogen, deuterium or alkyl, R 8 , R 9 , R 10 , R 11 or R 12 As defined in the compound of formula II, R 2 As defined in the compound represented by formula I.

[0046] In some embodiments, R 2 Selected from C 6-8 aryl or 5 to 8 membered heteroaryl, the aryl or heteroaryl being optionally substituted by one or more selected from deuterium, halogen, hydroxyl, C1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 heterocycloalkoxy, C 3-8 The alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy or cycloalkenyloxy groups are optionally substituted with one or more R 3 replaced by R', R" and R 3b As defined in the compound represented by formula I.

[0047] In some embodiments, R 2 Selected from C 6-8 Aryl, the aryl group is optionally substituted by one or more selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 heterocycloalkoxy, C 3-8 cycloalkenyloxy, -SR', -S(O)2R', -NR'(R"), -COR', -COOR' or -CONR'(R"), wherein the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy or cycloalkenyloxy is optionally substituted with 1 to 3 R 3b replaced by R', R" and R 3b As defined in the compound represented by formula I.

[0048] In some embodiments, R 2 Selected from C 6-8 Aryl, the aryl group is optionally substituted by 1 to 3 atoms selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 The alkyl, alkoxy or cycloalkoxy group is optionally substituted by 1 to 3 R 3b Replaced by R 3b As defined in the compound represented by formula I.

[0049] In other embodiments, R 2 Selected from C 6-8Aryl, wherein the aryl is optionally substituted by 1 to 3 groups selected from -SR', -S(O)2R', -NR'(R"), -COR', -COOR' or -CONR'(R"), wherein R' and R" are as defined in the compound represented by formula I.

[0050] In other embodiments, R 2 Selected from C 6-8 Aryl, the aryl group is optionally substituted by 1 to 3 selected from C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, 3 to 6 heterocycloalkyloxy or C 3-8 The alkenyloxy, alkynyloxy or cycloalkenyloxy group is optionally substituted by 1 to 3 R 3b Replaced by R 3b As defined in the compound represented by formula I.

[0051] In other embodiments, R 2 is selected from phenyl, wherein the phenyl is substituted by 1 to 3 groups selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy is substituted, and the alkyl or alkoxy is optionally substituted by 1 to 3 R 3b Replaced by R 3b As defined in the compound represented by formula I.

[0052] In some embodiments, R 2 is selected from phenyl, wherein the phenyl group is substituted by 1 to 3 selected from C 1-6 The moiety is substituted with an alkoxy group, for example, methoxy, ethoxy or propoxy.

[0053] On the other hand, some embodiments provide a compound of formula I or a pharmaceutically acceptable salt thereof:

[0054]

[0055] Among them, R 13 Selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 heterocycloalkoxy, C 3-8The alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy or cycloalkenyloxy groups are optionally substituted with one or more R 3b is substituted, o is selected from an integer between 0 and 6, R', R" and R 3b As defined in the compound of formula I, R 8 , R 9 , R 10 , R 11 or R 12 As defined in the compound represented by formula II.

[0056] In some embodiments, in the compound represented by Formula IVa or a pharmaceutically acceptable salt thereof, R 13 Selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 The alkyl, alkoxy or cycloalkoxy group is optionally substituted by 1 to 3 R 3b is substituted, o is selected from an integer between 1 and 3, R 3b As defined in the compound represented by formula I.

[0057] On the other hand, some embodiments provide a compound of formula I or a pharmaceutically acceptable salt thereof:

[0058]

[0059] Among them, R 13 Selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3 to 6 heterocycloalkoxy, C 3-8 The alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy or cycloalkenyloxy groups are optionally substituted with one or more R 3b replaced by R', R" and R 3b As defined in the compound of formula I, R 8 , R 9 , R 10 , R 11 or R 12 As defined in the compound of formula II, o is selected from an integer between 0 and 6, and X 1 As defined in the compound represented by formula I.

[0060] In some embodiments, in the compound represented by Formula Va or a pharmaceutically acceptable salt thereof, X 1 Selected from C 1-6 Alkylene, the alkylene is optionally substituted by one or more selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl or C 1-6 The moiety is substituted by an alkoxy group, preferably a methylene group, an ethylene group or a propylene group.

[0061] In other embodiments, R 8 , R 11 and R 12 is selected from hydrogen; R 9 Selected from C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl or 3 to 6 membered heterocycloalkoxy, wherein the cycloalkoxy, cycloalkyl, heterocycloalkyl or heterocycloalkyl is optionally substituted by 1 to 3 R 3a Replaced by R 3a As defined in the compound represented by formula I.

[0062] On the other hand, in some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof is

[0063]

[0064] Among them, X 2 is selected from -O-, -NH-, -S-, -S(O)- or -S(O)2-, R 10 , R 11 or R 12 As defined in the compound of formula II, R 13 , o as defined in the compound represented by formula Va, X 1 As defined in the compound of formula I.

[0065] In some embodiments, R 3a is selected from halogen, deuterium, hydroxy, oxo, nitro or cyano.

[0066] In some embodiments, R 3a Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy or C 3-8 The cycloalkenyloxy group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

[0067] In some embodiments, R 3 Selected from C 1-6 Alkoxy, C 3-6 cycloalkoxy, 3 to 6 membered heterocycloalkoxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 Alkoxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, 5- to 6-membered aryl or heteroaryl are optionally substituted with 1 to 3 groups selected from fluorine, chlorine, deuterium, hydroxy, oxo, nitro, and cyano.

[0068] In some embodiments, R 3a is selected from fluorine, chlorine, deuterium, oxo (=O), hydroxy, methoxy, cyclopropyloxy, cyclopropyl, 3,3-difluorocyclobutyl, cyclopentyl, pyridyl, piperidyl, phenyl, cyclopropylsulfide or tetrahydrothienyl.

[0069] In some embodiments, R 3b is selected from halogen, deuterium, hydroxy, oxo, nitro or cyano.

[0070] In some embodiments, R 3b is selected from fluorine, chlorine, deuterium, oxo (=O), hydroxy, methoxy, cyclopropyloxy, cyclopropyl, 3,3-difluorocyclobutyl, cyclopentyl, pyridyl, piperidyl, phenyl, cyclopropylsulfide or tetrahydrothienyl.

[0071] Typical compounds of Formula I or pharmaceutically acceptable salts thereof include, but are not limited to:

[0072]

[0073]

[0074] The present disclosure also provides a pharmaceutical composition, comprising at least one therapeutically effective amount of the compound represented by the aforementioned formula I or formula II or formula IIIa or formula IIIb or formula IVa or formula Va or formula VIa or VIb or VIc or a pharmaceutically acceptable salt thereof, or a compound or a pharmaceutically acceptable salt thereof prepared by the aforementioned method and a pharmaceutically acceptable excipient.

[0075] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0076] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt.

[0077] In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient.

[0078] The present disclosure also provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof.

[0079]

[0080] The method comprises the steps of reacting a compound of formula (1) with a compound of formula (2),

[0081]

[0082] Among them, A, R 1 , R 2 As defined in the compound of formula I, X 3 is selected from leaving groups, preferably halogen, benzenesulfonyl, mesyl or p-toluenesulfonyl.

[0083] The present disclosure also provides a compound represented by formula (3) or a pharmaceutically acceptable salt thereof

[0084] Among them, A, R 2 As defined in the compound of formula I.

[0085] On the other hand, the present disclosure also provides a method for preparing a compound represented by formula Va or a pharmaceutically acceptable salt thereof,

[0086]

[0087] The method comprises the steps of converting the compound of formula (3) into the compound of formula (4),

[0088]

[0089] Among them, X 1 , R 8 , R 9 , R 10 , R 11 or R 12 As defined in the compound represented by formula Va.

[0090] The present disclosure also provides a compound represented by formula (3) or a pharmaceutically acceptable salt thereof

[0091]

[0092] Among them, X 1 , R 8 , R 9 , R 10 , R 11 or R 12 As defined in the compound represented by formula Va.

[0093] The present disclosure also provides a compound represented by formula (3) or a pharmaceutically acceptable salt thereof

[0094] Among them, X 1 , R 8 , R 9 , R 10 , R 11 or R 12 As defined in the compound represented by formula Va. Typical compounds represented by formula (3) or pharmaceutically acceptable salts thereof include but are not limited to:

[0095]

[0096] Typical compounds represented by formula (4) or their pharmaceutically acceptable salts include but are not limited to:

[0097]

[0098] The present disclosure also provides a method for preventing and / or treating a patient suffering from a PDE-related disorder, which comprises administering to the patient a therapeutically effective amount of a compound as represented by the aforementioned formula I or formula II or formula IIIa or formula IIIb or formula IVa or formula Va or formula VIa or VIb or VIc, or a compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition prepared by the aforementioned method.

[0099] In some embodiments, the PDE-related disorder is preferably asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis or rheumatism.

[0100] The present disclosure also provides a method for preventing and / or treating patients suffering from asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis or rheumatism, which comprises administering to the patient a therapeutically effective amount of a compound represented by the aforementioned formula I or formula II or formula IIIa or formula IIIb or formula IVa or formula Va or formula VIa or VIb or VIc or a pharmaceutically acceptable salt thereof, or a compound or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition prepared by the aforementioned method.

[0101] The present disclosure also provides the use of a compound as shown in the aforementioned formula I or formula II or formula IIIa or formula IIIb or formula IVa or formula Va or formula VIa or VIb or VIc or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating a PDE-related disorder. In some embodiments, the PDE-related disorder is preferably asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis or rheumatism.

[0102] The present disclosure also provides the use of the compound represented by the aforementioned formula I or formula II or formula IIIa or formula IIIb or formula IVa or formula Va or formula VIa or VIb or VIc or its pharmaceutically acceptable salt or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis or rheumatism.

[0103] In another aspect, the pharmaceutically acceptable salts of the compounds described in the present disclosure are selected from inorganic salts or organic salts.

[0104] On the other hand, the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0105] In addition, the compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations.

[0106] The disclosed compounds may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The disclosed compounds containing asymmetric carbon atoms may be isolated in optically pure forms or in racemic forms. Optically pure forms may be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0107] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamates are generated from amines).

[0108] Although all of the above formulae are drawn in certain isomeric forms for the sake of simplicity, the present invention can include all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates and enantiomers.

[0109] Tautomers are structural isomers of organic compounds that are easily interconvertible through a chemical reaction known as tautomerization. This reaction often results in the formal migration of hydrogen atoms or protons, accompanied by the conversion of single bonds and adjacent double bonds. Some common tautomeric pairs are: keto-enol, lactam-lactim. An example of a lactam-lactim equilibrium is between A and B as shown below.

[0110]

[0111] All compounds in the present invention can be drawn as type A or type B. All tautomeric forms are within the scope of the present invention. The naming of the compounds does not exclude any tautomers. "

[0112] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0113] Unless otherwise specified, when a position is specifically designated as deuterium (D), the position is understood to have deuterium (i.e., at least 10% deuterium incorporation) at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). The natural abundance of the compound in the example may be at least 1000 times greater than deuterium, at least 2000 times greater than deuterium, at least 3000 times greater than deuterium, at least 4000 times greater than deuterium, at least 5000 times greater than deuterium, at least 6000 times greater than deuterium or more. The present disclosure also includes various deuterated forms of the formula (I) compound. Each available hydrogen atom connected to a carbon atom may be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of the formula (I) compound with reference to the relevant literature. In preparing deuterated forms of compounds of formula (I), commercially available deuterated starting materials may be used, or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, and the like.

[0114] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally C substituted with halogen or cyano 1-6The term "alkyl" means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted with halogen or cyano and the case where the alkyl is not substituted with halogen and cyano.

[0115] In the chemical structure of the compound described in the present invention, the bond " / " indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond " / " can be or or include both and Two configurations.

[0116] Terminology explanation:

[0117] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0118] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or livestock animals.

[0119] As used herein, an "effective amount" or "therapeutically effective amount" includes an amount sufficient to ameliorate or prevent the symptoms or symptoms 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 method, route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

[0120] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched isomers thereof. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro and cyano.

[0121] "Alkenyl" includes branched and straight chain alkenes having 2 to 12 carbon atoms or alkenes containing aliphatic hydrocarbon groups. For example, "C 2-6 "Alkenyl" means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro and cyano.

[0122] "Alkynyl" includes branched and straight chain alkynyl or aliphatic hydrocarbon-containing alkenes having 2 to 12 carbon atoms, or if a specific number of carbon atoms is specified, that specific number is intended. Examples include ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl, and 1-methylpent-2-ynyl. Alkynyl may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro and cyano.

[0123] The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyls include spirocyclic, fused and bridged cycloalkyls. Cycloalkyls may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro and cyano.

[0124] The cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro and cyano.

[0125] The term "cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms. Examples include, but are not limited to, cyclopentenyl, cyclohexenyl or cyclohexadienyl. Cycloalkenyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, which are independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro and cyano.

[0126] The term "heterocycloalkyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O). m (wherein m is an integer from 0 to 2) heteroatoms, but does not include -OO-, -OS- or -SS- ring parts, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyls include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocycloalkyls include spirocyclic, fused ring and bridged heterocycloalkyls. Non-limiting examples of "heterocycloalkyls" include:

[0127]

[0128] etc.

[0129] The heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocycloalkyl, non-limiting examples of which include:

[0130] wait.

[0131] The heterocycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro and cyano.

[0132] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:

[0133]

[0134] Aryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 Alkyl, C 1-6Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro and cyano.

[0135] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12 members, more preferably 5 or 6 members. For example. Non-limiting examples include: imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazine, etc.

[0136] The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0137]

[0138] The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro and cyano.

[0139] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5-6 membered aryl or heteroaryl are optionally substituted by one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano. Similarly, the definitions of "alkynyloxy", "alkenyloxy", "cycloalkoxy", "heterocycloalkoxy", and "cycloalkenyloxy" are the same as those of "alkoxy" above.

[0140] The term "hydroxy" refers to an -OH group.

[0141] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0142] The term "cyano" refers to -CN.

[0143] The term "nitro" refers to -NO2.

[0144] The term "oxo" refers to a =0 substituent.

[0145] "Monovalent group" refers to a compound that "formally" eliminates a monovalent atom or group. "Subunit" refers to a compound that "formally" eliminates two monovalent or one divalent atoms or groups. Example "alkyl" refers to the part remaining after removing one hydrogen atom from an alkane molecule, including straight and branched monovalent groups of 1 to 20 carbon atoms. "Alkylene (-CH2-)" means the part remaining after removing two hydrogen atoms from an alkane molecule, including straight and branched subunits of 1 to 20 carbon atoms. Non-limiting examples of alkylene groups containing 1 to 6 carbon atoms include methylene (-CH2-), ethylene (such as -CH2CH2- or -CH(CH3)-), propylene (such as -CH2CH2CH2- or -CH(CH2CH3)-), and butylene (such as -CH2CH2CH2CH2-). The alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C3-8 Cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 The cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro and cyano.

[0146] Similarly, the definitions of "alkyleneoxy", "alkenylene", "alkenyleneoxy", "cycloalkylene" and "heterocycloalkylene" are the same as "alkylene".

[0147] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds. DETAILED DESCRIPTION

[0148] 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.

[0149] The experimental methods in the examples of this disclosure that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by raw material or product manufacturers. Reagents that do not specify specific sources are conventional reagents purchased from the market.

[0150] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (Methanol-d4) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.

[0151] HPLC determination used Agilent1100 high pressure liquid chromatograph, GAS15B DAD UV detector, WaterVbridge C18 150*4.6mm 5um chromatographic column.

[0152] MS was determined using an Agilent 6120 triple quadrupole mass spectrometer, a G1315D DAD detector, a Waters Xbridge C18 4.6*50 mm, 5 um chromatographic column, scanning in positive / negative ion mode with a mass scanning range of 80-1200.

[0153] The thin layer chromatography silica gel plate used was Yantai Huanghai HSGF254 silica gel plate. The specification of silica gel plate used in thin layer chromatography (TLC) was 0.2mm±0.03mm, and the specification of thin layer chromatography separation and purification product was 0.4mm-0.5mm.

[0154] The flash column purification system used was Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

[0155] Forward column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh or 300-400 mesh silica gel as the carrier, or uses Changzhou Santai pre-filled ultra-pure normal phase silica gel column (40-63μm, 60g, 24g, 40g, 120g or other specifications).

[0156] The known starting materials in the present disclosure can be synthesized by methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Bid Pharmaceuticals and other companies.

[0157] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0158] Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a capacity of about 1L.

[0159] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0160] Hydrogen was produced by a QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instrument Co., Ltd.

[0161] The nitrogen atmosphere or hydrogen atmosphere is usually evacuated and filled with nitrogen or hydrogen, and the operation is repeated 3 times.

[0162] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0163] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0164] The progress of the reactions in the examples was monitored by thin layer chromatography (TLC).

[0165] Example 1

[0166]

[0167] Compound 2a

[0168] At room temperature, add pyridinium tribromide (23.12g, 72.28mmol) to a 250ml single-mouth bottle, add dichloromethane (100ml) and stir until dissolved. Compound 1a (10g, 65.71mmol) is dissolved in dichloromethane (60ml) and slowly added dropwise to the single-mouth bottle. After the addition is complete, the reaction is stirred overnight. TLC detection reaction is complete, then 1M hydrochloric acid (50ml) is added to quench, ethyl acetate (150ml x 3) is extracted, and the extracts are combined. The extracts are washed with water (150ml) and saturated sodium chloride water (150ml) in turn. After the organic phase is dried over anhydrous sodium sulfate, the organic phase is concentrated under reduced pressure to obtain the target compound 2a (12.1g).

[0169] 1 H NMR: (400MHz, CDCl3) δ6.96(dd,J=7.4,1.9Hz,2H),6.82–6.76(m,1H),5.66(s,1H),4.55(dq,J=12.0,6.0Hz,1H),1.38(s,3H),1.36(s,3H).

[0170] Compound 3a

[0171] At room temperature, compound 2a (10.1 g, 9.79 mmol) was added to a 250 ml single-mouth bottle, and acetonitrile / water (16 ml: 4 ml) was added and stirred until dissolved, followed by adding potassium hydroxide (49.06 g, 4.76 mmol) and diethyl bromofluoromethylphosphonate (23.34 g, 4.76 mmol) in batches. The reaction solution was stirred at room temperature overnight. After TLC detection, the reaction was completed, extracted with ethyl acetate (150 ml x 3), and the extracts were combined. The extracts were washed with water (150 ml) and saturated sodium chloride water (150 ml) in turn. The organic phase was concentrated under reduced pressure and column chromatography (petroleum ether) was used to obtain the target compound compound 3a (7.3 g).

[0172] 1 H NMR: (400MHz, DMSO-d6)δ7.37(s,1H),7.22–6.82(m,3H),4.77–4.62(m,1H),1.28(s,3H),1.27(s,3H).

[0173] Compound 4a

[0174] At room temperature, under nitrogen protection, compound 3a (5.1 g, 18.4 mmol) was added to a 250 ml single-mouth bottle, and dioxane (80 ml) was added and stirred until dissolved, followed by the addition of biboric acid pinacol ester (6.91 g, 27.21 mmol), potassium acetate (3.56 g, 36.29 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (664 mg, 0.91 mmol). The reaction solution was heated to 80°C and stirred overnight. After the reaction was completed by TLC detection, the mixture was cooled and filtered. The filtrate was concentrated under reduced pressure and then subjected to column chromatography (ethyl acetate / petroleum ether) to obtain the target compound 4a (3.7 g).

[0175] 1 H NMR (400MHz, CDCl3) δ7.28 (dd, J=27.6, 26.4Hz, 2H), 7.07 (d, J=7.8Hz, 1H), 6.53 (t, J=7 5.5Hz, 1H), 4.57 (dq, J = 12.6, 6.3Hz, 1H), 1.28 (d, J = 6.1Hz, 6H), 1.26 (d, J = 3.4Hz, 12H).

[0176] Compound 6a

[0177] Add compound 5a (3.44 g, 61.38 mmol) and N,N-dimethylformamide (80 ml) to a single-mouth bottle at room temperature, stir until dissolved, cool to 0°C, and add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (11.67 g, 30.69 mmol) in batches. Stir for 10 min after addition, then add 2-ethoxybenzoic acid (5.1 g, 30.69 mmol) and N,N-diisopropylethylamine (11.9 g, 92.07 mmol). After stirring at room temperature for 16 hours, pour into water (150 ml), extract with ethyl acetate (150 ml x 3), and combine the extracts. Wash the extracts with water (150 ml) and saturated sodium chloride water (150 ml) in turn. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (ethyl acetate / petroleum ether) to obtain the target compound 6a (3.9 g).

[0178] LCMS: m / z 205.1 (M+H) + .

[0179] Compound 7a

[0180] At room temperature, compound 6a (2.0 g, 9.79 mmol) was added to a 100 ml single-mouth bottle, and N,N-dimethylformamide (20 ml) was added and stirred until dissolved, followed by the addition of ammonium chloride (576 mg, 10.77 mmol) and sodium azide (668 mg, 10.28 mmol) and the system was heated to 125°C for 16 hours. After cooling to room temperature and adding 2M hydrochloric acid (20 mL), a large amount of white solid was generated, which was filtered and the filter cake was washed with water (20 ml) until pH = 7. The filter cake was dried to obtain the target compound 7a (1.2 g).

[0181] LCMS: m / z 248.1 (M+H) + .

[0182] Compound 1

[0183] At room temperature, in an oxygen atmosphere, compound 8a (300 mg, 1.21 mmol), compound 4a (796 mg, 2.43 mmol) and 1,2-dichloroethane (5 ml) were added to a 50 ml single-necked bottle in sequence and stirred until dissolved. 1 ,N 2 -dimethylethane-1,2-diamine (11 mg, 0.12 mmol), copper chloride (16 mg, 0.12 mmol) and potassium carbonate (544.0 mg, 3.94 mmol). The reaction solution was heated to 70 ° C in an oil bath and stirred for 16 hours. LCMS monitored the completion of the reaction. After the reaction solution was cooled to room temperature, it was filtered, diluted with 2-methyltetrahydrofuran (100 ml), and washed with water (100 ml) and saturated brine (100 ml) in turn. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative liquid chromatography (formic acid / acetonitrile / water system) to obtain compound 1 (7.3 mg,).

[0184] LCMS: m / z 448.3 (M+H) + , 1 H NMR (400MHz, CDCl3) δ8.99(s,1H),8.44(s,1H),7.76(d,J=30.8Hz,2H),7.47(d,J=6.6Hz,1H),7.32(d,J=6.8Hz,1H),7.11(s,1H),7.02 (d,J=8.0Hz,1H),6.62(t,J=74.8Hz,1H),4.86(d,J=118.6Hz,3H),4.26(d,J=6.4Hz,2H),1.57(t,J=6.0Hz,3H),1.43(d,J=5.2Hz,6H).

[0185] Example 2

[0186]

[0187] Compound 2b

[0188] Under ice-water cooling, add isopropanol (460mg, 7.68mmol) to a 50 ml single-mouth bottle, add N,N-dimethylformamide (10ml) and stir until dissolved, then add sodium hydride (purity 60%, dispersed in mineral oil) (333mg, 8.31mmol) and stir at this temperature for 30 minutes. Then add compound 2a (2.0g, 6.39mmol) and continue to stir at room temperature for 16 hours. TLC detection reaction is complete, the reaction solution is quenched by adding water (10ml), and extracted with ethyl acetate (50mlX 3). Combine the extracts, wash with saturated sodium chloride solution (50ml), and dry over anhydrous sodium sulfate. After concentration, the crude product is purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 2b (1.63g).

[0189] LCMS: m / z: 293.0 (M+H) + .

[0190] Compound 2

[0191] Compound 7a (50 mg, 0.20 mmol), compound 2b (71 mg, 0.24 mmol), cuprous iodide (8 mg, 0.04 mmol), cesium carbonate (130 mg, 0.40 mmol) and N,N-dimethylformamide (2 ml) were added to a 5 ml microwave tube at room temperature. Nitrogen was bubbled for 3 minutes, the microwave tube was sealed, and microwaves were heated to 100 ° C for 1 hour. The reaction was completed after LCMS monitoring. After cooling to room temperature, the mixture was filtered. The filtrate was purified by preparative liquid chromatography (formic acid / acetonitrile / water system) to obtain compound 2 (25.91 mg).

[0192] LCMS: m / z: 413.2 (M+H) + , 1 H NMR (400MHz, CDCl3) δ7.36(d,J=7.5Hz,1H),7.29(dd,J=11.4,4.5Hz,1H),6.94(t,J=7.2Hz,1H),6.72(d,J=8.3Hz,2H ), 6.25 (s, 1H), 5.42 (s, 2H), 4.86 (dt, J = 12.4, 6.2Hz, 1H), 3.85 (d, J = 6.5Hz, 2H), 3.74 (s, 3H), 1.25 (t, J = 6.6Hz, 9H).

[0193] Biological evaluation

[0194] The present disclosure is further described and explained below in conjunction with test examples, but these test examples are not meant to limit the scope of the present disclosure.

[0195] Test Example 1 In vitro PDE4B enzyme activity assay

[0196] 1. Experimental Materials

[0197]

[0198]

[0199] 2. Experimental Procedure

[0200] For compound testing, prepare a 10 mM stock solution of the compound in 90% DMSO (10% water) in a test tube and use it to prepare a 1:5 dilution series starting from 100 uM and going down to 0.05 nM. For enzyme assays, transfer 0.2 ul of compound solution to a 384-well plate, and transfer 0.2 ul of 100% DMSO to both the negative and positive controls. Then add 10 ul of 2x PDE4B1 enzyme solution (final concentration 0.04 nM) to each well, and replace the enzyme solution with 10 ul of 1x reaction buffer for the no enzyme control wells. Centrifuge at 1000 rpm for 1 min and incubate at room temperature for 15 min. Then add 10 ul of 2x FAM-cAMP substrate solution (final substrate concentration 0.1 uM) to each well of the 384-well plate, centrifuge at 1000 rpm for 1 min, and react at 25°C for 30 min. After the reaction, 60ul of the reaction stop solution was added to each well of the 384-well reaction plate to terminate the reaction, and the plate was incubated for 60 minutes at room temperature with a shaker at 600rpm in the dark. After the incubation, the RLU data was read and the inhibition rate was calculated. The IC50 value was calculated based on the concentration and inhibition rate fitting curve, where the maximum value refers to the reading of the DMSO control and the minimum value refers to the reading of the no enzyme activity control.

[0201] The inhibition of PDE4B2 enzyme activity in vitro by the embodiments of the present disclosure was determined by the above test, and the measured IC50 values ​​are shown in Table 1.

[0202] Table 1

[0203] serial number <![CDATA[PDE4B1 IC 50 (nM)]]> Compound 1 94 Compound 2 >1000

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

2. A pharmaceutical composition comprising at least one therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

3. Use of the compound according to claim 1 or the pharmaceutical composition according to claim 2 in the preparation of a medicament for preventing and / or treating a PDE-related disorder.

4. The use according to claim 3, wherein the PDE-related disorder is selected from obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis or rheumatism.

5. The use according to claim 3, wherein the PDE-related disorder is selected from asthma.

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