Aryl- or heteroaryl-substituted five-membered heteroaromatic compounds and their uses

Abstract

The present disclosure relates to aryl- or heteroaryl-substituted five-membered heteroaromatic compounds and their uses. Specifically, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , Y 1 , ring A and ring B are as defined herein. #imgabs0#

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine and relates to an aryl- or heteroaryl-substituted five-membered heteroaromatic compound and its use. Background Art

[0002] Phosphodiesterases (PDEs) are a class of intracellular enzymes that cleave phosphodiester bonds in the second messenger molecules 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP). The cyclic nucleotides cAMP and cGMP act as second messengers in various cellular pathways. Among them, PDE4 is highly specific for cAMP and has 4 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 effects on central nervous system function, cardiovascular function, the inflammatory / immune system, cell adhesion, etc. PDE4 plays a major regulatory role in the expression of pro-inflammatory mediators and anti-inflammatory mediators, and PDE4 inhibitors can inhibit the release of harmful mediators by inflammatory cells.

[0003] In recent years, many PDE4 inhibitors have been discovered. For example, roflumilast has been approved for use in severe chronic obstructive pulmonary disease (COPD) to reduce the number of exacerbations or prevent the worsening of COPD symptoms, and apremilast has been approved for the treatment of adults with active psoriatic arthritis. Although PDE4 inhibitors show good pharmacological activity, these PDE inhibitors can have side effects such as induced gastrointestinal symptoms such as vomiting and diarrhea, and there is still a need to develop selective PDE4 inhibitors, especially selective PDE4 inhibitors that have an 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 linked compounds of the present disclosure have not been disclosed in any literature. Summary of the Invention

[0005] The present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof

[0006]

[0007] Wherein, R 1Selected from aryl or heteroaryl, the aryl or heteroaryl being optionally substituted by one or more substituents selected from deuterium, halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy, and / or the aryl or heteroaryl being fused to cycloalkyl or heterocycloalkyl, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or fused ring being optionally substituted by one or more R A1 substituents;

[0008] R A1 selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered 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, aryl or 5- to 6-membered heteroaryl being optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino;

[0009] R 2 selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, the aryl or heteroaryl being optionally substituted by one or more substituents selected from deuterium, halogen, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy, cycloalkenyloxy, -SR', -S(O)2R', -NR'(R”), -COR', -COOR' or -CONR'(R”), the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy being optionally substituted by one or more R A2 substituents;

[0010] R A2 selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, C6-10 An aryl or 5- to 6-membered heteroaryl, wherein 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, C 6-10 aryl or 5- to 6-membered heteroaryl is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino;

[0011] Ring A is selected from 5-membered heteroaromatic rings, said heteroaromatic ring being optionally substituted with one or more R A3 and R 1 is in the meta position to ring B on ring A;

[0012] R A3 is selected from halogen, deuterium, hydroxy, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino;

[0013] Ring B is selected from 3- to 6-membered carbocyclic or heterocyclic rings, said ring B being optionally substituted with one or more R A4 ;

[0014] R A4 is selected from halogen, deuterium, hydroxy, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino;

[0015] Y 1 is selected from a bond, -C(=O)-, -C(=O)N(R 3 )-, -N(R 4 )C(=O)-, -S(O) n -, -S(O) mN(R 3 )- or -

[0016] N(R 4 )S(O) m -, R 3 or R 4 is independently selected from hydrogen, deuterium or C 1-6 alkyl, and n and m are each independently selected from integers from 0 to 2;

[0017] R' or R” is independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano or amino.

[0018] In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 is selected from C 6-10 aryl or 5- to 10-membered heteroaryl, and the aryl or heteroaryl is optionally substituted by one or more selected from deuterium, halogen, hydroxy, amino, 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 cycloalkenyloxy, and / or the aryl or heteroaryl is fused to a 3- to 10-membered cycloalkyl or 3- to 10-membered heterocycloalkyl, and the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or fused ring is optionally substituted by one or more R A1 as defined above. A1 R

[0019] In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 is selected from C 6-10 aryl, and the aryl is optionally substituted by one or more selected from deuterium, halogen, hydroxy, amino, C 1-6 alkyl, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl or C 3-6 cycloalkenyloxy, and / or the aryl is fused to a 3- to 10-membered cycloalkyl, and the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or fused ring is optionally substituted by one or more R A1 as defined above. A1 R

[0020] In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof 1 is selected from C 6-10 aryl, the aryl being optionally substituted with one or more substituents selected from C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy, and / or the aryl being fused to a 3- to 10-membered heterocycloalkyl, the alkoxy, cycloalkoxy or fused ring being optionally substituted with one or more R A1 as defined above. A1 As defined above.

[0021] In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof 1 is selected from C 6-10 aryl, the aryl being optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy or amino.

[0022] On the other hand, some embodiments provide that the compound of formula I is

[0023]

[0024] wherein R 6 , R 7 , R 8 , R 9 or R 10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, 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 cycloalkenyloxy, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, cycloalkyl, heterocycloalkoxy or heterocycloalkyl being optionally substituted with one or more R A1 as defined above, or R 6 , R 7 form a 5- to 10-membered carbocyclic or 5- to 10-membered heterocyclic ring with adjacent carbon atoms, the carbocyclic or heterocyclic ring being optionally substituted with one or more R A1 as defined above, R A1 As defined above.

[0025] In some embodiments, R in the compound of formula IIA or a pharmaceutically acceptable salt thereof 8 is selected from hydrogen, deuterium, halogen, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy, the alkyl or alkoxy being optionally substituted with 1 to 3 R A1 as defined above, RA1 As defined above.

[0026] In some embodiments, R in the compound of formula IIA or a pharmaceutically acceptable salt thereof 8 is selected from C 1-6 alkoxy, wherein the alkoxy is optionally substituted with 1 to 3 R A1 as defined above. A1 As defined above.

[0027] In some embodiments, R in the compound of formula IIA or a pharmaceutically acceptable salt thereof 8 is 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, heterocycloalkoxy or heterocycloalkyl is optionally substituted with 1 to 3 R A1 as defined above. A1 As defined above.

[0028] In some other embodiments, R in the compound of formula IIA or a pharmaceutically acceptable salt thereof 6 is selected from hydrogen, deuterium, halogen, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with 1 to 3 R A1 as defined above. In some embodiments, R A1 is selected from hydrogen or deuterium. In some embodiments, R 6 is selected from hydrogen. 6 is selected from hydrogen.

[0029] In some other embodiments, R in the compound of formula IIA or a pharmaceutically acceptable salt thereof 10 is selected from hydrogen, deuterium, halogen, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with 1 to 3 R A1 as defined above. In some embodiments, R A1 is selected from hydrogen or deuterium. In some embodiments, R 10 is selected from hydrogen. 10 is selected from hydrogen.

[0030] On the other hand, in some embodiments, R in the compound of formula II or a pharmaceutically acceptable salt thereof 7 is selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 alkyl or C 1-6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with 1 to 3 RA1 is replaced by R A1 as defined above.

[0031] In some embodiments, R in the compound of formula II or a pharmaceutically acceptable salt thereof 7 is selected from C 1-6 alkoxy, and the alkoxy is optionally substituted by 1 to 3 R A1 as defined above. A1 is replaced by R

[0032] In some embodiments, R in the compound of formula II or a pharmaceutically acceptable salt thereof 7 is 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, and the alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, cycloalkyl, heterocycloalkoxy or heterocycloalkyl is optionally substituted by 1 to 3 R A1 as defined above. A1 is replaced by R

[0033] In other embodiments, R in the compound of formula II or a pharmaceutically acceptable salt thereof 7 is selected from 3- to 6-membered heterocycloalkoxy, preferably heterocycloalkoxy containing at least one heteroatom selected from N, O or S, and the heterocycloalkoxy is optionally substituted by 1 to 3 R A1 as defined above. In some embodiments, the heterocycloalkoxy includes but is not limited to A1 is replaced by R

[0034] In other embodiments, R 6 , R 9 or R 10 in the compound of formula II or a pharmaceutically acceptable salt thereof is selected from hydrogen or deuterium. In some embodiments, R 8 in the compound of formula II or a pharmaceutically acceptable salt thereof is selected from C 1-6 alkoxy, and the alkoxy is optionally substituted by 1 to 3 R A1 as defined above; R 7 is selected from C 1-6 alkoxy, and the alkoxy is optionally substituted by 1 to 3 R A1 as defined above.

[0035] In some embodiments, R 8 in the compound of formula II or a pharmaceutically acceptable salt thereof is selected from C 1-6 alkoxy, and the alkoxy is optionally substituted by 1 to 3 R A1 as defined above; R7 Selected from C 1-6 alkoxy, the alkoxy being optionally substituted by 1 to 3 R A1 ; R 6 , R 9 and R 10 are each independently selected from hydrogen or deuterium.

[0036] In some embodiments, R 7 in the compound of formula II or a pharmaceutically acceptable salt thereof is selected from heterocyclic alkoxy containing at least one heteroatom selected from N, O or S, the heterocyclic alkoxy being optionally substituted by 1 to 3 R A1 ; R A1 is as defined above; R 8 is selected from C 1-6 alkoxy, the alkoxy being optionally substituted by 1 to 3 R A1 ; R 6 , R 9 or R 10 is selected from hydrogen or deuterium.

[0037] In other embodiments, R 6 , R 7 and the adjacent carbon atoms form a 5- to 10-membered heterocycle, the heterocycle being optionally substituted by 1 to 3 R A1 ; R A1 is as defined above.

[0038] In some embodiments, R 6 , R 7 and the adjacent carbon atoms form a 5- to 10-membered heterocycle, the heterocycle being optionally substituted by 1 to 3 R A1 ; R A1 is as defined in claim 1; R 8 is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, the alkyl or alkoxy being optionally substituted by 1 to 3 R A1 ; R A1 is as defined above.

[0039] In some embodiments, R 6 , R 7 and the adjacent carbon atoms form a 5- to 10-membered heterocycle, the heterocycle being optionally substituted by 1 to 3 R A1 ;

[0040] R 8 is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl or C 1-6an alkoxy group, wherein the alkyl or alkoxy group is optionally substituted by 1 to 3 R A1 substituted;

[0041] R 9 or R 10 is selected from hydrogen;

[0042] R A1 as defined above.

[0043] In some other embodiments, in the compound of formula I or its pharmaceutically acceptable salt, R 1 is selected from 5- to 10-membered heteroaryl groups, wherein the heteroaryl group is optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino, 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 cycloalkenyloxy, and / or the aryl group is fused to a 3- to 10-membered cycloalkyl or 3- to 10-membered heterocycloalkyl group, and the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or fused ring is optionally substituted by one or more R A1 substituted, R A1 as defined above.

[0044] In some embodiments, in the compound of formula I or its pharmaceutically acceptable salt, R 1 is selected from 5- to 10-membered heteroaryl groups, wherein the heteroaryl group is optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy, and the alkyl or alkoxy group is optionally substituted by one or more R A1 substituted, R A1 as defined above.

[0045] On the other hand, the present disclosure provides that the compound of formula I is

[0046]

[0047] wherein, R 11 , R 12 , R 13 , R 14 or R 15 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, and the alkyl or alkoxy group is optionally substituted by one or more R A1 substituted, R A1 as defined above.

[0048] In some embodiments, Y in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof 1 is selected from -C(=O)N(R 3 )- or -N(R 4 )C(=O)-, R 3 or R 4 is independently selected from hydrogen, deuterium or C 1-6 alkyl.

[0049] In some embodiments, R 2 -Y 1 - in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is: R 2 -C(=O)N(R 3 )-, R 3 is independently selected from hydrogen, deuterium or C 1-6 alkyl.

[0050] In some embodiments, R 2 -Y 1 - in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is: R 2 -C(=O)N(R 3 )-, R 3 is independently selected from hydrogen.

[0051] Some embodiments provide that the compound of formula I is

[0052]

[0053] In some embodiments, R 2 -Y 1 - in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is: R 2 -N(R 4 )C(=O)-, R 4 is independently selected from hydrogen, deuterium or C 1-6 alkyl.

[0054] In some embodiments, R 2 -Y 1 - in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is: R 2 -N(R 4 )C(=O)-, R 4 is independently selected from hydrogen.

[0055] In some embodiments, Y in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof 1 is selected from a bond, -C(=O)-.

[0056] In some embodiments, Y in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof1 Selected from -S(O) n -, -S(O) m N(R 3 )- or -N(R 4 )S(O) m -, n and m are each independently selected from integers from 0 to 2, R 3 or R 4 is independently selected from hydrogen, deuterium or C 1-6 alkyl.

[0057] In some embodiments, in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof, R 2 is selected from C 6-10 aryl or a 5- to 9-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, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, -SR', -S(O)2R', -NR'(R”), -COR', -COOR' or -CONR'(R”), the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy being optionally substituted by one or more R A2 as defined above, and R', R” and R A2 are as defined above.

[0058] In some embodiments, in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof, R 2 is selected from C 6-10 aryl, the aryl 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, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, -SR', -S(O)2R', -NR'(R”), -COR', -COOR' or -CONR'(R”), the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy being optionally substituted by 1 to 3 R A2 as defined above, and R', R” and R A2 are as defined above.

[0059] In some embodiments, in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof, R 2 is selected from C 6-10An aryl group, said aryl group being optionally substituted by 1 to 3 members selected from the group consisting of deuterium, halogen, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 3-6 cycloalkoxy, said alkyl, alkoxy or cycloalkoxy being optionally substituted by 1 to 3 R A2 groups, R A2 being as defined above.

[0060] In some embodiments, R 2 in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is selected from C 6-10 aryl, said aryl group being optionally substituted by C 1-6 alkoxy, said alkoxy being optionally substituted by 1 to 3 R A2 groups, R A2 being as defined above.

[0061] In some embodiments, R 2 in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is selected from C 6-10 aryl, said aryl group being optionally substituted by 1 to 3 members selected from the group consisting of -SR', -S(O)2R', -NR'(R”), -COR', -COOR' or -CONR'(R”), where R' and R” are as defined above.

[0062] In some embodiments, R 2 in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is selected from C 6-10 aryl, said aryl group being optionally substituted by 1 to 3 members selected from the group consisting of C 2-6 alkenyloxy, C 2-6 alkynyloxy, 3 to 6 membered heterocycloalkoxy or C 3-8 cycloalkenyloxy, said alkenyloxy, alkynyloxy or cycloalkenyloxy being optionally substituted by 1 to 3 R A2 groups, R A2 being as defined above.

[0063] In some embodiments, R 2 in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is selected from phenyl, said phenyl being substituted by 1 to 3 members selected from the group consisting of deuterium, halogen, hydroxy, C 1-6 alkyl or C 1-6 alkoxy, said alkyl or alkoxy being optionally substituted by 1 to 3 R A2 groups, R A2 being as defined above.

[0064] In some embodiments, R 2 in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is selected from phenyl, said phenyl being substituted by 1 to 3 members selected from the group consisting of C 1-6substituted by an alkoxy group, such as a methoxy group, an ethoxy group or a propoxy group.

[0065] In some embodiments, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof 2 is selected from 5- to 9-membered heteroaryl, and the heteroaryl is optionally substituted by 1 to 3 substituents selected from deuterium, halogen, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 3-6 cycloalkoxy, and the alkyl, cycloalkyl, alkoxy or cycloalkoxy is optionally substituted by 1 to 3 R A2 as defined above. A2 as defined above.

[0066] In some embodiments, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof 2 is selected from

[0067] Furthermore, the R 2 is optionally substituted by 1 to 3 substituents selected from deuterium, halogen, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 3-6 cycloalkoxy.

[0068] In some embodiments, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof 2 is selected from:

[0069]

[0070] In some embodiments, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof 2 is selected from C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 3 substituents selected from deuterium, halogen, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 3-6 cycloalkoxy, and the alkyl, cycloalkyl, alkoxy or cycloalkoxy is optionally substituted by 1 to 3 R A2 as defined above. A2 as defined above.

[0071] On the other hand, in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof in the present disclosure, ring A is selected from

[0072]

[0073] Furthermore, the ring A ring is optionally substituted by one or more RA3 is replaced by R A3 as defined above.

[0074] In some embodiments, ring A in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is selected from

[0075] Further, said ring A is optionally substituted with one or more R A3 is replaced by R A3 as defined above.

[0076] In some embodiments, ring A in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is selected from

[0077]

[0078] In some embodiments, ring A in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is selected from

[0079] In some embodiments, in the compound of formula I is:

[0080]

[0081] In some embodiments, in the compound of formula I is:

[0082]

[0083] The compound of formula I or formula II provided by some embodiments is

[0084]

[0085] On the other hand, in some embodiments, ring B in the compound of formula I or formula II is selected from a 3- to 6-membered carbocyclic ring, and said ring B is optionally substituted with one or more R A4 is replaced.

[0086] In some embodiments, ring B in the compound of formula I or formula II is selected from Further, said ring B is optionally substituted with one or more R A4 is replaced.

[0087] The compound of formula I or formula II provided by the present disclosure is

[0088] Wherein P is an integer between 0 and 3. In some embodiments, p = 0, 1, or 2 in the compound of formula VA or a pharmaceutically acceptable salt thereof. In some embodiments, p = 0 in the compound of formula VA or a pharmaceutically acceptable salt thereof.

[0089] In other embodiments, ring B in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is selected from a 4- to 6-membered nitrogen-containing heterocycle or an oxygen-containing heterocycle, and the ring B is optionally substituted by one or more R A4 substituents.

[0090] In some embodiments, ring B in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is selected from

[0091] Furthermore, the ring B is optionally substituted by one or more R A4 substituents.

[0092] On the other hand, in some embodiments, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof A1 is selected from halogen, deuterium, nitro, or cyano, preferably halogen, such as fluorine.

[0093] In some embodiments, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof A1 is selected from hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, and the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, or 3- to 6-membered heterocycloalkoxy is optionally substituted by one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino.

[0094] In some embodiments, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof A1 is selected from phenyl or 5- to 6-membered heteroaryl, and the phenyl or 5- to 6-membered heteroaryl is optionally substituted by one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino.

[0095] In some embodiments, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof A2 is selected from halogen, deuterium, nitro, or cyano, preferably halogen, such as fluorine.

[0096] In some embodiments, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof A2 is selected from hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, and the C 1-6 alkyl, C 1-6 alkoxy, C 3-6The cycloalkyloxy or 3- to 6-membered heteroalkyloxy is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, and amino.

[0097] In some embodiments, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof A3 is selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.

[0098] In some embodiments, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof A3 is selected from hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl or 3- to 6-membered heteroalkyl, wherein the C 1-6 alkyl, C 1-6 alkyloxy, C 3-6 cycloalkyloxy or 3- to 6-membered heteroalkyloxy is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, and amino.

[0099] In some embodiments, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof A4 is selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.

[0100] In some embodiments, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof A4 is selected from hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl or 3- to 6-membered heteroalkyl, wherein the C 1-6 alkyl, C 1-6 alkyloxy, C 3-6 cycloalkyloxy or 3- to 6-membered heteroalkyloxy is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, and amino.

[0101] In some embodiments, R' or R'' in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof independently is selected from hydrogen, C 1-6 alkyl or C 1-6 alkyloxy, wherein the C 1-6 alkyl or C 1-6 alkyloxy is optionally substituted with one or more substituents selected from halogen or deuterium.

[0102] Furthermore, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof provided by the present disclosure 2 is selected from a 5- to 6-membered heteroaromatic ring. In some embodiments, R 2 is selected from thiazolyl, imidazolyl, pyridyl, oxazolyl, pyrimidinyl or pyrazolyl, and further the R 2 is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, C 1-6 alkyl or C1-6 an alkoxy group, wherein the alkyl or alkoxy group is optionally substituted by one or more R A2 as defined above. A2 as defined above.

[0103] In some other embodiments, R 2 is selected from thiazolyl, wherein the thiazolyl is optionally substituted by one or more selected from deuterium, halogen, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy group, wherein the alkyl or alkoxy group is optionally substituted by one or more R A2 as defined above. A2 as defined above.

[0104] In some other embodiments, R 2 is selected from imidazolyl, wherein the imidazolyl is optionally substituted by one or more selected from deuterium, halogen, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy group, wherein the alkyl or alkoxy group is optionally substituted by one or more R A2 as defined above. A2 as defined above.

[0105] Some other embodiments provide that the compound of formula I is

[0106] wherein, R 16 or R 17 each independently is selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy group, wherein the alkyl or alkoxy group is optionally substituted by one or more R A1 as defined above. A1 as defined above.

[0107] In some embodiments, the compound of formula I is

[0108]

[0109] In some embodiments, in the compound of formula IIIC or a pharmaceutically acceptable salt thereof, R 16 or R 17 each independently is selected from hydrogen, deuterium or C 1-6 alkoxy group.

[0110] In some embodiments, in the compound of formula IIIC or a pharmaceutically acceptable salt thereof, R 16 or R 17 each independently is selected from hydrogen, halogen, amino, hydroxyl or C 1-6 alkoxy group.

[0111] In some embodiments, in the compound of formula IIIC or a pharmaceutically acceptable salt thereof, R16 or R 17 each independently selected from C 1-6 alkyl or C 1-6 alkoxy.

[0112] On the other hand, in some other embodiments, in the compounds of formula I or formula II or their pharmaceutically acceptable salts, R 2 is selected from pyridyl or oxazolyl, and the pyridyl or oxazolyl is optionally substituted with one or more selected from deuterium, halogen, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy, and the alkyl or alkoxy is optionally substituted with one or more R A2 as defined above. A2 as previously defined.

[0113] Some other embodiments provide that the compound of formula I is

[0114] wherein, R 18 or R 19 each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, R 20 is selected from hydrogen, deuterium or C 1-6 alkyl, and the alkyl or alkoxy is optionally substituted with one or more R A6 as defined above, R A6 is selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heteroalkoxy, and the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heteroalkoxy is optionally substituted with one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino.

[0115] In some embodiments, the compound of formula I is

[0116]

[0117] In some embodiments, in the compound of formula III or its pharmaceutically acceptable salt, R 18 or R 19 each independently selected from hydrogen, halogen, amino, hydroxyl or C 1-6 alkoxy, R 20 is selected from hydrogen, deuterium or C 1-6 alkyl.

[0118] In some embodiments, R in the compound of formula III or its pharmaceutically acceptable salt 18 or R 19 each independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy, R 20 is selected from hydrogen, deuterium or C 1-6 alkyl.

[0119] Some other embodiments provide that the compound of formula I is

[0120]

[0121] Some other embodiments provide that the compound of formula I is

[0122] Some other embodiments provide that the compound of formula I is

[0123] Some other embodiments provide that the compound of formula I is

[0124] Typical compounds of formula I or their pharmaceutically acceptable salts, including but not limited to:

[0125]

[0126]

[0127]

[0128] On the other hand, typical compounds of formula I or their pharmaceutically acceptable salts, including but not limited to:

[0129]

[0130] On the other hand, the present disclosure also provides a method for preparing a compound of formula I or its pharmaceutically acceptable salt, including the following reaction scheme,

[0131]

[0132] In some embodiments, the method for preparing the compound of formula IIIA or its pharmaceutically acceptable salt includes the step of reacting a compound of formula ZA with a compound of formula ZB to form a compound of formula IIIA.

[0133]

[0134] The present disclosure on the other hand also provides a compound of formula ZB or its pharmaceutically acceptable salt. In some embodiments, the compound of formula ZB or its pharmaceutically acceptable salt is used for synthesizing or preparing the compound of formula IIIA or its pharmaceutically acceptable salt.

[0135] In some embodiments, the ZB compound or a pharmaceutically acceptable salt thereof is

[0136]

[0137] The present disclosure also provides a pharmaceutical composition comprising at least one therapeutically effective amount of a compound of formula I or formula II as described above or a pharmaceutically acceptable salt thereof, or a compound obtained by the method described above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0138] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg - 1000 mg.

[0139] In certain embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01 - 99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.1 - 99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5% - 99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1% - 99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2% - 98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.

[0140] In certain embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01% - 99.99% of a pharmaceutically acceptable excipient. 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.

[0141] The present disclosure also provides a method for preventing and / or treating a patient suffering from a PDE-related disorder by administering to the patient a therapeutically effective amount of a compound of formula I or formula II as described above or a pharmaceutically acceptable salt thereof, or a compound obtained by the method described above or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition.

[0142] In some embodiments, the PDE-related disorder is preferably asthma, obstructive lung disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis or rheumatism.

[0143] The present disclosure also provides a method for preventing and / or treating a patient suffering from asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis or rheumatism, which comprises administering to the patient a therapeutically effective amount of a compound represented by the foregoing formula I or formula II or a pharmaceutically acceptable salt thereof, or administering to the patient a therapeutically effective amount of a compound prepared by the foregoing method or a pharmaceutically acceptable salt thereof, or administering to the patient a therapeutically effective amount of the foregoing pharmaceutical composition.

[0144] The present disclosure also provides the use of a compound represented by the foregoing formula I or formula II or a pharmaceutically acceptable salt thereof, or the foregoing pharmaceutical composition, in the preparation of a drug 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 colitis or rheumatism.

[0145] The present disclosure also provides the use of a compound represented by the foregoing formula I or formula II or a pharmaceutically acceptable salt thereof, or the foregoing pharmaceutical composition, in the preparation of a drug for preventing and / or treating asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis or rheumatism.

[0146] On the other hand, the pharmaceutically acceptable salts of the compounds in the present disclosure are selected from inorganic salts or organic salts.

[0147] 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, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereoisomer-enriched mixtures, all of which mixtures are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms may be isolated in optically pure form or in racemic form. The optically pure form may be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0148] The 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. 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, where the resulting mixture of diastereomers 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), diastereomeric salts are formed with a suitable optically active acid or base, and then the diastereomers are resolved by conventional methods known in the art, and the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography with a chiral stationary phase, optionally combined with chemical derivatization (such as formation of carbamates from amines).

[0149] In the chemical structure of the compounds described in the present disclosure, the bond represents an unspecified configuration, i.e., if chiral isomers are present in the chemical structure, the bond can be or or contain both and two configurations.

[0150] 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 terms "tautomer" or "tautomeric form" refer 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, lactam-lactim isomerization. An example of the lactam-lactim equilibrium is between A and B shown below.

[0151]

[0152] All compounds in the present disclosure can be drawn in the A form or the B form. All tautomeric forms are within the scope of the present disclosure. The naming of the compounds does not exclude any tautomer.

[0153] The present disclosure also includes isotopically labeled compounds of the present disclosure that are the same as those described herein, but with one or more atoms replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C,13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0154] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%), i.e., at least 10% deuterium incorporation. The deuterium in the compounds of the examples can have an abundance that is at least 1000 times greater than the natural abundance of deuterium, at least 2000 times greater than the natural abundance of deuterium, at least 3000 times greater than the natural abundance of deuterium, at least 4000 times greater than the natural abundance of deuterium, at least 5000 times greater than the natural abundance of deuterium, at least 6000 times greater than the natural abundance of deuterium, or a higher abundance of deuterium. The present disclosure also includes various deuterated forms of the compound of formula (I). Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated forms of the compound of formula (I) with reference to relevant literature. Commercially available deuterated starting materials can be used in the preparation of the deuterated forms of the compound of formula (I), or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated borane, tetrahydrofuran solution of trideuterated borane, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane, etc.

[0155] "Optionally" or "optional" means that the subsequent described event or circumstance can but does not have to occur, and this description includes the cases where the event or circumstance occurs or does not occur. For example, "optionally halogen- or cyano-substituted C 1-6 alkyl" means that halogen or cyano can but does not have to be present, and this description includes the cases where the alkyl is substituted by halogen or cyano and the cases where the alkyl is not substituted by halogen and cyano.

[0156] Term Explanation:

[0157] "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 the pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thereby exert biological activity.

[0158] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent that has been approved by the U.S. Food and Drug Administration as acceptable for use in humans or domestic animals.

[0159] As used herein, an "effective amount" or "effective therapeutic amount" includes an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical disorder. An effective amount also means an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the disorder being treated, the overall health of the patient, the method and route of administration and dosage, and the severity of side effects. The effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

[0160] "Alkyl" refers to saturated aliphatic hydrocarbon groups including straight-chain and branched-chain groups having from 1 to 20 carbon atoms. Alkyl groups having from 1 to 6 carbon atoms are 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 various branched isomers thereof, etc. The alkyl group 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, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 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, aryl or 5- to 6-membered heteroaryl, wherein 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, aryl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.

[0161] "Alkenyl" includes branched and straight-chain olefins having from 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups. For example, "C 2-6"Alkenyl" means an alkenyl having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl 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. The alkenyl can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment point, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered 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, aryl or 5- to 6-membered heteroaryl optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino

[0162] "Alkynyl" includes branched and straight-chain alkynyl having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups, or if a specific number of carbon atoms is specified, it means that specific number. For example, ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and 1-methylpent-2-ynyl. The alkynyl can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment point, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered 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 3-8The cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino.

[0163] 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 spiro, fused and bridged cycloalkyls. The cycloalkyl can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available attachment point, preferably one or more of the following groups, independently selected from 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 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered 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, aryl or 5- to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino.

[0164] The cycloalkyl ring can be fused to an aryl or heteroaryl ring, where the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl can 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, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 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, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6Cycloalkyloxy, 3- to 6-membered heterocycloalkyloxy, C 3-8 Cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino.

[0165] The term "cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic cyclic 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. The cycloalkenyl 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, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyloxy, 3- to 6-membered heterocycloalkyloxy, C 3-8 Cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyloxy, 3- to 6-membered heterocycloalkyloxy, C 3-8 Cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino.

[0166] The term "heterocycloalkyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but does not include the ring moieties of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. Preferably contains 3 to 12 ring atoms, where 1 to 4 are heteroatoms; more preferably contains 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocycloalkyl includes spiro, fused and bridged heterocycloalkyl. Non-limiting examples of "heterocycloalkyl" include:

[0167]

[0168] And so on.

[0169] The heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring connected to the parent structure is a heterocycloalkyl ring, and non-limiting examples thereof include:

[0170] etc.

[0171] The heterocycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, and 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, aryl or 5- to 6-membered heteroaryl is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.

[0172] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) 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, and non-limiting examples thereof include:

[0173]

[0174] The aryl may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from deuterium, halogen, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy, cycloalkenyloxy, -SR', -S(O)2R', -NR'(R”), -COR', -COOR' or -CONR'(R”), and R' or R” are independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano or amino.

[0175] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl is preferably 6 to 12-membered, more preferably 5-membered or 6-membered. For example, non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine, and so on.

[0176] The heteroaryl ring can be fused to an aryl, heterocycloalkyl, or cycloalkyl ring, where the ring connected to the parent structure is the heteroaryl ring. Non-limiting examples thereof include:

[0177]

[0178] The heteroaryl can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from deuterium, halogen, hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy, cycloalkenyloxy, -SR', -S(O)2R', -NR'(R”), -COR', -COOR', or -CONR'(R”), and R' or R” are independently selected from hydrogen, deuterium, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are optionally substituted with one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, or amino.

[0179] The term "alkoxy" refers to -O-(alkyl), where the alkyl is defined as above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. The alkoxy can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from 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 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl, or 5- to 6-membered heteroaryl, and 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 3-8The cycloalkenyloxy group, aryl group or 5- to 6-membered heteroaryl group is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, and amino. Similarly, the definitions of "alkynyloxy", "alkenyloxy", "cycloalkyloxy", "heterocycloalkyloxy", and "cycloalkenyloxy" are as defined for "alkoxy" above.

[0180] The term "heterocycloalkyloxy" refers to -O-(heterocycloalkyl), where heterocycloalkyl is as defined above.

[0181] The term "hydroxy" refers to the -OH group.

[0182] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0183] The term "cyano" refers to -CN.

[0184] The term "nitro" refers to -NO2.

[0185] The term "oxo" refers to the ═O substituent.

[0186] "Substituted" means that one or more, preferably at most 5, more preferably 1 to 3, hydrogen atoms in the group are independently replaced by the corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (by experiment or theory) the possible or impossible substitutions without undue effort.

[0187] Drawings of the specification

[0188] Figure 1 : Ear swelling inhibition rate of each group in the model.

[0189] Figure 2 : Increase in ear thickness of each group in the model. Detailed implementation mode

[0190] The present disclosure is further described below in conjunction with embodiments, but these embodiments do not limit the scope of the present disclosure.

[0191] For the experimental methods without specific conditions in the embodiments of the present disclosure, they are usually carried out according to conventional conditions, or according to the conditions recommended by the raw material or commodity manufacturer. Reagents without specific sources are conventional reagents purchased from the market.

[0192] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR measurement is performed using a Bruker AVANCE-400 nuclear magnetic resonance instrument, and the solvents for measurement are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (Methanol-d4), and the internal standard is tetramethylsilane (TMS).

[0193] For HPLC determination, an Agilent 1100 high-pressure liquid chromatograph, a GAS15B DAD ultraviolet detector, and a Waters Xbridge C18 150*4.6 mm 5 μm chromatographic column were used.

[0194] For MS determination, an Agilent 6120 triple quadrupole mass spectrometer, a G1315D DAD detector, and a Waters Xbridge C18 4.6*50 mm, 5 μm chromatographic column were used. Scanning was performed in positive / negative ion mode, and the mass scanning range was 80 - 1200.

[0195] For thin-layer chromatography, Yantai Huanghai HSGF254 silica gel plates were used. For thin-layer chromatography (TLC), the specification of the silica gel plates used was 0.2 mm ± 0.03 mm, and the specification for separating and purifying products by thin-layer chromatography was 0.4 mm - 0.5 mm.

[0196] For the rapid column purification system, Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage) was used.

[0197] For normal-phase column chromatography, silica gel with 200 - 300 mesh or 300 - 400 mesh from Yantai Huanghai was generally used as the carrier, or a pre-packed normal-phase silica gel column from Changzhou Santai (40 - 63 μm, 60 g, 24 g, 40 g, 120 g or other specifications) was used.

[0198] The known starting materials in the present disclosure can be synthesized by adopting or according to methods known in the art, or can be purchased from companies such as Shanghai Titan Scientific, ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Bidepharm.

[0199] Unless otherwise specified in the examples, the reactions can all be carried out under a nitrogen atmosphere.

[0200] A nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of about 1 L.

[0201] A hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

[0202] Hydrogen was prepared by a QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instrument Co., Ltd.

[0203] The nitrogen atmosphere or hydrogen atmosphere is usually evacuated, filled with nitrogen or hydrogen, and the operation is repeated 3 times.

[0204] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0205] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.

[0206] The progress of the reaction in the examples was monitored by thin-layer chromatography (TLC). For the developing agent used in the reaction, the eluent system of column chromatography for purifying the compound, and the developing agent system of thin-layer chromatography, the volume ratio of the solvents was adjusted according to the polarity of the compound. A small amount of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0207] Example 1

[0208]

[0209]

[0210] Step 1: Synthesis of Compound 1b

[0211] At room temperature, compound 1a (10.0 g, 55.5 mmol) was added to a 250 mL single-necked flask, and N,N-dimethylformamide (40 mL) was added and stirred until dissolved. Isopropyl bromide (8.50 g, 69.1 mmol) and potassium carbonate (9.55 g, 69.2 mmol) were added. The reaction solution was heated to 80°C and stirred for another 2 hours. After the reaction solution was cooled to room temperature, it was diluted with water (100 mL), extracted with ethyl acetate (200 mL × 2), and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound 1b (12 g crude product). LCMS: m / z 231.1 (M+H) + 。

[0212] Step 2: Synthesis of Compound 1c

[0213] Under an ice-water bath, compound 1b (12.0 g, 52.2 mmol) was added to a 250-mL single-necked flask, and ethyl acetate (80 mL) was added and stirred until dissolved. Subsequently, sulfamic acid (5.68 g, 58.5 mmol) and water (10 mL) were added. The reaction temperature was controlled below 20 °C, and an aqueous solution of sodium chlorite (21.2 g, 58.5 mmol, 25%) was added dropwise. After the addition was complete, the reaction was carried out until TLC detection was complete. Subsequently, an aqueous solution of sodium hydroxide (10 mL, 25%) and an aqueous solution of sodium sulfite (80.4 g, 63.8 mmol, 10%) were added in sequence, and stirring was continued for 15 minutes. Concentrated hydrochloric acid (2 mL) was added to the reaction system, and the organic phase was separated and concentrated under reduced pressure. Methanol (40 mL), water (80 mL) and an aqueous solution of sodium hydroxide (25%) were added to the concentrated residue, stirred until dissolved, concentrated hydrochloric acid was added dropwise, and stirring was carried out for 1 hour. Filtration was carried out, and the obtained filter cake was dried under vacuum to obtain compound 1c (6.4 g).

[0214] LCMS: m / z 245.0 (M-H) - 。

[0215] Step 3: Synthesis of compound 1d

[0216] At room temperature, compound 3c (6.4 g, 26 mmol) was added to a 250-mL single-necked flask, and acetonitrile (80 mL) was added and stirred until dissolved. Subsequently, carbonyldiimidazole (5.1 g, 31.2 mmol) was added. The reaction solution was stirred at room temperature for 3 hours, and then 28% concentrated ammonia water was added, and a large amount of white precipitate was formed. Filtration was carried out, and the filter cake was washed to obtain compound 1d (6.2 g). LCMS: m / z 246.1 (M+H) + 。

[0217] Step 4: Synthesis of compound 1e

[0218] At room temperature, compound 1d (5.5 g, 22.41 mmol), 1,3-dichloroacetone (5.46 g, 44.81 mmol) and toluene (55 mL) were added to a 100-mL single-necked flask. The reaction solution was heated to 130 °C and stirring was continued until the reaction was completed as monitored by TLC. After cooling to room temperature, the reaction solution was concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 1e (4.5 g). LCMS: m / z 317.9 (M+H) + 。

[0219] Step 5: Synthesis of compound 1f

[0220] At room temperature, compound 1e (4.5 g, 14.19 mmol), potassium acetate (1.66 g, 17.03 mmol) and N,N-dimethylformamide (50 mL) were added to a 250 mL single-necked flask. The reaction mixture was heated to 100 °C and reacted until the reaction was completed as monitored by TLC. The reaction mixture was cooled to room temperature, then diluted with water (500 mL) and extracted with dichloromethane (200 mL × 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain crude compound 1f (5.8 g).

[0221] LCMS: m / z 342.0 (M+H) + 。

[0222] Step 6: Synthesis of compound 1g

[0223] At room temperature, compound 1f (5.8 g, 17.0 mmol) was added to a 100 mL single-necked flask, and methanol (20 mL) and 25% aqueous sodium hydroxide solution (50 mL) were added. The reaction mixture was heated to 100 °C and stirred for 3 - 8 hours. Subsequently, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the resulting residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 1g (2.55 g). LCMS: m / z 300.0 (M+H) + 。

[0224] Step 7: Synthesis of compound 1h

[0225] At room temperature, compound 1g (1.5 g, 5.0 mmol) was added to a 250 mL single-necked flask, and tetrahydrofuran (15 mL) was added and stirred until dissolved. Subsequently, activated manganese dioxide (4.3 mg, 50.0 mmol) was added. The reaction mixture was heated to 70 °C and stirred until the reaction was complete as monitored by TLC. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 1h (1.36 g), CMS: m / z 298.0 (M+H) + 。

[0226] Step 8: Synthesis of compound 1i

[0227] At room temperature, compound 1h (1.55 g, 5.22 mmol), hydroxylamine hydrochloride (368 mg, 5.22 mmol), sodium acetate (428 mg, 5.22 mmol) were added to a 100 mL single-necked flask and ethanol (35 mL) was added and stirred until dissolved. The reaction mixture was heated to 85 °C and stirred for 2 - 10 hours. It was cooled to room temperature, the reaction mixture was concentrated, and the resulting residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 1i (825 mg), LCMS: m / z 313.0 (M+H)+ 。

[0228] Step 9: Synthesis of Compound 1j

[0229] At room temperature, add Compound 1i (825 mg, 2.64 mmol) and acetic anhydride (5 ml) to a 100-ml single-necked flask. Heat the reaction mixture to 120 °C and stir until the reaction is complete as monitored by LCMS. Cool the reaction mixture to room temperature, add saturated aqueous sodium bicarbonate solution (10 ml), and extract with dichloromethane (10 ml × 3). Wash the combined organic phases with saturated brine and dry over anhydrous sodium sulfate. Concentrate the organic phase, and purify the resulting residue by column chromatography (ethyl acetate / petroleum ether) to obtain Compound 1j (720 mg), LCMS: m / z 342.0 (M+H)+

[0230] Step 10: Synthesis of Compound 1k

[0231] At room temperature, add Compound 1j (100 mg, 0.34 mmol), diethyl ether (3 ml), and toluene (3 ml) to a 25-ml three-necked flask. Cool the reaction mixture to -78 °C, sequentially add titanium(IV) isopropoxide (0.13 ml, 0.41 mmol) and ethylmagnesium bromide (0.27 ml, 0.82 mmol), and react at -78 °C for 10 - 40 minutes. Rapidly warm to room temperature. Subsequently, add boron trifluoride diethyl etherate (0.07 ml, 0.09 mmol), and stir the reaction at room temperature until the reaction is complete as monitored by LCMS. Add 1 M dilute hydrochloric acid to the reaction mixture, then add 1 M aqueous sodium hydroxide solution, and extract with ethyl acetate (10 ml × 3). Wash the combined organic phases with saturated brine and dry over anhydrous sodium sulfate. Concentrate the organic phase, and purify the resulting residue by column chromatography (methanol / dichloromethane) to obtain Compound 1k (75 mg), LCMS: m / z 325.1 (M+H) + 。

[0232] Step 11: Synthesis of Compound 1

[0233] At room temperature, add Compound 1k (75 mg, 0.23 mmol), 2-ethoxybenzoic acid (38 mg, 0.23 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (132 mg, 0.35 mmol), N,N-diisopropylethylamine (60 mg, 0.46 mmol), and N,N-dimethylformamide (3 ml) to a 25-ml three-necked flask. Stir the reaction mixture at room temperature until the reaction is complete as monitored by LCMS. Concentrate the reaction mixture, and prepare the residue by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain Compound 1 (25 mg).

[0234] LCMS: m / z 473.5 (M+H)+

[0235] 1 1H NMR (400 MHz, CD3OD) δ 7.80 - 7.78 (m, 2H), 7.67 (d, J = 1.8 Hz, 1H), 7.56 (dd, J = 8.4, 1.8 Hz, 1H), 7.50–7.43 (m, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.80 (t, J = 74.9 Hz, 1H), 4.77–4.66 (m, 1H), 4.25 - 4.2 (m, 2H), 1.55–1.46 (m, 5H), 1.37 (d, J = 6.0 Hz, 6H), 1.30 - 1.27 (m, 4H).

[0236]

[0237] Compound 2 was prepared according to the method described in Example 1.

[0238] LCMS: m / z 430.1 (M + H) + 。

[0239] 1 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.57 (d, J = 4.1 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.89 - 7.87 (m, 1H), 7.59–7.50 (m, 3H), 7.48 - 7.45 (m, 1H), 7.18 (d, J = 8.3 Hz, 1H), 6.60 (t, J = 75.2 Hz, 1H), 473 - 4.65 (m, 1H), 1.59–1.55 (m, 2H), 1.39 (d, J = 6.1 Hz, 6H), 1.35 - 1.32 (m, 2H).

[0240]

[0241] Compound 3 was prepared according to the method described in Example 1.

[0242] LCMS: m / z 444.1 (M + H) + 。

[0243] 11H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 8.40 (d, J = 4.6 Hz, 1H), 7.68–7.46 (m, 4H), 7.34 (dd, J = 7.8, 4.6 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 6.60 (t, J = 75.3 Hz, 1H), 4.71 - 4.65 (m, 1H), 2.74 (s, 3H), 1.57–1.52 (m, 2H), 1.39 (d, J = 6.1 Hz, 6H), 1.33 - 1.29 (m, 2H).

[0244]

[0245] Compound 4 was prepared according to the method described in Example 1.

[0246] LCMS: m / z 431.0 (M + H) + 。

[0247] 1 1H NMR (400 MHz, CDCl3) δ 8.90 (d, J = 4.9 Hz, 2H), 8.66 (s, 1H), 7.62 (s, 1H), 7.58 - 7.53 (m, 2H),, 7.48 - 7.46 (m, 1H), 7.18 (d, J = 8.3 Hz, 1H), 6.60 (t, J = 75.2 Hz, 1H), 4.72 - 4.68 (m, 1H), 1.61–1.58 (m, 2H), 1.39 (d, J = 6.1 Hz, 6H), 1.37–1.33 (m, 2H).

[0248]

[0249] Compound 5 was prepared according to the method described in Example 1.

[0250] LCMS: m / z 474.1 (M + H) + 。

[0251] 11H NMR (400 MHz, methanol-d4) δ 8.37 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.93 - 7.89 (m, 2H), 7.67 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 8.0, 2.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.80 (t, J = 76.0 Hz, 1H), 4.75 - 4.69 (m, 1H), 4.43 (q, J = 8.0 Hz, 2H), 1.58 - 1.54 (m, 4H), 1.38 (d, J = 2.0 Hz, 6H), 1.32 - 1.29 (m, 3H).

[0252]

[0253] Compound 6 was prepared according to the method described in Example 1.

[0254] LCMS: m / z 420.2 (M+H) + 。

[0255] 1 1H NMR (400 MHz, methanol-d4) δ 8.61 - 8.44 (m, 2H), 7.74 - 7.64 (m, 2H), 7.56 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 6.79 (t, J = 74.9 Hz, 1H), 4.73 - 4.68 (m, 1H), 1.53 - 1.48 (m, 2H), 1.33 (d, J = 6.0 Hz, 6H), 1.32 - 1.28 (m, 2H).

[0256]

[0257] Compound 7 was prepared according to the method described in Example 1.

[0258] LCMS: m / z 433.1 (M+H) + 。

[0259] 1 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.14 (s, 1H), 7.87 - 7.86 (m, 2H), 7.55 – 7.50 (m, 2H), 7.33 – 6.96 (m, 2H), 4.75 - 4.69 (m, 1H), 3.85 (s, 3H), 1.34 - 1.30 (m, 8H), 1.15 - 1.12 (m, 2H).

[0260]

[0261] Prepare compound 8 according to the method described in Example 1.

[0262] LCMS: m / z 420.1 (M+H) + 。

[0263] 1 H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.72 (s, 1H), 7.59 - 7.52 (m, 3H), 7.24 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.61 (t, J = 76.0 Hz, 1H), 4.72 - 4.65 (m, 1H), 1.57–1.55 (m, 2H), 1.40 (d, J = 8.0 Hz, 6H), 1.36 - 1.33 (m, 2H).

[0264]

[0265] Prepare compound 9 according to the method described in Example 1.

[0266] LCMS: m / z 448.1 (M+H) + 。

[0267] 1 H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.39 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.59–7.43 (m, 4H), 7.18 (d, J = 8.0 Hz, 1H), 6.60 (t, J = 76.0 Hz, 1H), 4.71 - 4.65 (m, 1H), 1.56 - 1.53 (m, 2H), 1.39 (d, J = 8.0 Hz, 6H), 1.35 - 1.32 (m, 2H).

[0268]

[0269] Prepare compound 10 according to the method described in Example 1.

[0270] LCMS: m / z 477.1 (M+H) + 。

[0271] 11H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.0, 2.0 Hz, 1H), 7.35 - 7.29 (m, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.80 - 6.42 (m, 4H), 4.70 - 4.67 (m, 1H), 3.90 (s, 3H), 1.62–1.58 (m, 2H), 1.40 (d, J = 6.1 Hz, 6H), 1.35 - 1.32 (m, 2H).

[0272]

[0273] Compound 11 was prepared according to the method described in Example 1.

[0274] LCMS: m / z 460.1 (M + H) + 。

[0275] 1 1H NMR (400 MHz, deuterated methanol - d4) δ 8.37 - 8.18 (m, 1H), 7.82 (s, 1H), 7.70 - 7.68 (m, 4H), 7.24 (d, J = 8.0 Hz, 1H), 6.80 (t, J = 76.0 Hz, 1H), 4.75 - 4.69 (m, 1H), 3.98 (s, 3H), 1.54 - 1.48 (m, 2H), 1.38 (d, J = 4.0 Hz, 6H), 1.33 - 1.29 (m, 2H).

[0276]

[0277] Compound 12 was prepared according to the method described in Example 1.

[0278] LCMS: m / z 477.1 (M + H) + 。

[0279] 1 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 8.22 (dd, J = 8.8, 7.2 Hz, 1H), 7.58–7.53 (m, 3H), 7.18 (d, J = 8.4 Hz, 1H), 6.81–6.76 (m, 1H), 6.73 - 6.69 (m, 1H), 6.60 (d, J = 75.2 Hz, 1H), 4.71 - 4.65 (m, 1H), 3.99 (s, 3H), 1.55 - 1.53 (m, 2H), 1.39 (d, J = 6.4 Hz, 6H), 1.29–1.26 (m, 2H).

[0280]

[0281] Prepare compound 13 according to the method described in Example 1.

[0282] LCMS: m / z 464.1 (M+H) + 。

[0283] 1 H NMR (400 MHz, methanol-d4) δ 8.58 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 8.4, 2.0 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H), 6.79 (t, J = 74.8 Hz, 1H), 4.76 - 4.70 (m, 1H), 1.55–1.52 (m, 2H), 1.38 (d, J = 6.0 Hz, 6H), 1.36 - 1.33 (m, 2H).

[0284]

[0285] Prepare compound 14 according to the method described in Example 1.

[0286] LCMS: m / z 466.1 (M+H) + 。

[0287] 1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.60 (s, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 8.4, 2.0 Hz, 1H), 7.37–7.31 (m, 1H), 7.19 (d, J = 8.4 Hz, 1H), 6.60 (t, J = 75.2 Hz, 2H), 4.71 - 4.65 (m, 1H), 1.54 - 1.53 (m, 2H), 1.43 (d, J = 6.0 Hz, 6H), 1.34–1.30 (m, 2H).

[0288]

[0289] Prepare compound 15 according to the method described in Example 1.

[0290] LCMS: m / z 433.0 (M+H) + 。

[0291] 11H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.92 (s, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.51 (dd, J = 8.4, 1.8 Hz, 1H), 7.36 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 74.0 Hz, 1H), 6.99 (d, J = 1.2 Hz, 1H), 4.76–4.70 (m, 1H), 3.93 (s, 3H), 1.34 - 1.28 (m, 8H), 1.24–1.21 (m, 2H).

[0292]

[0293] Compound 16 was prepared according to the method described in Example 1.

[0294] LCMS: m / z 436.1 (M + H) + 。

[0295] 1 1H NMR (400 MHz, DMSO-d6) δ 9.19 (d, J = 2.0 Hz, 1H), 9.16 (s, 1H), 8.35 (d, J = 2.0 Hz, 1H), 7.90 (s, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.51 (dd, J = 8.4, 2.0 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.14 (t, J = 74.0 Hz, 1H), 4.76–4.70 (m, 1H), 1.37 - 1.34 (m, 2H), 1.31 (d, J = 6.0 Hz, 6H), 1.26 - 1.23 (m, 2H).

[0296]

[0297] Compound 17 was prepared according to the method described in Example 1.

[0298] LCMS: m / z 450.1 (M + H) + 。

[0299] 1 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.92 (s, 1H), 7.89 (s, 1H), 7.58 (s, 1H), 7.53–7.47 (m, 1H), 7.35–6.88 (m, 2H), 4.82–4.59 (m, 1H), 2.74 (s, 3H), 1.35 - 1.30 (m, 8H), 1.23 - 1.21 (m, 2H).

[0300]

[0301]

[0302] Step 1: Synthesis of Intermediate 18b

[0303] At room temperature, add 18a (20 g, 99.8 mmol) and N,N-dimethylformamide (300 mL) to a 500 mL single-necked flask and stir until dissolved. Add N-bromosuccinimide (19.6 g, 110.1 mmol) to the reaction solution in portions. Stir the reaction solution at room temperature for 3 hours. Monitor by LCMS until the reaction is complete. Dilute the reaction solution with water (100 mL), and extract with ethyl acetate (100 mL × 3). Wash the combined organic phases with saturated brine (100 mL), and dry over anhydrous sodium sulfate. Concentrate the organic phase under reduced pressure, and purify the residue by flash column chromatography (ethyl acetate / petroleum ether) to obtain the target compound 18b (25.5 g).

[0304] 1 H NMR (400 MHz, CDCl3) δ 7.42 - 7.38 (m, 6H), 7.06 (d, J = 2.2 Hz, 1H), 7.01 (dd, J = 8.4, 2.2 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.07 (s, 2H).

[0305] Step 2: Synthesis of Intermediate 18c

[0306] At room temperature, add 18b (25.5 g, 91.3 mmol), diethyl bromodifluoromethylphosphonate (48.8 g, 182.7 mmol) and acetonitrile (300 mL) to a 500 mL single-necked flask in sequence and stir until dissolved. Slowly add a solution of potassium hydroxide (25.7 g, 458.1 mmol) in water (100 mL) to the reaction solution. Stir the reaction solution at room temperature for 18 hours. Monitor by TLC until the reaction is complete. Dilute the reaction solution with water (100 mL), and extract with ethyl acetate (100 mL × 3). Wash the combined organic phases with saturated brine (100 mL), and dry over anhydrous sodium sulfate. Concentrate the organic phase under reduced pressure, and purify the obtained residue by column chromatography (petroleum ether) to obtain 18c (14.5 g).

[0307] 1 H NMR (400 MHz, CDCl3) δ 7.46–7.30 (m, 6H), 7.16 (d, J = 1.8 Hz, 1H), 7.08–7.01 (m, 1H), 6.53 (t, J = 74.8 Hz, 1H), 5.10 (s, 2H).

[0308] Step 3: Synthesis of Intermediate 18d

[0309] At room temperature, 18c (14.5 g, 44.0 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (16.8 g, 66.1 mmol) and dioxane (250 mL) were successively added to a 500 mL single-necked flask and stirred until dissolved. Potassium acetate (8.7 g, 88.6 mmol) and bis[5-(diphenylphosphino)cyclopent-1,3-dien-1-yl]iron dichloride palladium (1 g, 1.3 mmol) were added to the reaction solution. The reaction solution was stirred at 90 °C for 18 hours under nitrogen protection. Monitored by LCMS, the reaction was completed. The reaction solution was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (150 mL × 3), the organic phase was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain the target compound 18d (14.1 g).

[0310] LCMS: m / z 375.2 (M-H) + 。

[0311] Step 4: Synthesis of intermediate 18e

[0312] At room temperature, 18d (13.5 g, 35.8 mmol), dioxane (240 mL) and water (80 mL) were added to a 50 mL single-necked flask and stirred until dissolved. Ethyl 2-chloro-1,3-oxazole-4-carboxylate (6 g, 34.1 mmol), bis[5-(diphenylphosphino)cyclopent-1,3-dien-1-yl]iron dichloride palladium (1.3 g, 1.7 mmol) and potassium phosphate (16.6 g, 72.086 mmol) were successively added to the reaction solution. The reaction solution was reacted at 70 °C for 18 hours under nitrogen protection. Monitored by LCMS, the reaction was completed. The reaction solution was cooled to room temperature, diluted with water (80 mL), extracted with ethyl acetate (100 mL × 3), the organic phase was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain the target compound 18e (8.2 g).

[0313] 1 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.70 - 7.68 (m, 1H), 7.47 - 7.33 (m, 5H), 7.41 (d, J = 7.6 Hz, 1H), 6.64 (t, J = 74.8 Hz, 1H), 5.21 (s, 2H), 4.43 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H).

[0314] Step 5: Synthesis of Intermediate 18f

[0315] At room temperature, add 18e (8 g, 20.5 mmol) and methanol (80 mL) to a 50 mL single-necked flask and stir until dissolved. Add 7M ammonia-methanol solution (80 mL, 560 mmol) to the reaction solution. The reaction solution is stirred at 60 °C for 18 hours. Monitored by LCMS, the reaction is completed. Filter and concentrate the reaction solution. The target compound 17q (6.9 g) is obtained.

[0316] LCMS: m / z 361.3 (M+1) + 。

[0317] Step 6: Synthesis of Intermediate 18g

[0318] At room temperature, add 18f (6.9 g, 19.1 mmol) and dichloromethane (50 mL) to a 50 mL single-necked flask and stir until dissolved. Add Burgess reagent (9.1 g, 38.2 mmol) to the reaction solution. The reaction solution is stirred at room temperature for 18 hours. Monitored by LCMS, the reaction is completed. Add water (10 mL) to dilute the reaction solution, extract with ethyl acetate (50 mL × 3), wash the organic phase with saturated brine (50 mL), and dry over anhydrous sodium sulfate. Concentrate the organic phase under reduced pressure, and purify the residue by column chromatography (ethyl acetate / petroleum ether) to obtain the target compound 18g (4.9 g).

[0319] LCMS: m / z 343.2 (M+H) + 。

[0320] Step 7: Synthesis of Intermediate 18h

[0321] At room temperature, add 18g (500 mg, 1.4 mmol) and a mixed solvent of toluene (10 mL) and diethyl ether (10 mL) to a 50 mL three-necked flask and stir until dissolved. Cool the reaction solution to -78 °C, add titanium tetraisopropoxide (0.5 mL, 1.7 mmol) and 3M ethylmagnesium bromide (1.2 mL, 3.6 mmol) to the reaction solution. The reaction solution is stirred at -78 °C for 30 minutes and then warmed to room temperature and stirred for another 1 hour. Add boron trifluoride diethyl ether complex (0.01 mL, 0.07 mmol) to the reaction solution. The reaction solution is stirred for another 2 hours. Monitored by LCMS, the reaction is completed. Add 1M hydrochloric acid (10 mL) to dilute the system, and adjust the pH to 10 with 1M sodium hydroxide solution. Extract the mixture with ethyl acetate (30 mL × 3). Wash the combined organic phases with saturated brine (30 mL) and dry over anhydrous sodium sulfate. Concentrate the organic phase under reduced pressure, and purify the residue by column chromatography (methanol / dichloromethane) to obtain the target compound 18h (458 mg).

[0322] LCMS: m / z 373.1 (M+H) + 。

[0323] Step 8: Synthesis of Intermediate 18i

[0324] At room temperature, add 18h (600 mg, 1.61 mmol), 1-methyl-1H-imidazole-2-carboxylic acid (203 mg, 1.61 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.23 g, 3.23 mmol), N,N-diisopropylethylamine (416 mg, 3.23 mmol) and N,N-dimethylformamide (10 mL) to a 50 mL single-necked flask in sequence and stir until dissolved. Stir the reaction mixture at room temperature for 6 hours. Dilute the reaction mixture with water (40 mL), and extract with ethyl acetate (20 mL × 3). Wash the combined organic phases with saturated brine (100 mL), and dry over anhydrous sodium sulfate. Concentrate the organic phase under reduced pressure, and purify the residue by column chromatography (ethyl acetate / petroleum ether) to obtain 18i (499 mg).

[0325] LCMS m / z 480.6 (M+H) + 。

[0326] Step 9: Synthesis of Intermediate 18j

[0327] At room temperature, add 18i (499 mg, 1.04 mmol) and anhydrous methanol (10.0 mL) to a 25 mL three-necked flask and stir until completely dissolved. Add 10% palladium on carbon (40 mg) to the reaction mixture. Stir the reaction mixture under a hydrogen balloon at room temperature for 16 hours. Monitor by LCMS until the reaction is complete. Filter the reaction mixture, and concentrate the filtrate to obtain the target compound 18j (368 mg).

[0328] LCMS: m / z 391.1 (M+H) + 。

[0329] Step 10: Synthesis of Compound 18

[0330] At room temperature, add 18j (100 mg, 0.26 mmol), (S)-tetrahydrofuran-3-ol (22.56 mg, 0.26 mmol), triphenylphosphine (100.79 mg, 0.38 mmol) and tetrahydrofuran (5 mL) to a 25 mL three-necked flask in sequence and stir until dissolved. Add diisopropyl azodicarboxylate (93.57 mg, 0.41 mmol) to the reaction mixture. Stir the reaction mixture at room temperature for 16 hours. Monitor by LCMS until the reaction is complete. Concentrate the reaction mixture under reduced pressure, and purify the residue by preparative liquid chromatography to obtain the target compound 18 (8.45 mg).

[0331] LCMS: m / z 461.1 (M+H) + 。

[0332] 1 H NMR (400 MHz, deuterated methanol-d4) δ 7.82 (s, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.24 (s, 1H), 6.80 (t, J = 74.8 Hz, 1H), 5.17 - 5.15 (m, 1H), 4.03 (s, 3H), 4.02–3.96 (m, 3H), 3.93 - 3.88 (m, 1H), 2.35–2.25 (m, 1H), 2.20 - 2.14 (m, 1H), 1.52 - 1.48 (m, 2H), 1.35 - 1.31 (m, 2H).

[0333]

[0334] Compound 19 was prepared according to the method described in Example 18.

[0335] LCMS: m / z 461.1 (M+H) + 。

[0336] 1 H NMR (400 MHz, deuterated methanol-d4) δ 7.84 (s, 1H), 7.65 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.27 (d, J = 8.4 Hz, 2H), 6.80 (t, J = 74.8 Hz, 1H), 5.17 - 5.16 (m, 1H), 4.05 (s, 3H), 4.02 - 3.96 (m, 3H), 3.93 - 3.88 (m, 1H), 2.35 - 2.29 (m, 1H), 2.20–2.14 (m, 1H), 1.52–1.49 (m, 2H), 1.35 - 1.32 (m, 2H).

[0337]

[0338] Compound 20 was prepared according to the method described in Example 18.

[0339] LCMS: m / z 447.1 (M+H) + 。

[0340] 11H NMR (400 MHz, methanol-d4) δ 7.78 (s, 1H), 7.62 (dd, J = 8.4, 1.8 Hz, 1H), 7.30 - 7.28 (m, 2H), 7.24 (s, 1H), 7.07 - 6.70 (m, 2H), 5.48–5.36 (m, 1H), 5.06 (t, J = 6.8 Hz, 2H), 4.77 - 4.74 (m, 2H), 4.00 (s, 3H), 1.50 - 1.47 (m, 2H), 1.32 - 1.29 (m, 2H).

[0341]

[0342] Step 1: Synthesis of Intermediate 21a

[0343] At room temperature, 18h (620 mg, 1.67 mmol), thiazole-4-carboxylic acid (215 mg, 1.67 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (760 mg, 2.00 mmol), N,N-diisopropylethylamine (431 mg, 3.34 mmol) and N,N-dimethylformamide (10 mL) were successively added to a 25 mL single-necked flask. The reaction mixture was stirred at 20 °C for 6 hours. Monitored by LCMS, the reaction was completed. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate) to obtain 21a (483 mg).

[0344] LCMS: m / z: 484.0 (M+H) + .

[0345] Step 2: Synthesis of Intermediate 21b

[0346] At room temperature, 21b (200 mg, 0.41 mmol), trimethylsilyl iodide (331 mg, 1.65 mmol) and acetonitrile (4 mL) were successively added to a 25 mL single-necked flask and stirred until dissolved. The reaction mixture was stirred at 60 °C for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (50 mL), washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the residue was purified by preparative thin-layer chromatography to obtain 21c (86 mg).

[0347] LCMS: m / z 394.0 (M+H) + .

[0348] Step 3: Synthesis of Compound 21

[0349] At room temperature, 21c (40 mg, 0.11 mmol), (S)-tetrahydrofuran-3-ol (35.2 mg, 0.41 mmol), triphenylphosphine (107 mg, 0.41 mmol) and tetrahydrofuran (5 mL) were successively added to a 25 mL three-necked flask and stirred until dissolved. Diisopropyl azodicarboxylate (82.2 mg, 0.408 mmol) was added to the reaction solution. The reaction solution was stirred at room temperature for 16 hours. Monitored by LCMS, the reaction was completed. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain the target compound 21 (9.37 mg).

[0350] LCMS: m / z 464.2 (M + H) + 。

[0351] 1 H NMR (400 MHz, methanol-d4) δ 9.02 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.74 (s, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.60 (dd, J = 8.4, 2.0 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 74.4 Hz, 1H), 5.18 - 5.16 (m, 1H), 4.02 - 3.88 (m, 4H), 2.32 - 2.26 (m, 1H), 2.18 - 2.16 (m, 1H), 1.53 - 1.50 (m, 2H), 1.35 - 1.32 (m, 2H).

[0352]

[0353] Compound 22 was prepared according to the method described in Example 21.

[0354] LCMS: m / z 464.0 (M + H) + 。

[0355] 1 H NMR (400 MHz, methanol-d4) δ 9.02 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.74 (s, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.60 (dd, J = 8.4, 2.0 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 74.4 Hz, 1H), 5.18 - 5.17 (m, 1H), 4.03 - 3.88 (m, 4H), 2.35 - 2.26 (m, 1H), 2.19 - 2.14 (m, 1H), 1.53 - 1.50 (m, 2H), 1.34 - 1.32 (m, 2H).

[0356]

[0357] Prepare compound 23 according to the method described in Example 21.

[0358] LCMS: m / z 450.0 (M+H) + 。

[0359] 1 H NMR (400 MHz, methanol-d4) δ 9.02 (d, J = 1.6 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.73 (s, 1H), 7.62 (dd, J = 8.4, 1.6 Hz, 1H), 7.29 - 7.28 (m, 2H), 6.88 (t, J = 74.0 Hz, 1H), 5.42 - 5.38 (m, 1H), 5.05 (t, J = 6.8 Hz, 2H), 4.76 - 4.73 (m, 2H), 1.51 - 1.49 (m, 2H), 1.34 - 1.32 (m, 2H).

[0360]

[0361] Prepare compound 24 according to the method described in Example 21.

[0362] LCMS: m / z: 501.2 (M+H) + 。

[0363] 1 H NMR (400 MHz, methanol-d4) δ 7.80–7.78 (m, 2H), 7.65 (s, 1H), 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 7.48–7.45 (m, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.80 (t, J = 74.8 Hz, 1H), 5.18-5.17 (m, 1H), 4.23 (q, J = 7.0 Hz, 2H), 4.08-3.95 (m, 3H), 3.91-3.88 (m, 1H), 2.33-2.28 (m, 1H), 2.19-2.15 (m, 1H), 1.53-1.50 (m, 5H), 1.30-1.28 (m, 2H).

[0364]

[0365] Prepare compound 25 according to the method described in Example 21. + 。

[0366] 1 1H NMR (400 MHz, methanol-d4) δ 9.06 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.66 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.47 (t, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.07 (s, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.79 (t, J = 74.8 Hz, 1H), 4.73 - 4.67 (m, 1H), 4.21 (q, J = 7.2 Hz, 2H), 1.54 - 1.51 (m, 2H), 1.48 (t, J = 8.0 Hz, 3H), 1.42 - 1.39 (m, 2H), 1.37 (d, J = 6.0 Hz, 6H)

[0367]

[0368] Compound 26 was prepared according to the method described in Example 21.

[0369] LCMS: m / z 432.1 (M + H) + 。

[0370] 1 1H NMR (400 MHz, methanol-d4) δ 7.66 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 8.0, 1.6 Hz, 1H), 7.27 (s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.06 - 7.05 (m, 2H), 6.80 (t, J = 74.8 Hz, 1H), 4.72 - 4.70 (m, 1H), 4.00 (s, 3H), 1.53 - 1.49 (m, 2H), 1.43 - 1.39 (m, 2H), 1.37 (d, J = 6.4 Hz, 6H).

[0371]

[0372] Compound 27 was prepared according to the method described in Example 21.

[0373] LCMS: m / z 435.1 (M + H) + 。

[0374] 11H NMR (400 MHz, methanol-d4) δ 9.02 (d, J = 2.0 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 8.4, 2.0 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.03 (s, 1H), 6.79 (t, J = 74.8 Hz, 1H), 4.74 - 4.68 (m, 1H), 1.54 - 1.51 (m, 2H), 1.45 - 1.41 (m, 2H), 1.37 (d, J = 6.0 Hz, 6H).

[0375]

[0376] Compound 28 was prepared according to the method described in Example 1.

[0377] LCMS: m / z: 459.1 (M+H) + 。

[0378] 1 1H NMR (400 MHz, methanol-d4) δ 9.03 (s, 1H), 7.79 - 7.78 (m, 2H), 7.67 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 8.0, 2.0 Hz, 1H), 7.49 - 7.45 (m, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 6.82 (t, J = 76.0 Hz, 1H), 4.26 - 4.16 (m, 4H), 1.53 - 1.44 (m, 8H), 1.30 - 1.27 (m, 2H).

[0379] Biological evaluation

[0380] 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.

[0381] The structure of Compound A is:

[0382]

[0383] Compound A was prepared by the method disclosed in Example 1 on page 25 of the specification of Patent Application "CN104603116A".

[0384] Test Example 1: In vitro PDE4B enzyme activity detection experiment

[0385] 1. Experimental materials

[0386] Name Brand Article number / Model PDE4B1 BPS 60041 Trequinsin T℃RIS 2337 / 10 IMAP FP IPP Explorer Kit Molecular Device R8124 FAM-cAMP Molecular Device R7506 <![CDATA[OptiPlate TM -384F black assay plate]]> PerkinElmer 6007279 384-well Echo plate Labcyte PP-0200

[0387] 2. Experimental procedures

[0388] For compound testing, a 10 mM compound stock solution was first prepared in a test tube with 90% DMSO (10% water), and a series of dilutions with a dilution gradient of 1:5 were prepared using it, with the final concentrations starting from 100 μM and going as low as 0.05 nM. For enzyme assays, 0.2 μl of the compound solution was transferred into a 384-well reaction plate, and both the negative control and positive control were transferred with 0.2 μl of 100% DMSO. Then, 10 μl of 2-fold concentrated PDE4B1 enzyme solution (final concentration 0.04 nM) was added to the wells. For the enzyme-free control wells, the enzyme solution was replaced with 10 μl of 1-fold reaction buffer. Centrifuge at 1000 rpm for 1 min and incubate at room temperature for 15 minutes. Next, 10 μl of 2-fold FAM-cAMP substrate solution (substrate final concentration 0.1 μM) was added to each well of the 384-well reaction plate, centrifuge at 1000 rpm for 1 min, and react at 25 °C for 30 minutes. After the reaction, 60 μl of reaction termination solution was added to each well of the 384-well reaction plate to terminate the reaction, and incubate in the dark with shaking at 600 rpm at room temperature for 60 minutes. After incubation, the RLU data was read and the inhibition rate was calculated, and the IC 50 value was calculated by fitting a curve based on the concentration and inhibition rate, where the maximum value refers to the reading of the DMSO control and the minimum value refers to the reading of the enzyme-free control.

[0389] The inhibition of PDE4B1 enzyme activity in the examples of the present disclosure was measured through the above tests, and the measured IC 50 values are shown in Table 1.

[0390]

[0391]

[0392] Note: N / A not detected

[0393] Test Example 2: Inhibitory effect of compounds on the release of pro-inflammatory cytokines from peripheral blood mononuclear cells (PBMCs)

[0394] Thaw the cryopreserved PBMCs, and use trypan blue staining to detect cell viability and number. Wash the thawed PBMCs with RPMI1640 complete medium (RPMI1640 + 10% FBS + 1% PS), and discard the supernatant after centrifugation. Resuspend the PBMCs with RPMI1640 complete medium and adjust the cell density to 2×10 6 cells / mL. Seed 2×10 5PBMC cells were placed in a 96-well cell culture plate, and different concentrations of the test compound were added. Starting from the maximum concentration of the compound, 100 μM, nine concentration gradients were diluted in a 1:5 ratio, and double replicates were detected. LPS with a final concentration of 0.1 ng / mL was added, and the total volume was 200 μL. Negative and positive controls were set. In the negative control wells, only LPS and DMSO at the final concentration were added. In the positive control wells, in addition to cells and LPS, 1 μg / mL of dexamethasone was added as a positive control. The cells were incubated in an incubator at 37 °C for 24 hours. After incubation, 100 μL of cell culture supernatant was collected, and the level of TNF-α was detected by ELISA. 100 μL of CellTiter-Glo was added to the remaining cells in each well to detect the cell viability level. Calculate the IC 50 value.

[0395] The inhibition of PBMC pro-inflammatory cytokine release in vitro in the examples of the present disclosure was determined by the above tests, and the measured IC 50 values are shown in Table 2.

[0396] Table 2

[0397]

[0398]

[0399] Test Example 3 Allergic dermatitis inhibition experiment

[0400] An appropriate amount of Compound 21 was formulated into an ointment with the following components: 1% of Compound 21, 10% of glyceryl triacetate, 62.5% of white petrolatum, 20% of liquid paraffin, 3% of paraffin, and 3.5% of white beeswax, and mechanically stirred until it became an ointment

[0401] Model establishment and drug administration:

[0402] CD-1 male mice were selected. On the experimental day, the ear thickness was measured at a fixed position on the left ear of the experimental mice (MDC-1

[0403] “SB, Mitutoyo Corporation). Then, 20 μL of a solution of phorbol 12-myristate 13-acetate (PMA, P1585, Sigma) in acetone (2 μg / ear) was applied to the left ear 2 hours before and 15 minutes after inducing ear swelling. 10 mg of the test substance, positive drug, or blank preparation was applied to both the inner and outer surfaces of the left ear, that is, 20 mg / ear. The ear thickness was measured 6 hours after the application of PMA. In this experiment, a normal control group, a model control group, low, medium, and high dose groups, and a reference compound group were set.

[0404] Evaluation indices: The change in ear thickness 6 hours after PMA-induced ear swelling and the swelling inhibition rate ([IC - IT] / IC × 100%, where IC and IT are the increases in ear thickness (mm) of mice in the control group and the treatment group, respectively) were used as inflammation indices; the change in body weight 24 hours after PMA induction was used as an index of systemic toxic side effects.

[0405] Experimental results: Compound 21 could dose-dependently inhibit PMA-induced ear swelling in mice. The inhibition rates in the low, medium, and high dose groups were significantly higher than those in the model group, and the ear swelling inhibition rates were 36.7 ± 14.5%, 81.0% ± 18.5%, and 93.9 ± 5.9% (mean ± SD), respectively. The low and high doses of reference compound A also had inhibitory effects on PMA-induced ear swelling in mice, and the ear swelling inhibition rates in the low and high dose groups were 12.7% ± 16.2% and 45.3% ± 23.0% (mean ± SD), respectively.

[0406] The above results indicate that the therapeutic effect of compound 21 in the PMA-induced skin inflammation model is better than that of reference compound A.

Claims

1. The compound represented by Formula VA or a pharmaceutically acceptable salt thereof Among them, R 2 selected from phenyl or a 5- to 6-membered heteroaryl ring, said phenyl or 5- to 6-membered heteroaryl ring being optionally substituted by 1 to 3 substituents selected from deuterium, halogen, hydroxy, C 1-6 alkyl or C 1-6 alkoxy, said alkyl or alkoxy being optionally substituted by 1 to 3 R A2 substituents; R A2 Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl, 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, C 6-10 aryl or 5- to 6-membered heteroaryl, wherein 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, C 6-10 aryl or 5- to 6-membered heteroaryl is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino; R 6 、R 7 、R 8 、R 9 or R 10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, 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 cycloalkenyloxy, and the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, cycloalkyl, heterocycloalkoxy or heterocycloalkyl is optionally substituted by one or more R A1 . R A1 selected from 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 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, wherein 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, aryl or 5- to 6-membered heteroaryl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino; R A4 selected from halogen, deuterium, nitro or cyano; p is an integer between 0 and 3.

2. The compound or its pharmaceutically acceptable salt according to claim 1, wherein R 8 is selected from C 1-6 alkoxy, the alkoxy being optionally substituted by 1 to 3 R A1 as defined in claim 1. A1 ​ 3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 7 is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, and the alkyl or alkoxy is optionally substituted by 1 to 3 R A1 as defined in claim 1. A1 as defined in claim 1.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 7 is selected from C 1-6 alkoxy, the alkoxy being optionally substituted by 1 to 3 R A1 as defined in claim 1. A1 ​ 5. The compound or its pharmaceutically acceptable salt according to claim 1 or 2, wherein R 7 is selected from 3- to 6-membered heterocyclic alkoxy.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 7 is selected from heterocyclic alkoxy groups containing at least one heteroatom selected from N, O or S, and the heterocyclic alkoxy group is optionally substituted by 1 to 3 R A1 as defined in claim 1. A1 as defined in claim 1.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 6 , R 9 or R 10 is selected from hydrogen or deuterium.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein p = 0, 1 or 2.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein p = 0.

10. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R A1 is selected from halogen, deuterium, nitro or cyano.

11. The compound or a pharmaceutically acceptable salt thereof according to claim 9, wherein R A1 is selected from halogen.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 10, wherein R A1 is selected from fluorine.

13. The compound or its pharmaceutically acceptable salt according to claim 1 or 2, wherein R A2 is selected from halogen, deuterium, nitro or cyano.

14. The compound or a pharmaceutically acceptable salt thereof according to claim 12, wherein R A2 is selected from halogen.

15. The compound or a pharmaceutically acceptable salt thereof according to claim 13, wherein R A2 is selected from fluorine.

16. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is selected from thiazolyl, imidazolyl, pyridyl, oxazolyl, pyrimidinyl or pyrazolyl, and further wherein said R 2 is optionally substituted by one or more substituents selected from deuterium, halogen, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy, and said alkyl or alkoxy is optionally substituted by one or more R A2 wherein R A2 is as defined in claim 1.

17. The compound or a pharmaceutically acceptable salt thereof according to claim 16, wherein R 2 is selected from thiazolyl, the thiazolyl being optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy, the alkyl or alkoxy being optionally substituted with one or more R A2 as defined in claim 1. A2 as defined in claim 1.

18. The compound or a pharmaceutically acceptable salt thereof according to claim 16, wherein R 2 is selected from imidazolyl, said imidazolyl being optionally substituted by one or more members selected from deuterium, halogen, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy, said alkyl or alkoxy being optionally substituted by one or more R A2 as defined in claim 1, A2 wherein R is as defined in claim 1.

19. The compound or a pharmaceutically acceptable salt thereof 20. The compound or a pharmaceutically acceptable salt thereof according to claim 19, which is selected from 21. A pharmaceutical composition comprising at least one therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 20 and a pharmaceutically acceptable excipient.

22. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 20, or the pharmaceutical composition according to claim 21, in the manufacture of a medicament for preventing and / or treating PDE - related disorders.

23. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 20, or the pharmaceutical composition according to claim 21, in the manufacture of a medicament for preventing and / or treating asthma, obstructive lung disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis or rheumatism.

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