Compounds with bromodomain inhibitory activity and application thereof

Abstract

The invention belongs to the technical field of chemical medicines, and provides a bromodomain inhibitory activity compound and application thereof, and the compound has a structure as shown in a formula I; the compound provided by the invention can selectively inhibit the BET family BD2 bromodomain, and can be used as a new generation of bromodomain inhibitor for treating BET related diseases such as cancer, inflammation and the like.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemical medicine, and relates to a kind of bromodomain inhibitory activity compound and its use, especially to a kind of furanopyridinone compound as BET bromodomain inhibitor and its use. BACKGROUND

[0002] The dysfunction of epigenetic regulation is a common feature of cancer occurrence and development. Bromodomain is an epigenetic reader that specifically recognizes acetylated lysine of histone, can mediate protein-protein interaction, regulate chromatin structure opening and gene transcription, and bromodomain has become a hot new target in the field of cancer treatment with promising drug development prospects.

[0003] In human genome, 61 bromodomains are found in 46 proteins. At present, bromodomains are divided into 8 families according to sequence similarity. The bromodomain and extra-terminal domain (BET) family is the second family of bromodomains, which consists of four family members BRD4, BRD3, BRD2 and BRDT (bromodomain testis-specific protein). Structurally, BET family proteins have two N-terminal tandem bromodomains (BD1 and BD2). Under normal circumstances, BET family proteins are located in the nucleus, specifically bind to acetylated lysine residues in histone through BD1 and BD2 bromodomains, recruit transcriptional regulatory complexes, and thus participate in many DNA-centered life processes.

[0004] As a "reader" of lysine acetylation modification, BET bromodomain plays an important role in the regulation of signal transduction and gene network. Studies have found that overexpression of BET family proteins is highly related to the occurrence and development of many diseases such as cancer and inflammation. BET proteins can directly activate the transcription of oncogenes by binding to the hyperacetylated regulatory region of chromatin. BET proteins can also interact with transcriptional mediator complexes, thereby participating in the core transcription mechanism. The transcriptional mediator complex provides a platform for BET proteins to interact with P-TEFb, and causes phosphorylation of RNAPOL II, promoting transcriptional elongation of oncogenes. At present, several BET bromodomain inhibitors have entered clinical research.

[0005] The first generation of Pan-BET inhibitors have dose-limiting toxicities (DLT), such as thrombocytopenia, diarrhea, fatigue, nausea and vomiting, and hyperbilirubinemia. The phase I trial of BAY1238097 was terminated early due to serious toxic effects, and the compound INCB057643 was also terminated for safety reasons. The occurrence of toxic side effects limits the clinical advancement of BET inhibitors. Improving the target selectivity of BET bromodomain inhibitors and developing the next generation of BET inhibitors with BD1 or BD2 selectivity is the key to reducing toxic side effects.

[0006] AbbVie has disclosed a series of BET BD2 selective inhibitors in patent CN109071534, among which the compound ABBV-744 shows excellent efficacy and better safety, and the compound has entered the clinical stage. NUVATION has recently disclosed a BET BD2 selective inhibitor NUV-868, which also has better safety compared to the first generation of Pan-BET inhibitors, and is also in clinical research.

[0007] Therefore, developing a new generation of new and efficient BET inhibitors with BD2 selectivity has better clinical application prospects. SUMMARY

[0008] In view of the deficiencies of the prior art, the purpose of the present application is to provide a kind of bromodomain inhibition activity compound and its use. The present application takes BET protein as the target, and develops a kind of novel compound, which can selectively inhibit the binding of BET family bromodomain and acetylated lysine. It is used for treating cancer, inflammation and other BET related diseases.

[0009] In order to achieve the purpose of the present application, the following technical solutions are adopted:

[0010] In one aspect, the present application provides a compound, which has the structure shown in the following formula I:

[0011]

[0012] wherein: M1 and M2 are independently selected from N, NH, O and S;

[0013] X1, X2 and X3 are independently selected from N and C;

[0014] R1 is selected from hydrogen, C1-C15 alkyl, C1-C15 cycloalkyl, C1-C15 alkyl-substituted cycloalkyl, C1-C15 oxygen-containing alkyl, C1-C15 nitrogen-containing alkyl, C1-C15 sulfur-containing alkyl, oxygen-containing 3- to 7-membered saturated ring, sulfur-containing 3- to 7-membered saturated ring or nitrogen-containing 3- to 7-membered saturated ring, unsubstituted or substituted with R isubstituted C6-C15aryl;

[0015] said R i selected from hydrogen, C1-C10alkyl, C1-C10alkoxy, or -O(C1-C5alkyl)OH;

[0016] R2is selected from hydrogen, C1-C7alkyl, C1-C7cycloalkyl, C1-C7alkyl-substituted cycloalkyl, C1-C7oxygen-containing alkyl, C1-C7nitrogen-containing alkyl, C1-C7sulfur-containing alkyl, oxygen-containing 3- to 5-membered saturated ring, sulfur-containing 3- to 5-membered saturated ring, or nitrogen-containing 3- to 5-membered saturated ring;

[0017] R3, R9, and R 10 are each independently selected from H, halogen, C1-C6alkyl, C1-C6alkoxy;

[0018] R7is selected from C1-C10alkoxy, -(R a )2OH, -(R b )2OCR c , -CH2S(O)2R d , -NHS(O)2R e , -NHC(O)R f , or -S(O)2NR g R h ; R a , R b , R c , R d , R e , R f , R g , and R h are each independently selected from H, C1-C10alkyl.

[0019] R4, R5, and R6are each independently selected from H, halogen;

[0020] R8is selected from C1-C4alkyl or deuterated C1-C4alkyl.

[0021] In one embodiment, said M1is selected from N, M2is selected from NH, or M1is selected from NH, M2is selected from N.

[0022] In one embodiment, said compound has a structure according to Formula II:

[0023]

[0024] X1, X2, and X3are independently selected from being N, C;

[0025] R1is selected from hydrogen, C1-C15alkyl, C1-C15cycloalkyl, C1-C15alkyl- substituted cycloalkyl, C1-C15oxygen-containing alkyl, C1-C15nitrogen-containing alkyl, C1-C15sulfur-containing alkyl, oxygen-containing 3- to 7-membered saturated ring, sulfur-containing 3- to 7-membered saturated ring, or nitrogen-containing 3- to 7-membered saturated ring, unsubstituted or substituted C6-C15aryl; i unsubstituted or substituted C6-C15aryl;

[0026] R1is selected from hydrogen, C1-C15alkyl, C1-C15cycloalkyl, C1-C15alkyl- substituted cycloalkyl, C1-C15oxygen-containing alkyl, C1-C15nitrogen-containing alkyl, C1-C15sulfur-containing alkyl, oxygen-containing 3- to 7-membered saturated ring, sulfur-containing 3- to 7-membered saturated ring, or nitrogen-containing 3- to 7-membered saturated ring, unsubstituted or substituted C6-C15aryl; i C1-C10alkyl, C1-C10alkoxy, or -0(C1-C5alkyl)OH;

[0027] R2is selected from hydrogen, C1-C7alkyl, C1-C7cycloalkyl, C1-C7alkyl-substituted cycloalkyl, C1-C7oxygen-containing alkyl, C1-C7nitrogen-containing alkyl, C1-C7sulfur-containing alkyl, oxygen-containing 3- to 5-membered saturated ring, sulfur-containing 3- to 5-membered saturated ring, or nitrogen-containing 3- to 5-membered saturated ring;

[0028] R3, R9, and R 10 are each independently selected from H, halogen, C1-C6alkyl, C1-C6alkoxy;

[0029] R7is selected from C1-C10alkoxy, -(R a )2OH, -(R b )2OCR c , -CH2S(O)2R d , -NHS(O)2R e , -NHC(O)R f , or -S(O)2NR g R h ; R a , R b , R c , R d , R e , R f , R g , and R h are each independently selected from H, C1-C10alkyl.

[0030] R4, R5, and R6are each independently H, halogen.

[0031] In some preferred embodiments, R7is selected from C1-C10alkoxy.

[0032] In some preferred embodiments, R8is selected from methyl.

[0033] In another embodiment, the compound has the structure shown in Formula III:

[0034] R1is selected from hydrogen, C1-C15alkyl, C1-C15cycloalkyl, C1-C15alkyl- substituted cycloalkyl, C1-C15oxygen-containing alkyl, C1-C15nitrogen-containing alkyl, C1-C15sulfur-containing alkyl, oxygen-containing 3- to 7-membered saturated ring, sulfur-containing 3- to 7-membered saturated ring, or nitrogen-containing 3- to 7-membered saturated ring, unsubstituted or substituted C6-C15aryl;

[0035] X1, X2and X3are independently selected from N, C;

[0036] R1is selected from hydrogen, C1-C15alkyl, C1-C15cycloalkyl, C1-C15alkyl substituted cycloalkyl, C1-C15oxygen containing alkyl, C1-C15nitrogen containing alkyl, C1-C15sulfur containing alkyl, oxygen containing 3- to 7-membered saturated ring, sulfur containing 3- to 7-membered saturated ring, or nitrogen containing 3- to 7-membered saturated ring, unsubstituted or substituted C6-C15aryl; i unsubstituted or substituted C6-C15aryl;

[0037] said R i is selected from hydrogen, C1-C10alkyl, C1-C10alkoxy, or -O(C1-C5alkyl)OH;

[0038] R2is selected from hydrogen, C1-C7alkyl, C1-C7cycloalkyl, C1-C7alkyl substituted cycloalkyl, C1-C7oxygen containing alkyl, C1-C7nitrogen containing alkyl, C1-C7sulfur containing alkyl, oxygen containing 3- to 5-membered saturated ring, sulfur containing 3- to 5-membered saturated ring, or nitrogen containing 3- to 5-membered saturated ring;

[0039] R3is each independently selected from H, halogen, C1-C6alkyl, C1-C6alkoxy;

[0040] R4, R5, and R6are each independently selected from H, halogen;

[0041] R7is selected from C1-C3alkoxy.

[0042] In some preferred embodiments, R3is each independently selected from H, halogen.

[0043] In some preferred embodiments, R1is selected from hydrogen, C1-C15alkyl, C1-C15cycloalkyl, C1-C15alkyl substituted cycloalkyl, C1-C15oxygen containing alkyl, oxygen containing 3- to 7-membered saturated ring, unsubstituted or substituted C6-C15aryl; said R i is selected from hydrogen, C1-C6alkyl, C1-C6alkoxy, or -O(C1-C5alkyl)OH; R2is selected from hydrogen, C1-C7alkyl, C1-C7cycloalkyl, C1-C7alkyl substituted cycloalkyl, C1-C7oxygen containing alkyl, oxygen containing 3- to 5-membered saturated ring. i

[0044] In some preferred embodiments, X2is selected from C.

[0045] In some preferred embodiments, R4, R5, and R6are each independently selected from H, fluorine, chlorine.

[0046] ​In some preferred embodiments, R1 is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Unreplaced or R i Substituted C6-C15 aryl; the R i The R2 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, or -O(C1-C5 alkyl)OH. The R2 is selected from hydrogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, cyclopropyl, C1-C5 oxygen-containing alkyl, oxygen-containing 3-membered saturated ring, oxygen-containing 4-membered saturated ring, and oxygen-containing 5-membered saturated ring.

[0047] In a preferred embodiment, the compound of the present invention is any one of the following compounds:

[0048] 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(2-((3,5-dimethylpyridin-4-yl)oxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methylfuran[3,2-c]pyridin-4(5H)-one

[0049] 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(3-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methylfuran[3,2-c]pyridin-4(5H)-one

[0050] 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)pyridin-3-yl)-5-methylfuran[3,2-c]pyridin-4(5H)-one

[0051] 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methylfuran[3,2-c]pyridine-4(5H)-one

[0052] 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(hydroxymethyl)phenyl)-5-methylfuran[3,2-c]pyridin-4(5H)-one

[0053] 2-(2-cycloheptyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methylfuran[3,2-c]pyridin-4(5H)-one

[0054] 2-(2-(adamantan-1-yl)-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0055] 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methyl-2-(2- phenyl-1H-imidazol-5-yl)furo[3,2-c]pyridin-4(5H)-one

[0056] 2-(2-(adamantan-1-yl)-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0057] 2-(2-(adamantan-1-yl)-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0058] 2-(2-(adamantan-1-yl)-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0059] 2-(2-(adamantan-1-yl)-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0060] 2-(2-(adamantan-1-yl)-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0061] 2-(2-(adamantan-1-yl)-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0062] 2-(2-(adamantan-1-yl)-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0063] 2-(2-cyclohexyl-4-ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0064] 2-(2-cycloheptyl-4-ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0065] 2-(2-(bicyclo[2.2.1]heptan-2-yl)-4-ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0066] 2-(2-(adamantan-1-yl)-4-ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0067] 2-(2,4-dimethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0068] 2-(2-ethyl-4-methyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0069] 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(2-isopropyl-4- methyl-1H-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0070] 2-(2-cyclopropyl-4-methyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0071] 2-(2-cyclobutyl-4-methyl-1 H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0072] 2-(4-ethyl-2-methyl-1 H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0073] 2-(2,4-dimethyl-1 H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0074] 2-(4-ethyl-2-isopropyl-1 H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0075] 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methyl-2-(2- methyl-4-propyl-1 H-imidazol-5-yl)furo[3,2-c]pyridin-4(5H)-one

[0076] 2-(2-ethyl-4-propyl-1 H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0077] 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(4-isopropyl-2- methyl-1 H-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0078] 2-(2-ethyl-4-isopropyl-1 H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0079] 2-(2-ethyl-4-(methoxymethyl)-1 H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5- (2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0080] 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(2-isopropyl-4- (methoxymethyl)-1 H-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0081] 2-(2-cyclopropyl-4-(methoxymethyl)-1 H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5- (2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0082] 2-(2-cyclobutyl-4-(methoxymethyl)-1 H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5- (2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0083] 2-(2,4-dimethyl-1 H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0084] 2-(2-ethyl-4-methyl-1 H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0085] 7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(2-isopropyl- 4-methyl-1 H-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0086] 2-(2-cyclopropyl-4-methyl-1 H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5- (2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0087] 2-(2-cyclobutyl-4-methyl-1 H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5- (2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0088] 2-(4-ethyl-2-methyl-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0089] 2-(2,4-diethyl-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0090] 2-(4-ethyl-2-isopropyl-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0091] 7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methyl-2-(2- methyl-4-propyl-1H-imidazol-5-yl)furo[3,2-c]pyridin-4(5H)-one

[0092] 2-(2-ethyl-4-propyl-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0093] 7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(4-isopropyl-2- methyl-1H-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0094] 2-(2-ethyl-4-isopropyl-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0095] 2-(2-ethyl-4-(methoxymethyl)-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0096] 7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(2- isopropyl-4-(methoxymethyl)-1H-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0097] 2-(2-cyclopropyl-4-(methoxymethyl)-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0098] 2-(2-cyclobutyl-4-(methoxymethyl)-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0099] 2-(2-(adamantan-1-yl)-1H-imidazol-5-yl)-7-(3-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)- 5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(4H)-one

[0100] 7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5- methyl-2-(2-phenyl-1H-imidazol-5-yl)furo[3,2-c]pyridin-4(5H)-one

[0101] In another aspect, the present application provides pharmaceutically acceptable salts of the compounds as described above.

[0102] In the present application, the pharmaceutically acceptable salts are salts of the compounds and appropriate inorganic or organic acids in a suitable solvent or a combination of solvents to prepare a salt of a basic compound. Similarly, a salt of an acidic compound is formed by reaction with an appropriate inorganic base or organic base.

[0103] For example, the pharmaceutically acceptable salts of the compounds of the present application include the conventional nontoxic salts of the compounds of the present application as formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, or organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzoic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid.

[0104] In the present application, the synthetic route of the compound is as follows:

[0105] Scheme 1

[0106]

[0107] wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , M1, M2, X1, X2, X3 are defined by the compound of formula (I); Y is selected from -B(OH)2, pinacol boronic acid ester or neopentyl glycol boronic acid ester.

[0108] Scheme 2

[0109]

[0110] wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , M1, M2, X1, X2, X3 are defined by the compound of formula (I); Y is selected from -B(OH)2, pinacol boronic acid ester or neopentyl glycol boronic acid ester.

[0111] The application compounds can be prepared according to the synthetic route described in Scheme 1 or Scheme 2. Each product obtained in Scheme 1 or Scheme 2 can be obtained by conventional separation techniques, including but not limited to filtration, distillation, crystallization, chromatographic separation, etc. The starting materials can be obtained by self-synthesis or purchased from commercial reagent suppliers. These materials can be characterized using conventional means, such as hydrogen spectrum, etc.

[0112] In Scheme 1, the starting material 1 is subjected to rearrangement reaction in the presence of Ac2O to obtain intermediate 2. Intermediate 2 is subjected to alkylation under basic conditions to obtain intermediate 3. Intermediate 3 is subjected to halogenation in the presence of iodine to obtain intermediate 4. Intermediate 4 is subjected to Suzuki reaction with starting material 5 to obtain intermediate 6. Intermediate 6 is subjected to Sonogashira reaction with starting material 7 to obtain intermediate 8. Intermediate 8 is subjected to ring-closing reaction in the presence of triethylamine to obtain the target product shown in formula (I).

[0113] In Scheme 2, the starting material 9 is subjected to methoxylation under basic conditions to obtain intermediate 10. Intermediate 10 is subjected to halogenation in the presence of iodine to obtain intermediate 11. Intermediate 11 is subjected to Sonogashira reaction and ring-closing reaction with starting material 7 to obtain intermediate 12. Intermediate 12 is subjected to Suzuki reaction with starting material 5 to obtain the target product shown in formula (I).

[0114] In another aspect, the present application provides a bromodomain protein inhibitor, which comprises at least one of the compounds as described above.

[0115] Preferably, the bromodomain protein inhibitor is an inhibitor that selectively inhibits BET family bromodomain 2 (BD2).

[0116] Preferably, the bromodomain protein inhibitor is an inhibitor that selectively inhibits BRD4 family bromodomain 2 (BD2).

[0117] In another aspect, the present application provides a pharmaceutical composition comprising at least one of the compounds as described above or a pharmaceutically acceptable salt of the compounds as described above, and at least one pharmaceutically acceptable carrier and / or at least one other therapeutically active agent.

[0118] The other therapeutically active agent includes an HDAC inhibitor, a CDK6 inhibitor, a CDK9 inhibitor, a CXCR1 / 2 inhibitor, a PI3K inhibitor, an AKT inhibitor, a PARP inhibitor, a MEK inhibitor, etc.

[0119] The pharmaceuticals prepared from the BET protein inhibitors of the present application, and the pharmaceutical compositions described herein can be suitable for various routes of administration, typical but non-limiting examples of which are oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal, via lumbar puncture, transurethral, transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intrathecal, surgical implantation), etc.

[0120] The pharmaceutical compositions described herein can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid, or gaseous dosage forms, such as tablets, pills, capsules, powders, granules, creams, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres, or aerosols, etc.

[0121] The pharmaceutical compositions described herein can be manufactured by methods well known in the art, such as the conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying, or lyophilizing processes.

[0122] The pharmaceutical composition of the present application can be administered orally in solid, gel or liquid form. Examples of solid formulations include, but are not limited to, tablets, capsules, granules and bulk powders. These formulations can optionally contain binders, diluents, disintegrants, lubricants, glidants, sweeteners and flavorings. Examples of binders include, but are not limited to, microcrystalline cellulose, dextrose solution, acacia mucilage, gelatin solution, sucrose and starch paste; examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate, stearic acid; examples of diluents include, but are not limited to, lactose, sucrose, starch, mannitol, dicalcium phosphate; examples of glidants include, but are not limited to, silicon dioxide; examples of disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, alginic acid, cornstarch, potato starch, methylcellulose, agar and carboxymethylcellulose.

[0123] The pharmaceutical composition of the present application can be administered parenterally, typically by injection, including subcutaneous, intramuscular or intravenous injection. The injectable formulations can be prepared in any conventional form, such as liquid solutions or suspensions, solid forms suitable for dissolving or suspending in liquid prior to injection, or emulsions. Examples of pharmaceutically acceptable carriers that can be used in the injectable formulations of the present application include, but are not limited to, aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffering agents, antioxidants, suspending and dispersing agents, emulsifying agents, chelating agents and other pharmaceutically acceptable substances. Examples of aqueous carriers include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection; examples of non-aqueous carriers include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil; examples of antimicrobial agents include m-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride and the like; examples of isotonic agents include sodium chloride and dextrose; buffering agents include phosphate and citrate.

[0124] The pharmaceutical composition of the present application can also be prepared as sterile lyophilized powder for reconstitution into a solution prior to administration. The compound is dissolved in a sodium phosphate buffer solution containing dextrose or other suitable excipients, and the solution is then sterile filtered under standard conditions known to those skilled in the art, followed by lyophilization to obtain the desired formulation.

[0125] In another aspect, the present application provides the use of a compound as described above or a pharmaceutically acceptable salt thereof or the bromodomain protein inhibitor or the pharmaceutical composition in the manufacture of a medicament for a disease or disorder mediated by BET proteins.

[0126] Preferably, the disease or disorder includes, but is not limited to, cancer, inflammation, autoimmune disease, non-alcoholic fatty liver disease, cardiovascular disease, diabetes, antiviral, antibacterial, antiparasitic, pulmonary fibrosis, myelofibrosis, chronic obstructive pulmonary disease or male contraception.

[0127] Preferably, the cancer is selected from solid tumor or hematological tumor.

[0128] More preferably, the solid tumor is selected from breast cancer or prostate cancer.

[0129] More preferably, the hematological tumor is selected from acute myeloid leukemia, multiple myeloma or diffuse large B-cell lymphoma.

[0130] Compared with the prior art, the present application has the following beneficial effects:

[0131] The compound of the present application can selectively inhibit the binding of the BET family bromodomain to acetylated lysine, and can be used as a bromodomain inhibitor for treating BET-related diseases such as cancer, inflammation, etc. DETAILED DESCRIPTION

[0132] The technical solutions of the present application are further illustrated by the specific embodiments below. Those skilled in the art should understand that the embodiments are only used to help understand the present application and should not be regarded as specific limitations of the present application.

[0133] Unless otherwise specified, the temperature is in Celsius. The purchased reagents can be directly used without further purification, unless otherwise specified.

[0134] Unless otherwise specified, the following reactions are carried out under anhydrous solvent, nitrogen or argon at positive pressure or using a dry tube; the reaction bottle is closed with a rubber plug so as to add substrates and reagents through a syringe; and the glassware is used after being heated and dried.

[0135] The solvent used in the nuclear magnetic data is CDCl3, DMSO-d6, etc., with tetramethylsilane (0.00 ppm) or residual solvent peak as the reference (CDCl3: 7.26 ppm, DMSO-d6: 2.50 ppm). When the peak type diversity is marked, the following abbreviations represent different peak types: s (single peak), d (double peak), t (triple peak), q (quadruple peak), m (multiple peak), br (broad peak), dd (double doublet), dt (double triplet), td (triple doublet). The coupling constant given is in Hertz (Hz).

[0136] Preparation of intermediates:

[0137] The synthesis method of the intermediates used in the following preparation examples is as follows:

[0138] Intermediate 1: 4-ethyl-5-ethynyl-2-methyl-1H-imidazole

[0139] Step 1: 5-ethyl-2-methyl-1H-imidazole

[0140] To 5-ethynyl-2-methyl-lH-imidazole (106.13, 2.85 g, 27.480 mmol, 1 eq) in 50 mL of methanol, 280 mg of 5% palladium on carbon was added, purged with hydrogen gas, stirred at room temperature for 12 h under hydrogen gas atmosphere, checked for completion of reaction, filtered through celite, the solution was evaporated to dryness, dissolved in ethyl acetate / methanol, column chromatography on silica gel, evaporated to dryness to get the product 5-ethyl-2-methyl-lH-imidazole (110.16, 1.6 g, 14.524 mmol, 53%). 1 H NMR (500 MHz, DMSO-d6): δ 11.31 (s, 1H), 6.58 (s, 1H), 2.34-2.48 (m, 2H), 2.19 (s, 3H), 1.12 (t, 3H, J = 7.4 Hz).

[0141] Step 2: 4-ethyl-5-iodo-2-methyl-lH-imidazole

[0142] To compound 5-ethyl-2-methyl-lH-imidazole (110.16, 1.6 g, 14.524 mmol, 1 eq) in 26 mL of chloroform, iodine (253.18, 3.56 g, 14.061 mmol, 0.97 eq) was added followed by dropwise addition of 2 M NaOH solution (26 mL, 52.5 mmol, 3.6 eq), stirred at room temperature for 18 h. Checked for completion of reaction, extracted with ethyl acetate 3 times, washed with saturated sodium thiosulfate, dried over anhydrous sodium sulfate, column chromatography on silica gel, evaporated to dryness to get the product 4-ethyl-5-iodo-2-methyl-lH-imidazole (236.06, 2.7 g, 11.438 mmol, 79%) as a solid. 1 H NMR (500 MHz, DMSO-d6): δ 11.86 (s, 1H), 2.42 (q, 2H, J = 7.6 Hz), 2.21 (s, 3H), 1.09 (t, 3H, J = 7.5 Hz).

[0143] Step 3: 4-ethyl-2-methyl-5-((trimethylsilyl)ethynyl)-lH-imidazole

[0144] Double-necked flask was dried, and compound 4-ethyl-5-iodo-2-methyl-1H-imidazole (236.06, 2.7 g, 11.438 mmol, 1 eq), CuI (190.45, 44 mg, 0.231 mmol, 0.02 eq), PdCl2(PPh3)2 (701.9, 162 mg, 0.231 mmol, 0.02 eq) were added in sequence under strict aeration, and then dry diethylamine 12 mL, dry DMF 6 mL, trimethylsilyl acetylene (98.22, 3.3 mL, 23.351 mmol, 2 eq, 0.695 g / mL) were added by needle. The reaction was carried out at 40 °C in an oil bath for 3 h. After the completion of the reaction was detected, it was diluted with a large amount of ethyl acetate, extracted with water and saturated NaCl aqueous solution in sequence, dried over anhydrous sodium sulfate, and rotary evaporated. The product 4-ethyl-2-methyl-5-((trimethylsilyl)ethynyl)-1H-imidazole (206.36, 1.5 g, 7.269 mmol, 64%) was obtained by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1). 1 H NMR (500 MHz, DMSO-d6): δ 11.81 (s, 1H), 2.51-2.58 (m, 2H), 2.18 (s, 3H), 1.14 (t, 3H, J = 7.5 Hz), 0.19 (s, 9H).

[0145] Step 4: 4-ethyl-5-ethynyl-2-methyl-1H-imidazole

[0146] The compound 4-ethyl-2-methyl-5-((trimethylsilyl)ethynyl)-1H-imidazole (206.36, 1.5 g, 7.269 mmol, 1 eq) was dissolved in 20 mL of methanol, and potassium carbonate (138.21, 2.8 g, 20.259 mmol, 3 eq) was added. The mixture was stirred at room temperature for 3 h. After dilution with ethyl acetate, the mixture was filtered through diatomite, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and rotary evaporated. The product 4-ethyl-5-ethynyl-2-methyl-1H-imidazole (134.18, 500 mg, 3.726 mmol, 51%) was obtained by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1). 1 H NMR (500 MHz, DMSO-d6): δ 11.76 (s, 1H), 3.91 (s, 1H), 2.53-2.60 (m, 2H), 2.19 (s, 3H), 1.13 (t, 3H, J = 7.0 Hz).

[0147] Intermediate 2: 2,4-diethyl-5-ethynyl-1H-imidazole

[0148] The synthesis method was the same as that of Intermediate 1, and the yield was 75%. 1H NMR (500 MHz, DMSO-d6): δ 11.73 (s, 1H), 3.91 (s, 1H), 2.52-2.58 (m, 4H), 1.11-1.18 (m, 6H).

[0149] Intermediate 3: 4-ethyl-5-ethynyl-2-isopropyl-1H-imidazole

[0150] Synthesis as for Intermediate 1, yield 85%. 1 H NMR (500 MHz, DMSO-d6): δ 11.67 (s, 1H), 3.91 (s, 1H), 2.82-2.89 (m, 1H), 2.57 (q, 2H, J = 7.6 Hz), 1.11-1.20 (m, 9H).

[0151] Intermediate 4: 2-cyclopropyl-5-ethyl-4-ethynyl-1H-imidazole

[0152] Synthesis as for Intermediate 1, yield 66%. 1 H NMR (500 MHz, DMSO-d6): δ 11.77 (s, 1H), 3.91 (s, 1H), 2.54 (q, 2H, J = 7.4 Hz), 1.81-1.89 (m, 1H), 1.15 (t, 3H, J = 7.5 Hz), 0.85-0.91 (m, 2H), 0.77-0.80 (m, 2H).

[0153] Intermediate 5: 2-cyclobutyl-5-ethyl-4-ethynyl-1H-imidazole

[0154] Synthesis as for Intermediate 1, yield 89%. 1 H NMR (500 MHz, DMSO-d6): δ 11.77 (s, 1H), 3.94 (s, 1H), 3.39-3.44 (m, 1H), 2.56 (q, 2H, J = 7.2 Hz), 2.13-2.24 (m, 4H), 1.89-1.99 (m, 1H), 1.74-1.86 (m, 1H), 1.15 (t, 3H, J = 7.4 Hz).

[0155] Intermediate 6: 2-cyclopentyl-5-ethyl-4-ethynyl-1H-imidazole

[0156] Synthesis as for Intermediate 1, yield 75%. 1H NMR (500 MHz, DMSO-d6): δ 11.69 (s, 1H), 3.92 (s, 1H), 2.90-3.04 (m, 1H), 2.56-2.69 (m, 2H), 1.85-2.00 (m, 2H), 1.49-1.79 (m, 6H), 1.05-1.21 (m, 3H).

[0157] Intermediate 7: 2-cyclohexyl-5-ethyl-4-ethynyl-lH-imidazole

[0158] Synthesis as for Intermediate 1, yield 37%. 1 H NMR (500 MHz, DMSO-d6): δ 11.64 (s, 1H), 3.91 (s, 1H), 2.53-2.60 (m, 3H), 1.84-1.86 (m, 2H), 1.72-1.74 (m, 2H), 1.63-1.65 (m, 1H), 1.38-1.44 (m, 2H), 1.25-1.33 (m, 2H), 1.17-1.23 (m, 1H), 1.14 (t, 3H, J = 7.4 Hz).

[0159] Intermediate 8: 2-cycloheptyl-5-ethyl-4-ethynyl-lH-imidazole

[0160] Synthesis as for Intermediate 1, yield 76%. 1 H NMR (500 MHz, DMSO-d6): δ 11.62 (s, 1H), 3.92 (s, 1H), 2.71-2.80 (m, 1H), 2.56 (q, 2H, J = 7.5 Hz), 1.83-1.94 (m, 2H), 1.66-1.75 (m, 4H), 1.59-1.64 (m, 2H), 1.45-1.53 (m, 4H), 1.15 (t, 3H, J = 7.4 Hz).

[0161] Intermediate 9: 2-(bicyclo[2.2.1]heptan-2-yl)-5-ethyl-4-ethynyl-lH-imidazole

[0162] Synthesis as for Intermediate 1, yield 73%. 1 H NMR (500 MHz, DMSO-d6): δ 11.65 (s, 1H), 3.94 (s, 1H), 2.99-3.08 (m, 1H), 2.58 (q, 2H, J = 7.0 Hz), 2.40-2.47 (m, 1H), 2.20-2.30 (m, 1H), 1.70-1.80 (m, 2H), 1.43-1.51 (m, 2H), 1.33-1.35 (m, 1H), 1.19-1.27 (m, 2H), 1.04-1.17 (m, 4H).

[0163] Intermediate 10: 2-(adamantan-l-yl)-5-ethyl-4-ethynyl-lH-imidazole

[0164] Synthetic procedure was as for Intermediate 1, yield 42%. 1 H NMR (500 MHz, DMSO-d6): δ 11.54 (s, 1H), 3.92 (s, 1H), 2.56-2.61 (m, 2H), 1.97-2.07 (m, 3H), 1.83-1.94 (m, 6H), 1.65-1.78 (m, 6H), 1.16 (br s, 3H).

[0165] Intermediate 11: 5-ethynyl-2-isopropyl-4-methyl-lH-imidazole

[0166] Step 1: 2-isopropyl-4-methyl-lH-imidazole

[0167] Compound 40% methylglyoxal aqueous solution (72.06, 27 mL, 178.351 mmol, 1.08 eq, 1.19 g / mL) was diluted in 50 mL methanol solution, 100 mL water was added, then isobutyraldehyde (72.11, 15 mL, 164.332 mmol, 1 eq, 0.79 g / mL) was added, cooling in ice bath. Then 28% ammonia water (35.05, 82 mL, 655.064 mmol, 4 eq) was added slowly dropwise, after dropwise addition was completed, reaction was carried out in ice bath for 1 h, then at room temperature overnight. After reaction was detected to be completed, saturated sodium chloride solution was added, ethyl acetate was back-extracted several times, dried over anhydrous sodium sulfate, and the product 2-isopropyl-4-methyl-lH-imidazole (124.19, 15.5 g, 124.809 mmol, 76%) was obtained by rotary evaporation. 1 H NMR (500 MHz, DMSO-d6): δ 11.54 (s, 1H), 3.92 (s, 1H), 2.56-2.61 (m, 2H), 1.97-2.07 (m, 3H), 1.83-1.94 (m, 6H), 1.65-1.78 (m, 6H), 1.16 (br s, 3H).

[0168] Step 2: 5-iodo-2-isopropyl-4-methyl-lH-imidazole

[0169] Take compound 2-isopropyl-4-methyl-1H-imidazole (124.19, 15.5 g, 124.809 mmol, 1 eq) dissolved in 225 mL of chloroform, add iodine monomer (253.18, 30.9 g, 122.048 mmol, 0.98 eq), then drop 2M NaOH solution (225 mL, 450 mmol, 3.6 eq), stir at room temperature overnight. Detect the completion of the reaction, extract with enough ethyl acetate for 3 times, wash with saturated sodium thiosulfate, dry with anhydrous sodium sulfate, and column chromatography with sand core, and rotary evaporation to get solid product 5-iodo-2-isopropyl-4-methyl-1H-imidazole (250.08, 29 g, 115.963 mmol, 93%). 1 H NMR (500 MHz, DMSO-d6): δ 11.81 (s, 1H), 2.81-2.90 (m, 1H), 2.08 (s, 3H), 1.18 (d, 6H, J = 7.0 Hz).

[0170] Step 3: 2-isopropyl-4-methyl-5-((trimethylsilyl)ethynyl)-1H-imidazole

[0171] Double mouth bottle dry, take compound 5-iodo-2-isopropyl-4-methyl-1H-imidazole (250.08, 29 g, 115.963 mmol, 1 eq), CuI (190.45, 442 mg, 2.321 mmol, 0.02 eq), PdCl2(PPh3)2 (701.9, 1.6 g, 2.280 mmol, 0.02 eq), strictly after air exchange, needle dry diethylamine 110 mL, dry DMF 55 mL, trimethylacetylenyl silicon (98.22, 33 mL, 233.506 mmol, 2 eq, 0.695 g / mL) in turn, and then oil bath 40°C for 3h. After detecting the completion of the reaction, dilute with a large amount of ethyl acetate, extract with water and saturated NaCl aqueous solution in turn, dry with anhydrous sodium sulfate, rotary evaporation, and get product 2-isopropyl-4-methyl-5-((trimethylsilyl)ethynyl)-1H-imidazole (220.39, 10.8 g, 49.004 mmol, 42%) with petroleum ether: ethyl acetate = 1:1. 1 H NMR (500 MHz, DMSO-d6): δ 11.72 (s, 1H), 2.79-2.87 (m, 1H), 2.16 (s, 3H), 1.18 (d, 6H, J = 7.0 Hz), 0.19 (s, 9H).

[0172] Step 4: 5-ethynyl-2-isopropyl-4-methyl-1H-imidazole

[0173] To compound 2-isopropyl-4-methyl-5-((trimethylsilyl)ethynyl)-1H-imidazole (220.39, 10.8 g, 49.004 mmol, 1 eq) was dissolved in 150 mL of methanol, potassium carbonate (138.21, 21.7 g, 157.007 mmol, 3 eq) was added, stirred at room temperature overnight. Diluted with ethyl acetate, filtered with diatomite, washed with saturated aqueous NaCl, dried with anhydrous sodium sulfate, rotary evaporated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give the product 5-ethynyl-2-isopropyl-4-methyl-1H-imidazole (148.21, 4.4 g, 29.688 mmol, 61%). 1 H NMR (500 MHz, DMSO-d6): δ 11.70 (s, 1H), 3.92 (s, 1H), 2.80-2.90 (m, 1H), 2.17 (s, 3H), 1.18 (d, 6H, J = 7.0 Hz).

[0174] Intermediate 12: 5-ethynyl-2,4-dimethyl-1H-imidazole

[0175] Synthetic method as Intermediate 11, yield 25%. 1 H NMR (500 MHz, DMSO-d6): δ 11.75 (s, 1H), 3.92 (s, 1H), 2.18 (s, 6H).

[0176] Intermediate 13: 2-ethyl-5-ethynyl-4-methyl-1H-imidazole

[0177] Synthetic method as Intermediate 11, yield 49%. 1 H NMR (500 MHz, DMSO-d6): δ 11.75 (s, 1H), 3.92 (s, 1H), 2.50-2.54 (m, 2H), 2.16 (s, 3H), 1.16 (t, 3H, J = 7.6 Hz).

[0178] Intermediate 14: 2-cyclopropyl-5-ethynyl-4-methyl-1H-imidazole

[0179] Synthetic method as Intermediate 11, yield 84%. 1 H NMR (500 MHz, DMSO-d6): δ 11.76 (s, 1H), 3.92 (s, 1H), 2.15 (s, 3H), 1.79-1.85 (m, 1H), 0.82-0.87 (m, 2H), 0.73-0.79 (m, 2H).

[0180] Intermediate 15: 2-cyclobutyl-5-ethynyl-4-methyl-1H-imidazole

[0181] Synthesis as for intermediate 11, yield 32%. 1 H NMR (500 MHz, DMSO-d6): δ 11.78 (s, 1H), 3.93 (s, 1H), 3.42-3.47 (m, 1H), 2.19-2.28 (m, 4H), 2.17 (s, 3H), 1.89-1.98 (m, 1H), 1.75-1.86 (m, 1H).

[0182] Intermediate 16: 2-cyclopentyl-5-ethynyl-4-methyl-1H-imidazole

[0183] Synthesis as for intermediate 11, yield 38%. 1 H NMR (500 MHz, DMSO-d6): δ 11.71 (s, 1H), 3.92 (s, 1H), 2.90-3.01 (m, 1H), 2.16 (s, 3H), 1.84-1.96 (m, 2H), 1.51-1.76 (m, 6H).

[0184] Intermediate 17: 2-cyclohexyl-5-ethynyl-4-methyl-1H-imidazole

[0185] Synthesis as for intermediate 11, yield 75%. 1 H NMR (500 MHz, DMSO-d6): δ 11.67 (s, 1H), 3.91 (s, 1H), 2.51-2.59 (m, 1H), 2.16 (s, 3H), 1.80-1.91 (m, 2H), 1.69-1.79 (m, 2H), 1.59-1.66 (m, 1H), 1.37-1.44 (m, 2H), 1.26-1.33 (m, 2H), 1.15-1.24 (m, 1H).

[0186] Intermediate 18: 2-(adamantan-1-yl)-5-ethynyl-4-methyl-1H-imidazole

[0187] Synthesis as for intermediate 11, yield 70%. 1 H NMR (500 MHz, DMSO-d6): δ 11.60 (s, 1H), 3.91 (s, 1H), 2.17 (s, 3H), 1.95-2.04 (m, 3H), 1.82-1.92 (m, 6H), 1.63-1.76 (m, 6H).

[0188] Intermediate 19: 5-ethynyl-2-methyl-4-propyl-1H-imidazole

[0189] Synthesis as for intermediate 11, yield 59%. 1H NMR (500 MHz, DMSO-de): δ 11.74 (s, 1H), 3.90 (s, 1H), 2.35-2.49 (m, 2H), 2.19 (s, 3H), 1.53-1.60 (m, 2H), 0.86 (t, 3H, J = 7.3 Hz).

[0190] Intermediate 20: 2-Ethyl-5-ethynyl-4-propyl-lH-imidazole

[0191] Synthesis as for Intermediate 11, yield 36%. 1 H NMR (500 MHz, DMSO-de): δ 11.69 (s, 1H), 3.89 (s, 1H), 2.51-2.62 (m, 4H), 1.52-1.60 (m, 2H), 1.15 (t, 3H, J = 7.6 Hz), 0.86 (t, 3H, J = 7.4 Hz).

[0192] Intermediate 21 : 5-Ethynyl-4-isopropyl-2-methyl-lH-imidazole

[0193] Synthesis as for Intermediate 11, yield 20%. 1 H NMR (500 MHz, DMSO-de): δ 11.70 (s, 1H), 3.91 (s, 1H), 2.98-3.04 (m, 1H), 2.19 (s, 3H), 1.19 (d, 6H, J = 7.0 Hz).

[0194] Intermediate 22: 2-Ethyl-5-ethynyl-4-isopropyl-lH-imidazole

[0195] Synthesis as for Intermediate 11, yield 52%. 1 H NMR (500 MHz, DMSO-de): δ 11.64 (s, 1H), 3.91 (s, 1H), 2.96-3.04 (m, 1H), 2.51-2.55 (m, 2H), 1.14-1.20 (m, 9H).

[0196] Intermediate 23: 2-Ethyl-5-ethynyl-4-(methoxymethyl)-lH-imidazole

[0197] Synthesis as for Intermediate 11, yield 68%. 1 H NMR (500 MHz, CD3OD): δ 4.43 (s, 2H), 3.70 (s, 1H), 3.35 (s, 3H), 2.69 (q, 2H, J = 7.6 Hz), 1.28 (t, 3H, J = 7.6 Hz).

[0198] Intermediate 23: 5-ethynyl-2-isopropyl-4-(methoxymethyl)-1H-imidazole

[0199] Synthetic procedure as for Intermediate 11, yield 56%. 1 H NMR (500 MHz, CD3OD): δ 4.43 (s, 2H), 3.64 (s, 1H), 3.35 (s, 3H), 2.95-3.05 (m, 1H), 1.30 (d, 6H, J = 7.0 Hz).

[0200] Intermediate 24: 2-cyclopropyl-5-ethynyl-4-(methoxymethyl)-1H-imidazole

[0201] Synthetic procedure as for Intermediate 11, yield 58%. 1 H NMR (500 MHz, CD3OD): δ 4.40 (s, 2H), 3.67 (s, 1H), 3.34 (s, 3H), 1.90-1.98 (m, 1H), 0.97-1.01 (m, 2H), 0.90-0.94 (m, 2H).

[0202] Intermediate 25: 2-cyclobutyl-5-ethynyl-4-(methoxymethyl)-1H-imidazole

[0203] Synthetic procedure as for Intermediate 11, yield 48%. 1 H NMR (500 MHz, CD3OD): δ 4.43 (s, 2H), 3.70 (s, 1H), 3.52-3.59 (m, 1H), 3.35 (s, 3H), 2.29-2.39 (m, 4H), 2.02-2.12 (m, 1H), 1.88-1.97 (m, 1H).

[0204] Example 1: 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(2-((3,5-dimethylpyridin-4-yl)oxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0205]

[0206] Step 1: 3,5-dimethyl-4-nitropyridine 1-oxide

[0207] To compound 3,5-dimethylpyridine 1-oxide (123.16, 2 g, 16.239 mmol, 1 eq) was dissolved in 5 mL of concentrated sulfuric acid, 1.7 mL of concentrated nitric acid was added dropwise under ice bath, after stirring for 15 min under ice bath, it was heated to 90 °C under oil bath overnight. The reaction was detected to be complete, cooled in ice bath, adjusted to neutral pH with 10 M sodium hydroxide solution, diluted with water, and then extracted with dichloromethane three times, dried over anhydrous sodium sulfate, and purified by column chromatography (pure dichloromethane), and then (pure ethyl acetate) to give the product 3,5-dimethyl-4-nitropyridine 1-oxide (168.15, 2.2 g, 13.084 mmol, 80%). 1 H NMR (400 MHz, DMSO-d6): δ 8.31 (s, 2H), 2.27 (s, 6H).

[0208] Step 2: 4-methoxy-3,5-dimethylpyridine 1-oxide

[0209] The reaction was pumped dry with an oil pump, and compound 3,5-dimethyl-4- nitropyridine 1-oxide (168.15, 1 g, 5.947 mmol, 1 eq) was dissolved in 10 mL of methanol solution. At this time, the reaction was not very soluble, and the temperature was increased to 70 °C and refluxed. After the reaction was completely dissolved, 30% sodium methoxide in methanol (1.4 mL, 7 mmol, 1.18 eq, 5 mmol / mL) was added dropwise through a dropping funnel. After the addition was completed, it was protected under argon gas, and reacted at 65 °C for 12 hours under oil bath. After the reaction was detected to be complete, it was cooled to room temperature, adjusted to neutral pH with acetic acid, diluted with ethyl acetate, dried over anhydrous sodium sulfate, and then concentrated to give yellow crude product 4-methoxy-3,5-dimethylpyridine 1-oxide (153.18, 800 mg, 5.223 mmol, 88%). 1 H NMR (500 MHz, DMSO-d6): δ 8.00 (s, 2H), 3.72 (s, 3H), 2.15 (s, 6H).

[0210] Step 3: 4-methoxy-3,5-dimethylpyridine

[0211] Into a dry flask, take zirconium tetrachloride (233.04, 27.4 g, 117.576 mmol, 1.02 eq), sodium borohydride (37.83, 23 g, 607.983 mmol, 5.2 eq) and add dry tetrahydrofuran 300 mL, cool in ice bath. Meanwhile, take compound 4-methoxy-3,5-dimethylpyridine 1-oxide (153.18, 18 g, 117.509 mmol, 1 eq) and dissolve in 300 mL dry tetrahydrofuran, then add dropwise into the reaction system. After dropwise addition is completed, react at room temperature for 24 h. After the reaction is detected to be completed, cool the reaction solution in an ice bath and add dilute hydrochloric acid dropwise to terminate the reaction. Then, filter through a Buchner funnel, dilute the filter residue with a large amount of ethyl acetate, stir and filter again, and rotary evaporate the solvent to obtain the crude product. Repeat 2-3 times until there is no product in the filter residue; rotary evaporate the tetrahydrofuran from the filtrate, then dilute with a saturated sodium chloride solution, and extract with ethyl acetate 2-3 times until there is no product. Dry over anhydrous sodium sulfate. Rotary evaporation is performed, and the obtained crude product is subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 4-methoxy-3,5-dimethylpyridine (137.18, 10.8 g, 78.729 mmol, 67%). 1 H NMR (500 MHz, DMSO-d6): δ 8.25 (s, 2H), 3.89 (s, 3H), 2.25 (s, 6H).

[0212] Step 4: 3,5-dimethylpyridin-4-ol

[0213] Take compound 4-methoxy-3,5-dimethylpyridine (137.18, 10.8 g, 78.729 mmol, 1 eq) and dissolve in 150 mL of toluene, then slowly add concentrated hydrochloric acid 11 mL dropwise under ice bath. A large amount of foam is generated during the dropwise addition process. After the dropwise addition is completed, reflux at 110°C for 18 h. After the reaction is detected to be completed, neutralize the partial acidity with sodium hydroxide. Keep the solution acidic, and rotary evaporation to obtain crude compound 3,5-dimethylpyridin-4-ol. No purification is needed before proceeding to the next step.

[0214] Step 5: methyl 3-bromo-4-((3,5-dimethylpyridin-4-yl)oxy)benzoate

[0215] Into a sealed tube, add compound 3,5-dimethylpyridin-4-ol (123.16, 8 g, 64.956 mmol, 1 eq), methyl 3-bromo-4-fluorobenzoate (233.03, 17 g, 72.952 mmol, 1.12 eq), dissolve in dry DMF (100 mL), then add cesium carbonate (325.82, 60 g, 184.151 mmol, 2.8 eq), and react at 80 °C in an oil bath for 3-5 h. After the reaction is detected to be completed, dilute with ethyl acetate, and filter with diatomite. The filtrate is concentrated at 80 °C, dissolved in ethyl acetate / dichloromethane / methanol, and subjected to column chromatography on a sand core to obtain a crude product. Concentrate by rotary evaporation to obtain a large amount of solid, and let the solid precipitate. After the solid is precipitated, filter with a Buchner funnel to obtain a solid product. The filtrate is subjected to column chromatography on silica gel (dichloromethane: ethyl acetate = 2:1) to obtain methyl 3-bromo-4-((3,5-dimethylpyridin-4-yl)oxy)benzoate (336.18, 11 g, 32.721 mmol, 50%). 1 H NMR (500 MHz, DMSO-d6): δ 8.29 (s, 1H), 8.08 (d, 1H, J = 8.1 Hz), 7.76 (d, 1H, J = 8.2 Hz), 7.72 (s, 2H), 3.91 (s, 3H), 1.90 (s, 6H).

[0216] Step 6: 2-(3-bromo-4-((3,5-dimethylpyridin-4-yl)oxy)phenyl)propan-2-ol

[0217] Into a dry three-necked flask, add compound methyl 3-bromo-4-((3,5-dimethylpyridin-4-yl)oxy)benzoate (336.18, 5 g, 14.873 mmol, 1 eq), and after aeration, add 100 mL of dry THF. Cool in an ice bath, then add 3M methyl magnesium bromide tetrahydrofuran solution (15 mL, 45 mmol, 3 eq) dropwise into the reaction system. Stir in an ice bath for 1 h, add 50 mL of dry dioxane to assist dissolution, and stir at room temperature for 3 h. After the reaction is completed, add 20 mL of methanol to quench. Remove solid impurities by column chromatography on a sand core, concentrate the filtrate, dilute with ethyl acetate / water, extract with ethyl acetate 3 times, dry with anhydrous sodium sulfate, and subject to column chromatography on silica gel (dichloromethane:methanol = 25:1) to obtain 2-(3-bromo-4-((3,5-dimethylpyridin-4-yl)oxy)phenyl)propan-2-ol (336.23, 4.2 g, 12.491 mmol, 84%). 1 H NMR (500 MHz, DMSO-d6): δ 7.88 (s, 1H), 7.65 (s, 2H), 7.60 (d, 1H, J = 8.2 Hz), 7.52 (d, 1H, J = 8.2 Hz), 5.36 (s, 1H), 1.88 (s, 6H), 1.45 (s, 6H).

[0218] Step 7: 2-(3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-((3,5-dimethylpyridin-4- yl)oxy)phenyl)propan-2-ol

[0219] The flask was dried under nitrogen, 2-(3-bromo-4-((3,5-dimethylpyridin-4- yl)oxy)phenyl)propan-2-ol (336.23, 8.4 g, 24.983 mmol, 1 eq), bis(pinacolato)diboron (225.89, 14 g, 61.977 mmol, 2.5 eq), meCgPPh (292.31, 73 mg, 0.250 mmol, 0.01 eq), Pd2(dba)3 (915.72, 70 mg, 0.0764 mmol, 0.003 eq), finally anhydrous potassium acetate (98, 7.4 g, 75.510 mmol, 3 eq) was added quickly under the oven-dried environment, and the oil pump was strictly ventilated for 30 min. Then dry dioxane (160 mL) was added to the reaction system, and the oil bath was strictly ventilated at 80 °C for 24 h. After the reaction was detected to be completed, the diatomaceous earth was filtered, the filtrate was diluted with a large amount of ethyl acetate, and the saturated sodium chloride solution was washed, and the organic phase was dried with anhydrous sodium sulfate, and the crude product 2-(3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-((3,5-dimethylpyridin-4-yl)oxy)phenyl)propan-2-ol (386.27, 9.6 g, 24.853 mmol, 99%) was obtained. 1 H NMR (500 MHz, DMSO-d6): δ 7.89 (d, 1H, J = 2.2 Hz), 7.62-7.65 (m, 3H), 7.31 (d, 1H, J = 8.2 Hz), 5.21 (s, 1H), 3.58 (s, 4H), 1.89 (s, 6H), 1.45 (s, 6H), 0.91 (s, 6H).

[0220] Step 8: 5-(2-((3,5-dimethylpyridin-4-yl)oxy)-5-(2-hydroxypropan-2-yl)phenyl)-3-iodo-4-methoxy-1-methylpyridin-2(1H)-one

[0221] Take compound 3,5-diiodo-4-methoxy-1-methylpyridin-2(1H)-one (390.95, 3.8 g, 9.720 mmol, 1 eq), potassium phosphate (212.27, 11.967 g, 56.376 mmol, 5.79 eq), catalyst PdCl2(dppf)·CH2Cl2(816.65, 1.8 g, 2.204 mmol, 0.226 eq) in a two-necked flask, aeration for 45 min; at the same time, another two-necked flask was added with 2-(3-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-4-((3,5-dimethylpyridin-4-yl)oxy)phenyl)propan-2-ol (386.27, 4.5 g, 11.650 mmol, 1.2 eq), 44 mL of dioxane and 22 mL of water, ice bath aeration for 45 min. Then under negative pressure, two needle heads were used to add the dioxane / water solution of 2-(3-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-4-((3,5-dimethylpyridin-4-yl)oxy)phenyl)propan-2-ol into the reaction system, oil bath 60°C reflux for 45 min, after detection of the end of the reaction, standing and separating the water layer, the organic phase was diluted with a large amount of dichloromethane, dried over anhydrous sodium sulfate, and then subjected to silica gel column chromatography (dichloromethane:methanol = 100:1) to recover the starting material 3,5-diiodo-4-methoxy-1-methylpyridin-2(1H)-one, (dichloromethane:methanol = 25:2) to obtain 5-(2-((3,5-dimethylpyridin-4-yl)oxy)-5-(2-hydroxypropan-2-yl)phenyl)-3-iodo-4-methoxy-1-methylpyridin-2(1H)-one (520.37, 970 mg, 1.864 mmol, 16%). 1 H NMR (500 MHz, DMSO-d6): δ 7.80 (s, 1H), 7.67 (dd, 1H, J = 8.3, 2.1 Hz), 7.60 (d, 1H, J = 2.0 Hz), 7.50 (s, 2H), 7.47 (d, 1H, J = 8.3 Hz), 5.25 (s, 1H), 3.56 (s, 3H), 3.46 (s, 3H), 1.77 (s, 6H), 1.48 (s, 6H).

[0222] Step 9: 3-((2-cyclopentyl-1H-imidazol-5-yl)ethynyl)-5-(2-((3,5-dimethylpyridin-4-yl)oxy)-5-(2-hydroxypropan-2-yl)phenyl)-4-methoxy-1-methylpyridin-2(1H)-one

[0223] The reactants were pre-evacuated, and compound 5-(2-((3,5-dimethylpyridin-4-yl)oxy)-5-(2- hydroxypropan-2-yl)phenyl)-3-iodo-4-methoxy-1-methylpyridin-2(1H)-one (520.37, 420 mg, 0.807 mmol, 1 eq), CuI (190.45, 8 mg, 0.0420 mmol, 0.05 eq), PdCl2(PPh3)2 (701.9, 17 mg, 0.0242 mmol, 0.03 eq), 2-cyclopentyl-5-ethynyl-1H-imidazole (160.22, 324 mg, 2.022 mmol, 2.5 eq), strict air exchange, dry DMF 4 mL, diethylamine 5 mL were added, and after strict air exchange, the reaction was carried out at 45 °C in an oil bath for 4 h. After the reaction was detected to be complete, it was dried, and silica gel column chromatography (dichloromethane:methanol = 100:1) was performed to remove impurities, and (dichloromethane:methanol:triethylamine = 50:1:1) to obtain 3-((2-cyclopentyl-1H-imidazol-5-yl)ethynyl)-5-(2-((3,5-dimethylpyridin-4-yl)oxy)-5-(2-hydroxypropan-2-yl)phenyl)-4-methoxy-1-methylpyridin-2(1H)-one (552.68, 200 mg, 0.362 mmol, 45%). 1 H NMR (500 MHz, DMSO-d6): δ 11.95 (s, 1H), 7.95 (s, 1H), 7.72 (s, 1H), 7.64 (dd, 1H, J = 8.2, 2.0 Hz), 7.55 (s, 2H), 7.50 (d, 1H, J = 2.0 Hz), 7.44 (d, 1H, J = 8.2 Hz), 5.23 (s, 1H), 3.87 (s, 3H), 3.41 (s, 3H), 3.00-3.04 (m, 1H), 1.90-1.94 (m, 2H), 1.81 (s, 6H), 1.66-1.73 (m, 4H), 1.56-1.60 (m, 2H), 1.48 (s, 6H).

[0224] Step 10: 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(2-((3,5-dimethylpyridin-4-yl)oxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0225] Sealed tube was charged with compound 3-((2-cyclopentyl-lH-imidazol-5-yl)ethynyl)-5-(2-((3,5-dimethylpyridin-4-yl)oxy)-5-(2-hydroxypropan-2-yl)phenyl)-4-methoxy-l- methylpyridin-2(lH)-one (552.68, 188 mg, 0.198 mmol, 1 eq), dry acetonitrile (2 mL), dry DMF (1 mL) and dry triethylamine (8 mL), gas exchange, oil bath 80 °C for 8 days. After the reaction was completed, 55 °C rotary evaporation was concentrated, column chromatography (dichloromethane:methanol:triethylamine = 225:13:1) to get the crude product. Preparative liquid chromatography purification to get the pure product 2-(2-cyclopentyl-lH-imidazol-5-yl)-7-(2-((3,5-dimethylpyridin-4-yl)oxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one (538.65, 11 mg, 0.0204 mmol, 10%). 1 H NMR (500 MHz, DMSO-d6): δ 12.01 (s, 1H), 7.65-7.74 (m, 3H), 7.65 (s, 2H), 7.53 (d, 1H, J = 8.1 Hz), 7.36 (s, 1H), 6.63 (s, 1H), 5.26 (s, 1H), 3.59 (s, 3H), 3.02-3.08 (m, 1H), 1.93-1.99 (m, 2H), 1.69-1.77 (m, 4H), 1.57-1.62 (m, 8H), 1.52 (s, 6H).

[0226] Example 2: 2-(2-cyclopentyl-lH-imidazol-5-yl)-7-(3-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0227]

[0228] Step 1: Methyl 3-bromo-5-fluoro-4-(4-fluoro-2,6-dimethylphenoxy)benzoate

[0229] To compound 4-fluoro-2,6-dimethylphenol (140.16, 5.6 g, 39.954 mmol, 1 eq), 3-bromo-4,5-difluoromethyl benzoate (251.03, 10.0 g, 39.836 mmol, 1 eq) were dissolved in 45 mL DMF, cesium carbonate (325.82, 18 g, 55.245 mmol, 1.38 eq) was added, and the mixture was stirred at 80 °C in an oil bath for 3 h. After the reaction was completed, the mixture was diluted with ethyl acetate, filtered with diatomite, and the filtrate was washed with water and saturated sodium chloride solution successively, dried over anhydrous sodium sulfate, and purified by column chromatography on silica gel (pure petroleum ether) to give methyl 3-bromo-5-fluoro-4-(4-fluoro-2,6-dimethylphenoxy)benzoate (371.18, 8.7 g, 23.439 mmol, 59%). 1 H NMR (500 MHz, DMSO-d6): δ 8.06 (s, 1H), 7.76 (dd, 1H, J = 12.4, 1.8 Hz), 6.99 (d, 2H, J = 9.0 Hz), 3.86 (s, 3H), 2.10 (s, 6H).

[0230] Step 2: 2-(3-bromo-5-fluoro-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)propan-2-ol

[0231] To compound methyl 3-bromo-5-fluoro-4-(4-fluoro-2,6-dimethylphenoxy)benzoate (371.18, 8.7 g, 23.439 mmol, 1 eq) in a dry three-necked flask, 100 mL dry THF was added, and the mixture was cooled in an ice bath after strict air exchange. Then 3M methyl magnesium bromide in tetrahydrofuran (30 mL, 90 mmol, 3.84 eq) was added dropwise to the reaction system, and the mixture was stirred in an ice bath for 3 h. After the reaction was completed, 20 mL of methanol was added to quench the reaction, and the solid impurities were removed by column chromatography on silica gel. After drying, the product was diluted with ethyl acetate / water, and the organic phase was dried over anhydrous sodium sulfate. Column chromatography (petroleum ether: ethyl acetate = 4:1) gave 2-(3-bromo-5-fluoro-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)propan-2-ol (371.22, 8.4 g, 22.628 mmol, 96.5%). 1 H NMR (500 MHz, DMSO-d6): δ 7.58 (s, 1H), 7.27 (dd, 1H, J = 13.8, 1.8 Hz), 6.94 (d, 2H, J = 9.0 Hz), 5.29 (s, 1H), 2.10 (s, 6H), 1.40 (s, 6H).

[0232] Step 3: 2-(3-(5,5-dimethyl-1,3,2-dioxaborane-2-yl)-5-fluoro-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)prop-2-ol

[0233] The double-necked flask was dried, and 2-(3-bromo-5-fluoro-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)prop-2-ol (367.26 g, 8.4 g, 22.872 mmol, 1 eq), neopentyl glycol diboronate (225.89 g, 12.9 g, 57.107 mmol, 2.5 eq), meCgPPh (292.31 mg, 67 mg, 0.229 mmol, 0.01 eq), and Pd2(dba)3 (915.72 mg, 63 mg, 0.0688 mmol, 0.003 eq) were added. Finally, anhydrous potassium acetate (98 g, 6.7 g, 68.367 mmol, 3 eq) was rapidly added under oven drying conditions, and the mixture was strictly ventilated for 30 min. Then, dried dioxane (160 mL) was added to the reaction system, and the mixture was strictly ventilated and reacted in an oil bath at 80°C for 24 h. After the reaction was completed, the diatomaceous earth was filtered, diluted with a large amount of ethyl acetate, and then extracted successively with water and saturated NaCl aqueous solution. After drying with anhydrous sodium sulfate, the solution was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 6:1) 2-(3-(5,5-dimethyl-1,3,2-dioxaborane-2-yl)-5-fluoro-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)prop-2-ol (404.26 g, 8.7 g, 21.521 mmol, 94%). 1 H NMR (500MHz, CDCl3): δ7.26 (s, 1H), 7.21 (d, 1H, J = 13.4Hz), 6.73 (d, 2H, J = 8.8Hz), 3.50 (s, 4H), 2.14 (s, 6H), 1.55 (s, 6H), 0.94 (s, 6H).

[0234] Step 4: 5-(3-fluoro-2-(4-fluoro-2,6-dimethylphenyl)-5-(2-hydroxypropyl-2-yl)phenyl)-3-iodo-4-methoxy-1-methylpyridin-2(1H)-one

[0235] The double-mouth flask was dried and oven-dried, and then compound 3,5-diiodo-4-methoxy-1-methylpyridin-2(1H)-one (390.95, 7 g, 17.905 mmol, 1 eq), PdCl2(dppf)·CH2Cl2(816.65, 1.7 g, 2.082 mmol, 0.116 eq), K3PO4(212.27, 26.5 g, 124.841 mmol, 7 eq) were added, and the air was replaced for 40 min. Another double-mouth flask was prepared, and 2-(3-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-5-fluoro-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)propan-2-ol (404.26, 8.7 g, 21.521 mmol, 1.2 eq), 64 mL of dioxane and 32 mL of water were added, and the air was replaced for 40 min before being added to the reaction system. After the air was replaced, the oil bath was heated to 60°C, and refluxed for 4 h. After the reaction was detected to be completed, ethyl acetate was added for dilution, and diatomite was used for suction filtration. The filtrate was extracted with water and saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to remove impurities, and then (pure ethyl acetate) to obtain 5-(3-fluoro-2-(4-fluoro-2,6-dimethylphenyl)-5-(2-hydroxypropan-2-yl)phenyl)-3-iodo-4-methoxy-1-methylpyridin-2(1H)-one (555.36, 2.6 g, 4.682 mmol, 26%). 1 H NMR (500 MHz, DMSO-d6): δ 7.66 (s, 1H), 7.34 (d, 1H, J = 13.7 Hz), 7.20 (s, 1H), 6.78 (d, 2H, J = 9.0 Hz), 5.21 (s, 1H), 3.50 (s, 3H), 3.44 (s, 3H), 1.99 (s, 6H), 1.43 (s, 6H).

[0236] Step 5: 3-((2-Cyclopentyl-1H-imidazol-5-yl)ethynyl)-5-(3-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-4-methoxy-1-methylpyridin-2(1H)-one

[0237] The reactants were pre-evacuated and dry, CuI (190.45, 8 mg, 0.0420 mmol, 0.05 eq), PdCl2(PPh3)2(701.9, 17 mg, 0.0242 mmol, 0.03 eq), 2-cyclopentyl-5-ethynyl-1H-imidazole (160.22, 324 mg, 2.022 mmol, 2.5 eq) were taken, and strict air exchange was performed. Another two-port bottle was taken to add compound 5-(3-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-3-iodo-4-methoxy-1-methylpyridin-2(1H)-one (555.36, 448 mg, 0.807 mmol, 1 eq), dry DMF 3 mL, diethylamine 6 mL, and after air exchange, it was added to the reaction system, and after strict air exchange, it was reacted in an oil bath at 45°C for 4 h. After detecting the completion of the reaction, it was diluted with a large amount of ethyl acetate, sequentially extracted with water and saturated sodium chloride, concentrated, sampled with dichloromethane, and column chromatography (pure ethyl acetate) was performed to remove impurities, (ethyl acetate:methanol:triethylamine = 250:5:4) to obtain 3-((2-cyclopentyl-1H-imidazol-5-yl)ethynyl)-5-(3-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-4-methoxy-1-methylpyridin-2(1H)-one (587.67, 287 mg, 0.488 mmol, 60%). 1 H NMR (500 MHz, DMSO-d6): δ 11.97 (s, 1H), 7.66 (s, 1H), 7.35 (s, 1H), 7.29 (d, 1H, J = 13.4 Hz), 7.13 (s, 1H), 6.84 (d, 2H, J = 9.0 Hz), 5.15 (s, 1H), 4.05 (s, 3H), 3.40 (s, 3H), 3.02-3.08 (m, 1H), 2.02 (s, 6H), 1.92-1.95 (m, 2H), 1.69-1.77 (m, 4H), 1.56-1.63 (m, 2H), 1.43 (s, 6H).

[0238] Step 6: 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(3-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0239] To 3-((2-cyclopentyl-lH-imidazol-5-yl)ethynyl)-5-(3-fluoro-2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-4-methoxy-l-methylpyridin-2(lH)- one (587.67, 287 mg, 0.488 mmol, 1 eq) was dissolved in 2 mL of dry acetonitrile and 8 mL of dry triethylamine, gassed, sealed and heated in an oil bath at 80 °C for 5 days. The reaction was checked for completion, diluted with a large volume of ethyl acetate, washed with water, saturated sodium chloride solution in turn, concentrated and purified by column chromatography on silica gel (petroleum ether: ethyl acetate: methanol: triethylamine = 50:200:2:5) to give 2-(2-cyclopentyl-lH-imidazol-5-yl)-7-(3-fluoro-2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one (573.64, 96 mg, 0.167 mmol, 34%). 1 H NMR (500 MHz, DMSO-d6): δ 12.02 (s, 1H), 7.66 (s, 1H), 7.32-7.37 (m, 3H), 6.81 (s, 1H), 6.73 (d, 2H, J = 9.0 Hz), 5.18 (s, 1H), 3.54 (s, 3H), 3.04-3.11 (m, 1H), 1.93-2.01 (m, 8H), 1.69-1.78 (m, 4H), 1.56-1.63 (m, 2H), 1.46 (s, 6H).

[0240] Example 3: 2-(2-cyclopentyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)- 5-(2-hydroxypropan-2-yl)pyridin-3-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0241]

[0242] Synthetic method as in Example 2, yield 50%. 1 H NMR (500 MHz, DMSO-d6): δ 12.02 (s, 1H), 8.15 (d, 1H, J = 2.2 Hz), 8.07 (d, 1H, J = 2.2 Hz), 7.84 (s, 1H), 7.34 (s, 1H), 6.87-6.95 (m, 3H), 5.21 (s, 1H), 3.61 (s, 3H), 3.05-3.11 (m, 1H), 2.00 (s, 6H), 1.95-1.97 (m, 2H), 1.70-1.80 (m, 4H), 1.50-1.57 (m, 2H), 1.50 (s, 6H).

[0243] Example 4: 2-(2-cyclopentyl-lH-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0244]

[0245] Synthetic procedure as in example 2, yield 13%. 1 H NMR (500 MHz, DMSO-d6): δ 12.04 (s, 1H), 7.69-7.77 (m, 2H), 7.35 (s, 1H), 7.01 (d, 2H, J = 9.0 Hz), 6.91 (s, 1H), 6.08 (d, 1H, J = 12.6 Hz), 5.34 (s, 1H), 3.60 (s, 3H), 3.05-3.14 (m, 1H), 2.06 (s, 6H), 1.94-2.00 (m, 2H), 1.70-1.78 (m, 4H), 1.58-1.64 (m, 2H), 1.51 (s, 6H).

[0246] Example 5: 2-(2-cyclopentyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)- 5-(hydroxymethyl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0247]

[0248] Step 1: 3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)benzaldehyde

[0249] Take compound 4-fluoro-2,6-dimethylphenol (140.16, 6g, 42.808mmol, 1 eq), 3-bromo-4-fluorobenzaldehyde (203.01, 9.74g, 47.978mmol, 1.12 eq), dissolved in 50 mL DMF, then add cesium carbonate (325.82, 42g, 128.906mmol, 3 eq), react at room temperature overnight. After detecting the completion of the reaction, dissolve with enough ethyl acetate, wash with water, saturated sodium chloride solution in turn, dry with anhydrous sodium sulfate, spin dry, and column chromatography (pure dichloromethane) to get the product 3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)benzaldehyde (323.16, 12g, 37.133mmol, 88%). 1H NMR (500 MHz, DMSO-d6): δ 9.87 (s, 1H), 8.25 (d, 1H, J = 1.9 Hz), 7.80 (dd, 1H, J = 8.4, 1.9 Hz), 7.11 (d, 2H, J = 9.1 Hz), 6.58 (d, 1H, J = 8.5 Hz), 2.05 (s, 6H).

[0250] Step 2: (3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)methanol

[0251] To compound 3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)benzaldehyde (323.16, 6.1 g, 18.176 mmol, 1 eq), THF (20 mL), methanol (20 mL), sodium borohydride (37.83, 750 mg, 19.826 mmol, 0.75 eq) was added portionwise under ice bath, and the reaction was stirred at room temperature for 2 h. After the reaction was detected to be completed, the reaction mixture was diluted with ethyl acetate, washed with water and saturated NaCl aqueous solution respectively, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (petroleum ether: dichloromethane = 2: 1) to give (3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)methanol (325.18, 2.5 g, 7.688 mmol, 42%). 1 H NMR (500 MHz, DMSO-d6): δ 7.62 (s, 1H), 7.15 (d, 1H, J = 8.4 Hz), 7.06 (d, 2H, J = 9.1 Hz), 6.32 (d, 1H, J = 8.4 Hz), 5.24 (t, 1H, J = 5.8 Hz), 4.17 (d, 2H, J = 5.7 Hz), 2.04 (s, 6H).

[0252] Step 3: ((3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)benzyl)oxy)(tert-butyl)dimethylsilane

[0253] To compound (3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)methanol (325.18, 6.5 g, 20.060 mmol, 1 eq), imidazole (68.08, 3.4 g, 49.941 mmol, 2.5 eq), TBDMSCl (150.72, 3.6 g, 23.885 mmol, 1.2 eq) in a flask, after aeration, 75 mL of dry DMF solution was added, stirred at room temperature overnight. After detecting the completion of the reaction, it was diluted with a large amount of ethyl acetate, and then washed with water, saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and column chromatography on silica gel (petroleum ether: ethyl acetate = 45: 1) to obtain the product ((3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)benzyl)oxy)(tert-butyl)dimethylsilane (439.44, 8.1 g, 18.433 mmol, 92%). 1 H NMR (500 MHz, DMSO-d6): δ 7.56 (d, 1H, J = 1 Hz), 7.05 (dd, 1H, J = 8.4, 1 Hz), 6.80 (d, 2H, J = 8.8 Hz), 6.30 (d, 1H, J = 8.4 Hz), 4.64 (s, 2H), 2.11 (s, 6H), 0.93 (s, 9H), 0.09 (s, 6H).

[0254] Step 4: tert-butyl ((3-(5,5-dimethyl-1,3,2-dioxaboran-2-yl)-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)oxy)dimethylsilane

[0255] The two-necked flask was dried and ((3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)benzyl)oxy)(tert-butyl)dimethylsilane (439.44, 8.1 g, 18.433 mmol, 1 eq), bis(pinacolato)diboron (225.89, 10 g, 44.269 mmol, 2.5 eq), meCgPPh (292.31, 54 mg, 0.185 mmol, 0.01 eq), Pd2(dba)3 (915.72, 51 mg, 0.0557 mmol, 0.003 eq) were added, and anhydrous potassium acetate (98, 5.42 g, 55.306 mmol, 3 eq) was quickly added under an oven-dried environment. The reaction was stirred for 30 min under strict air exchange with an oil pump. After the reaction was completed, the reaction system was filtered with diatomite, diluted with a large amount of ethyl acetate, and then extracted with water and saturated NaCl aqueous solution in sequence. The organic phase was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain tert-butyl ((3-(5,5-dimethyl-1,3,2-dioxaboran-2-yl)-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)oxy)dimethylsilane (386.27, 6.7 g, 17.345 mmol, 94%). 1 H NMR (500 MHz, DMSO-d6): δ 7.86 (s, 1H), 7.16 (d, 1H, J = 8.3 Hz), 7.00 (d, 2H, J = 9.2 Hz), 6.20 (d, 1H, J = 8.8 Hz), 4.61 (s, 2H), 3.75 (s, 4H), 2.04 (s, 6H), 0.98 (s, 6H), 0.87 (s, 9H), 0.04 (s, 6H).

[0256] Step 5: 5-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)-3-iodo-4-methoxy-1-methylpyridin-2(1H)-one

[0257] A two-necked flask was dried and 3,5-diiodo-4-methoxy-1-methylpyridin-2(1H)-one (390.95, 6.2 g, 15.859 mmol, 1 eq), K3PO4 (212.27, 13.5 g, 63.598 mmol, 4 eq), catalyst PdCl2(dppf)·CH2Cl2(816.65, 388 mg, 0.475 mmol, 0.04 eq) were added, and the system was purged with air for 45 min. Meanwhile, another two-necked flask was added with tert-butyl ((3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)oxy)dimethylsilane (386.27, 6.7 g, 17.345 mmol, 1.1 eq), 80 mL of dioxane and 28 mL of water, and the system was purged with air for 45 min. Then the dioxane / water solution of tert-butyl ((3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)oxy)dimethylsilane was added to the reaction system, and the system was refluxed at 60 °C for 5 h in an oil bath. After the reaction was detected to be completed, ethyl acetate was added for dilution, and then water and saturated NaCl aqueous solution were added for extraction, respectively. After drying over anhydrous sodium sulfate, the solvent was removed by rotary evaporation. Silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) gave 5-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)-3-iodo-4-methoxy-1-methylpyridin-2(1H)-one (623.58, 870 mg, 1.395 mmol, 9%). 1 H NMR (500 MHz, DMSO-d6): δ 7.83 (s, 1H), 7.29 (d, 1H, J = 1.8 Hz), 7.20 (dd, 1H, J = 8.4, 1.8 Hz), 7.02 (d, 2H, J = 9.0 Hz), 6.29 (d, 1H, J = 8.4 Hz), 4.66 (s, 2H), 3.54 (s, 3H), 3.46 (s, 3H), 2.02 (s, 6H), 0.87 (s, 9H), 0.05 (s, 6H).

[0258] Step 6: 5-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)-3-((2-cyclopentyl-1H-imidazol-5-yl)ethynyl)-4-methoxy-1-methylpyridin-2(1H)-one

[0259] The reactants were pre-evacuated and dry, CuI (190.45, 7 mg, 0.0368 mmol, 0.05 eq), PdCl2(PPh3)2(701.9, 14 mg, 0.0199 mmol, 0.03 eq), 2-cyclopentyl-5-ethynyl-1H-imidazole (160.22, 277 mg, 1.729 mmol, 2.5 eq) were taken, and strict air exchange was performed. Another two-port bottle was taken to add compound 5-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)-3-iodo-4-methoxy-1-methylpyridin-2(1H)-one (623.58, 430 mg, 0.690 mmol, 1 eq), dry THF 3 mL, diethylamine 8 mL, and after air exchange, it was added to the reaction system, and after strict air exchange, it was reacted in an oil bath at 40°C for 4 h. After detecting the completion of the reaction, it was diluted with a large amount of ethyl acetate, sequentially extracted with water and saturated sodium chloride, concentrated, and then subjected to column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain 5-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)-3-((2-cyclopentyl-1H-imidazol-5-yl)ethynyl)-4-methoxy-1-methylpyridin-2(1H)-one (552.68, 100 mg, 0.181 mmol, 26%). 1 H NMR (500 MHz, DMSO-d6): δ 11.96 (s, 1H), 7.74 (s, 1H), 7.35 (s, 1H), 7.21 (s, 1H), 7.17 (d, 1H, J = 8.5 Hz), 7.01 (d, 2H, J = 9.0 Hz), 6.27 (d, 1H, J = 8.4 Hz), 4.66 (s, 2H), 3.99 (s, 3H), 3.47 (s, 3H), 3.01-3.09 (m, 1H), 2.02 (s, 6H), 1.89-1.96 (m, 2H), 1.68-1.78 (m, 4H), 1.55-1.64 (m, 2H), 0.88 (s, 9H), 0.06 (s, 6H).

[0260] Step 7: 7-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)-2-(2-cyclopentyl-1H-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0261] To 5-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)-3-((2-cyclopentyl-1H-imidazol-5-yl)ethynyl)-4-methoxy-1-methylpyridin-2(1H)-one (552.68, 265 mg, 0.479 mmol, 1 eq) was dissolved in 2 mL dry acetonitrile and 8 mL dry triethylamine, gassed, sealed and heated in an oil bath at 80 °C for 5 days. The reaction was checked for completion, diluted with a large volume of ethyl acetate, washed with water, then saturated sodium chloride solution, concentrated and purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:2) to give 7-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)-2-(2-cyclopentyl-1H-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one (641.86, 35 mg, 0.0545 mmol, 11%). 1 H NMR (500 MHz, CDC13): δ 7.44 (s, 1H), 7.37 (s, 1H), 7.28 (s, 1H), 7.18-7.23 (m, 2H), 6.76 (d, 2H, J = 8.7 Hz), 6.40 (d, 1H, J = 8.5 Hz), 4.74 (s, 2H), 3.72 (s, 3H), 3.18-3.25 (m, 1H), 2.11-2.15 (m, 2H), 2.07 (s, 6H), 1.80-1.89 (m, 4H), 1.62-1.71 (m, 2H), 0.94 (s, 9H), 0.13 (s, 6H).

[0262] Step 8: 2-(2-Cyclopentyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5- (hydroxymethyl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0263] Compound 7-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-fluoro-2,6- dimethylphenoxy)phenyl)-2-(2-cyclopentyl-lH-imidazol-5-yl)-5-methylfuro[3,2- c]pyridin-4(5H)-one (641.86, 35 mg, 0.0545 mmol, 1 eq) was dissolved in 5 mL of anhydrous THF, 1 M Tetrabutylammonium fluoride in THF (261.46, 0.16 mL, 0.160 mmol, 2.9 eq) was added, stirred at room temperature for 2 h. The reaction was checked to be complete, spin dry, column chromatography (dichloromethane: methanol = 40: 1) to get the solid crude product, liquid phase purification to get the pure product 2-(2-cyclopentyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5- (hydroxymethyl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one (527.60, 10 mg, 0.0190 mmol, 35%). 1 H NMR (500 MHz, DMSO-d6): δ 12.01 (s, 1H), 7.70 (s, 1H), 7.42 (s, 1H), 7.30 (s, 1H), 7.24 (d, 1H, J = 8.6 Hz), 6.98 (d, 2H, J = 8.9 Hz), 6.88 (s, 1H), 6.32 (d, 1H, J = 8.4 Hz), 5.19 (s, 1H), 4.49 (s, 2H), 3.59 (s, 3H), 3.03-3.10 (m, 1H), 2.02 (s, 6H), 1.95-1.98 (m, 2H), 1.68-1.77 (m, 4H), 1.56-1.63 (m, 2H).

[0264] Example 6: 2-(2-cyclopentyl-lH-imidazol-5-yl)-7-(4-fluoro-2,6-dimethylphenoxy)-5- (hydroxymethyl)phenyl-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0265]

[0266] Synthetic method as example 5, yield 30%. 1H NMR (500 MHz, DMSO-d6): δ 12.04 (s, 1H), 7.72 (s, 1H), 7.57 (d, 1H, J = 8.2 Hz), 7.33 (s, 1H), 7.02 (d, 2H, J = 9.0 Hz), 6.91 (s, 1H), 6.12 (d, 1H, J = 11.2 Hz), 5.28-5.34 (br s, 1H), 4.53 (d, 2H, J = 4.3 Hz), 3.60 (s, 3H), 3.04-3.11 (m, 1H), 2.05 (s, 6H), 1.94-2.00 (m, 2H), 1.70-1.78 (m, 4H), 1.57-1.63 (m, 2H).

[0267] Example 7: 2-(2-cycloheptyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)- 5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0268]

[0269] Step 1: cycloheptanecarboxaldehyde

[0270] Compound (hydroxymethyl)cycloheptane (128.21, 10 g, 77.997 mmol, 1 eq) was dissolved in 50 mL DMSO, triethylamine 34 mL was added, sulfur trioxide pyridine complex (159.16, 27.3 g, 171.526 mmol, 2.2 eq) was added under ice bath stirring, then the reaction was carried out at room temperature overnight. The reaction was detected to be completed, diluted with water, extracted with petroleum ether for several times, dried over anhydrous sodium sulfate, and rotary evaporated to get the crude product cycloheptanecarboxaldehyde, which was directly used for the next step without purification.

[0271] Step 2: 2-cycloheptyl-lH-imidazole

[0272] Compound cycloheptanecarboxaldehyde (126.20, 6.3 g, 49.921 mmol, 1 eq) was diluted in 40 mL methanol solution, 80 mL water was added, then 40% glyoxal aqueous solution (58.04, 7 mL, 61.027 mmol, 1.2 eq, 1.265 g / mL) was added under ice bath cooling. Then 28% ammonia water (35.05, 25 mL, 199 mmol, 4 eq) was slowly added dropwise, after the addition was completed, the reaction was carried out at ice bath for 1 h, then at room temperature overnight. The reaction was detected to be completed, saturated sodium chloride solution was added, extracted with ethyl acetate for several times, dried over anhydrous sodium sulfate, and rotary evaporated to get the product 2-cycloheptyl-lH-imidazole (164.25, 8 g, 48.706 mmol, 97.6%). 1HNMR (500 MHz, DMSO-d6): δ 11.54 (s, 1H), 6.83 (s, 2H), 3.00-3.08 (m, 1H), 2.06-2.08 (m, 2H), 1.85-1.96 (m, 4H), 1.60-1.67 (m, 6H).

[0273] Step 3: 2-Cycloheptyl-4,5-diiodo-1H-imidazole

[0274] Take 2-cycloheptyl-1H-imidazole (164.25, 10.5 g, 63.927 mmol, 1 eq) dissolved in 160 mL chloroform, add iodine (253.18, 35 g, 138.242 mmol, 2.16 eq), add 2M NaOH solution (160 mL, 320 mmol, 4.9 eq), stir at room temperature for 18 h. Check the reaction is complete, add saturated sodium thiosulfate, ethyl acetate back extraction twice. The organic phase is washed with saturated sodium thiosulfate again, saturated sodium chloride, dried over anhydrous sodium sulfate, and column chromatography on silica gel, and rotary evaporation to obtain solid product 2-cycloheptyl-4,5-diiodo-1H-imidazole (416.04, 20 g, 48.072 mmol, 75%). 1 H NMR (500 MHz, DMSO-d6): δ 12.38 (s, 1H), 2.80-2.85 (m, 1H), 1.83-1.88 (m, 2H), 1.64-1.68 (m, 4H), 1.56-1.60 (m, 2H), 1.43-1.52 (m, 4H).

[0275] Step 4: 2-Cycloheptyl-5-iodo-1H-imidazole

[0276] Take compound 2-cycloheptyl-4,5-diiodo-1H-imidazole (416.04, 20 g, 48.072 mmol, 1 eq), Na2SO3 (126.04, 70 g, 555.379 mmol, 11.5 eq), suspended in ethanol-water solution (250 mL + 500 mL), a small amount of methanol to promote dissolution, 80 °C reflux stirring for 5 days. Check the reaction is complete, rotary evaporation to remove most of the solvent, dilute with enough ethyl acetate, saturated NaCl aqueous solution, dry over anhydrous sodium sulfate, rotary evaporation, and column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1) to obtain solid product 2-cycloheptyl-5-iodo-1H-imidazole (290.15, 10 g, 34.465 mmol, 72%). 1H NMR (500 MHz, DMSO-d6): δ 11.90 (s, 1H), 7.15 (s, 1H), 2.80-2.84 (m, 1H), 1.84-1.94 (m, 2H), 1.66-1.69 (m, 4H), 1.59-1.63 (m, 2H), 1.45-1.52 (m, 4H).

[0277] Step 5: 2-cycloheptyl-5-((trimethylsilyl)ethynyl)-1H-imidazole

[0278] Double mouth flask was dried, and compound 2-cycloheptyl-5-iodo-1H-imidazole (290.15, 10 g, 34.465 mmol, 1 eq), CuI (190.45, 66 mg, 0.347 mmol, 0.01 eq), PdCl2(PPh3)2 (701.9, 242 mg, 0.345 mmol, 0.01 eq) were added, and then dry diethylamine 28 mL, dry tetrahydrofuran 14 mL, trimethylsilyl acetylene (98.22, 9.75 mL, 68.991 mmol, 1.978 eq, 0.695 g / mL) were added in order under strict air exchange. The reaction was carried out at 45 °C in an oil bath for 3 h. After the completion of the reaction was detected, it was diluted with a large amount of ethyl acetate, washed with water and saturated NaCl aqueous solution in order, dried over anhydrous sodium sulfate, and column chromatography was performed on silica gel. The crude product 2-cycloheptyl-5-((trimethylsilyl)ethynyl)-1H-imidazole (260.46, 8.0 g, 30.715 mmol, 89%) was obtained by rotary evaporation. 1 H NMR (500 MHz, DMSO-d6): δ 11.86 (s, 1H), 7.32 (s, 1H), 2.78-2.81 (m, 1H), 1.82-1.93 (m, 2H), 1.66-1.74 (m, 4H), 1.58-1.62 (m, 2H), 1.44-1.52 (m, 4H), 0.18 (s, 9H).

[0279] Step 6: 2-cycloheptyl-5-ethynyl-1H-imidazole

[0280] The compound 2-cycloheptyl-5-((trimethylsilyl)ethynyl)-1H-imidazole (260.46, 8.9 g, 34.170 mmol, 1 eq) was dissolved in 25 mL of methanol, and potassium carbonate (138.21, 9.5 g, 68.736 mmol, 2 eq) was added. Stirring was carried out at room temperature for 3 h. Ethyl acetate was added for dilution, and filtration was performed on diatomite. Washing was performed with saturated NaCl aqueous solution, and drying was performed over anhydrous sodium sulfate. Rotary evaporation was performed, and column chromatography was performed on silica gel (petroleum ether: ethyl acetate = 3:1). The product 2-cycloheptyl-5-ethynyl-1H-imidazole (188.27, 1.8 g, 9.561 mmol, 28%) was obtained. 1H NMR (500 MHz, DMSO-d6): δ 12.12 (s, 1H), 7.22 (s, 1H), 3.96 (s, 1H), 2.78-2.82 (m, 1H), 1.83-1.94 (m, 2H), 1.65-1.71 (m, 4H), 1.57-1.60 (m, 2H), 1.45-1.54 (m, 4H).

[0281] Step 7: 3-((2-cyclopentyl-lH-imidazol-5-yl)ethynyl)-5-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-4-methoxy-l-methylpyridin-2(lH)- one

[0282] The reactants were pre-dried, and compound 5-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-3-iodo-4-methoxy-l-methylpyridin-2(lH)-one (537.37, 400 mg, 0.744 mmol, 1 eq), CuI (190.45, 8 mg, 0.0420 mmol, 0.05 eq), PdCl2(PPh3)2 (701.9, 15 mg, 0.0214 mmol, 0.03 eq), 2-cycloheptyl-5-ethynyl-lH-imidazole (188.27, 300 mg, 1.593 mmol, 2.14 eq) were strictly aerated. Dry DMF 2 mL, triethylamine 8 mL were added by needle, strictly aerated, and the reaction was carried out at 40 °C in an oil bath overnight. After checking the completion of the reaction, it was diluted with a large amount of ethyl acetate, washed sequentially with water and saturated sodium chloride solution, concentrated, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate:methanol:triethylamine = 50:200:2:5) to give 3-((2-cyclopentyl-lH-imidazol-5-yl)ethynyl)-5-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-4-methoxy-l-methylpyridin-2(lH)-one (597.73, 300 mg, 0.502 mmol, 67%). 1 H NMR (500 MHz, DMSO-d6): δ 11.91 (s, 1H), 7.75 (s, 1H), 7.38 (s, 1H), 7.32 (d, 1H, J = 8.4 Hz), 7.02 (d, 2H, J = 9.0 Hz), 6.22 (d, 1H, J = 8.5 Hz), 4.99 (s, 1H), 4.01 (s, 3H), 3.49 (s, 3H), 2.80-2.89 (m, 1H), 2.04 (s, 6H), 1.87-1.97 (m, 2H), 1.69-1.77 (m, 4H), 1.58-1.66 (m, 2H), 1.47-1.56 (m, 4H), 1.43 (s, 6H).

[0283] Step 8: 2-(2-cyclopentyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5- (2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0284] To 3-((2-cyclopentyl-lH-imidazol-5-yl)ethynyl)-5-(2-(4-fluoro-2,6-dimethylphenoxy)- 5-(2-hydroxypropan-2-yl)phenyl)-4-methoxy-l-methylpyridin-2(lH)-one (597.73, 210 mg, 0.351 mmol, leq) was dissolved in 50 mL dry DMSO and 50 mL dry triethylamine, gassed, sealed and heated in an oil bath at 80 °C for 5 days. The reaction was checked for completion, diluted with a large volume of ethyl acetate, washed sequentially with water, saturated sodium chloride solution, concentrated and purified by column chromatography on silica gel (dichloromethane:methanol = 500:17) to give 2-(2-cyclopentyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5- (2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one (583.70, 100 mg, 0.171 mmol, 49%). 1 H NMR (500 MHz, DMSO-d6): δ 11.95 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.38 (d, 1H, J = 8.2 Hz), 7.31 (s, 1H), 6.98 (d, 2H, J = 8.8 Hz), 6.89 (s, 1H), 6.30 (d, 1H, J = 8.4 Hz), 5.02 (s, 1H), 3.61 (s, 3H), 2.83-2.90 (m, 1H), 2.04 (s, 6H), 1.88-1.99 (m, 2H), 1.67-1.78 (m, 4H), 1.59-1.66 (m, 2H), 1.50-1.57 (m, 4H), 1.47 (s, 6H).

[0285] Example 8: 2-(2-(adamantan-l-yl)-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)- 5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0286]

[0287] Synthetic procedure as in Example 7, yield 23%. 1H NMR (500 MHz, DMSO-d6): δ 11.93 (s, 1H), 7.73 (s, 1H), 7.60 (s, 1H), 7.35-7.39 (m, 2H), 6.99 (d, 2H, J = 8.9 Hz), 6.92 (s, 1H), 6.30 (d, 1H, J = 8.6 Hz), 5.03 (s, 1H), 3.61 (s, 3H), 1.99-2.08 (m, 9H), 1.90-1.96 (m, 6H), 1.68-1.78 (m, 6H), 1.47 (s, 6H).

[0288] Example 9: 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5- methyl-2-(2-phenyl-lH-imidazol-5-yl)furo[3,2-c]pyridin-4(5H)-one

[0289]

[0290] Synthesis as in Example 7, yield 26%. 1 H NMR (500 MHz, DMSO-d6): δ 12.90 (s, 1H), 7.97 (d, 1H, J = 7.4 Hz), 7.76 (s, 1H), 7.58-7.67 (m, 2H), 7.46-7.49 (m, 2H), 7.37-7.40 (m, 2H), 7.07 (s, 1H), 6.97 (d, 2H, J = 9.0 Hz), 6.31 (d, 1H, J = 8.6 Hz), 5.03 (s, 1H), 3.62 (s, 3H), 2.06 (s, 6H), 1.48 (s, 6H).

[0291] Example 10: 2-(2-(bicyclo[2.2.1]heptan-2-yl)-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0292]

[0293] Synthesis as in Example 7, yield 33%. 1H NMR (500 MHz, DMSO-d6): δ 11.97 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.29-7.45 (m, 2H), 6.97 (d, 2H, J = 8.6 Hz), 6.91 (s, 1H), 6.29 (d, 1H, J = 8.6 Hz), 5.02 (s, 1H), 3.60 (s, 3H), 3.09-3.17 (m, 1H), 2.43-2.46 (m, 1H), 2.22-2.30 (m, 1H), 2.03 (s, 6H), 1.75-1.88 (m, 2H), 1.41-1.52 (s, 6H), 1.33-1.38 (m, 1H), 1.23-1.29 (m, 2H), 0.97-1.07 (m, 1H).

[0294] Example 11: 2-(2-cyclopentyl-4-methyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0295]

[0296] Synthetic procedure as for Example 7, step 7 and step 8, yield 13%. 1 H NMR (500 MHz, DMSO-d6): δ 11.77 (s, 1H), 7.71 (s, 1H), 7.60 (s, 1H), 7.37 (d, 1H, J = 8.6 Hz), 6.97 (d, 2H, J = 9.0 Hz), 6.76 (s, 1H), 6.30 (d, 1H, J = 8.6 Hz), 5.01 (s, 1H), 3.61 (s, 3H), 2.97-3.03 (m, 1H), 2.28 (s, 3H), 2.01 (s, 6H), 1.91-1.94 (m, 2H), 1.67-1.75 (m, 4H), 1.56-1.63 (m, 2H), 1.45 (s, 6H).

[0297] Example 12: 2-(2-cyclohexyl-4-methyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0298]

[0299] Synthetic procedure as for Example 7, step 7 and step 8, yield 15%. 1H NMR (500 MHz, DMSO-d6): δ 11.74 (s, 1H), 7.71 (s, 1H), 7.60 (s, 1H), 7.36 (d, 1H, J = 8.6 Hz), 6.96 (d, 2H, J = 8.8 Hz), 6.77 (s, 1H), 6.29 (d, 1H, J = 8.6 Hz), 5.02 (s, 1H), 3.60 (s, 3H), 2.55-2.60 (m, 1H), 2.26 (s, 3H), 1.99 (s, 6H), 1.83-1.91 (m, 2H), 1.70-1.79 (m, 2H), 1.64-1.69 (m, 1H), 1.39-1.51 (m, 8H), 1.27-1.34 (m, 2H), 1.19-1.25 (m, 1H).

[0300] Example 13: 2-(2-(adamantan-l-yl)-4-methyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridine- 4(5H)-one

[0301]

[0302] Synthesis was carried out according to the procedure of Example 7, step 7 and step 8, in 21% yield. 1 H NMR (500 MHz, DMSO-d6): δ 11.67 (s, 1H), 7.72 (s, 1H), 7.61 (s, 1H), 7.37 (d, 1H, J = 8.6 Hz), 6.97 (d, 2H, J = 9.0 Hz), 6.73 (s, 1H), 6.30 (d, 1H, J = 8.7 Hz), 4.99 (s, 1H), 3.61 (s, 3H), 2.30 (s, 3H), 1.99-2.07 (m, 9H), 1.87-1.94 (m, 6H), 1.70-1.75 (m, 6H), 1.46 (s, 6H).

[0303] Example 14: 2-(2-cyclopropyl-4-ethyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridine- 4(5H)-one

[0304]

[0305] Synthesis was carried out according to the procedure of Example 7, step 7 and step 8, in 21% yield. 1H NMR (500 MHz, DMSO-d6): δ 11.82 (s, 1H), 7.73 (s, 1H), 7.60 (s, 1H), 7.38 (d, 1H, J = 8.5 Hz), 6.97 (d, 2H, J = 9.0 Hz), 6.79 (s, 1H), 6.31 (d, 1H, J = 8.6 Hz), 5.00 (s, 1H), 3.61 (s, 3H), 3.46-3.49 (m, 1H), 2.65-2.72 (m, 2H), 2.20-2.32 (m, 4H), 2.01 (s, 6H), 1.92-1.97 (m, 1H), 1.79-1.87 (m, 1H), 1.46 (s, 6H), 1.08 (t, 3H, J = 7.4 Hz).

[0306] Example 15: 2-(2-cyclobutyl-4-ethyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridine- 4(5H)-one

[0307]

[0308] Synthetic procedure as for Example 7, step 7 and step 8, yield 41%. 1 H NMR (500 MHz, DMSO-d6): δ 11.82 (s, 1H), 7.73 (s, 1H), 7.60 (s, 1H), 7.38 (d, 1H, J = 8.5 Hz), 6.97 (d, 2H, J = 9.0 Hz), 6.79 (s, 1H), 6.31 (d, 1H, J = 8.6 Hz), 5.00 (s, 1H), 3.61 (s, 3H), 3.46-3.49 (m, 1H), 2.65-2.72 (m, 2H), 2.20-2.32 (m, 4H), 2.01 (s, 6H), 1.92-1.97 (m, 1H), 1.79-1.87 (m, 1H), 1.46 (s, 6H), 1.08 (t, 3H, J = 7.4 Hz).

[0309] Example 16: 2-(2-cyclopentyl-4-ethyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridine- 4(5H)-one

[0310]

[0311] Synthetic procedure as for Example 7, step 7 and step 8, yield 41%. 1H NMR (500 MHz, DMSO-d6): δ 11.74 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.38 (d, 1H, J = 8.0 Hz), 6.97 (d, 2H, J = 8.6 Hz), 6.75 (s, 1H), 6.31 (d, 1H, J = 8.3 Hz), 5.00 (s, 1H), 3.61 (s, 3H), 2.97-3.09 (m, 1H), 2.63-2.74 (m, 2H), 2.01 (s, 6H), 1.92-1.97 (m, 2H), 1.68-1.78 (m, 4H), 1.55-1.64 (m, 2H), 1.46 (s, 6H), 1.04-1.13 (m, 3H).

[0312] Example 17: 2-(2-cyclohexyl-4-ethyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0313]

[0314] Synthetic procedure as for Example 7, step 7 and step 8, in 38% yield. 1 H NMR (500 MHz, DMSO-d6): δ 11.71 (s, 1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.36 (d, 1H, J = 8.4 Hz), 6.96 (d, 2H, J = 8.8 Hz), 6.76 (s, 1H), 6.29 (d, 1H, J = 8.6 Hz), 5.00 (s, 1H), 3.60 (s, 3H), 2.64-2.72 (m, 2H), 2.56-2.61 (m, 1H), 1.99 (s, 6H), 1.84-1.92 (m, 2H), 1.71-1.80 (m, 2H), 1.62-1.70 (m, 1H), 1.47-1.52 (m, 2H), 1.46 (s, 6H), 1.27-1.35 (m, 3H), 1.06 (t, 3H, J = 7.2 Hz).

[0315] Example 18: 2-(2-cycloheptyl-4-ethyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0316]

[0317] Synthetic procedure as for Example 7, step 7 and step 8, in 23% yield.1 H NMR (500 MHz, DMSO-d6): δ 11.70 (s, 1H), 7.71 (s, 1H), 7.59 (s, 1H), 7.37 (d, 1H, J = 8.4 Hz), 6.97 (d, 2H, J = 8.9 Hz), 6.72 (s, 1H), 6.30 (d, 1H, J = 8.3 Hz), 4.99 (s, 1H), 3.61 (s, 3H), 2.76-2.83 (m, 1H), 2.65-2.73 (m, 2H), 2.01 (s, 6H), 1.88-1.96 (m, 2H), 1.67-1.76 (m, 4H), 1.58-1.65 (m, 2H), 1.49-1.57 (m, 4H), 1.46 (s, 6H), 1.03-1.12 (m, 3H).

[0318] Example 19: 2-(2-(Bicyclo[2.2.1]heptan-2-yl)-4-ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridine- 4(5H)-one

[0319]

[0320] Synthetic procedure like Example 7, step 7 and step 8, yield 42%. 1 H NMR (500 MHz, DMSO-d6): δ 11.69 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.38 (d, 1H, J = 8.8 Hz), 6.97 (d, 2H, J = 9.0 Hz), 6.76 (s, 1H), 6.31 (d, 1H, J = 8.6 Hz), 5.00 (s, 1H), 3.61 (s, 3H), 3.04-3.13 (m, 1H), 2.65-2.75 (m, 2H), 2.45-2.51 (m, 1H), 2.22-2.29 (m, 1H), 2.00 (s, 6H), 1.75-1.83 (m, 2H), 1.46-1.54 (s, 8H), 1.32-1.38 (m, 1H), 1.20-1.27 (m, 2H), 1.03-1.12 (m, 4H).

[0321] Example 20: 2-(2-(Adamantan-1-yl)-4-ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridine- 4(5H)-one

[0322]

[0323] Synthetic procedure like example 7, step 7 and step 8, yield 44%. 1 H NMR (500 MHz, DMSO-d6): δ 11.59 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.38 (d, 1H, J = 8.5 Hz), 6.98 (d, 2H, J = 9.0 Hz), 6.73 (s, 1H), 6.30 (d, 1H, J = 8.6 Hz), 5.00 (s, 1H), 3.61 (s, 3H, N-CH3), 2.66-2.77 (m, 2H), 1.97-2.07 (m, 9H), 1.88-1.96 (m, 6H), 1.68-1.79 (m, 6H), 1.46 (s, 6H), 1.03-1.14 (m, 3H).

[0324] Example 21 : 2-(2,4-Dimethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0325]

[0326] Step 1 : 5-Bromo-4-methoxy-1 -methylpyridin-2(1 H)-one

[0327] Take compound 5-bromo-4-chloro-1 -methylpyridin-2(1 H)-one (220.47, 1 g, 4.536 mmol, 1 eq) in a flask, add 20 mL of dioxane to dissolve, then add 5.4 M sodium methoxide methanol solution (32.04, 4.5 mL, 24.36 mmol, 5.3 eq), air exchange, oil bath 50 °C for 3 h. Check the reaction completion, add enough ethyl acetate, wash with saturated NaCl aqueous solution twice, dry with anhydrous sodium sulfate, rotary evaporation to get the crude product 5-bromo-4-methoxy-1 -methylpyridin-2(1 H)-one (218.05, 600 mg, 2.752 mmol, 60%). 1 H NMR (500 MHz, DMSO-d6): δ 8.03 (s, 1H), 5.93 (s, 1H), 3.81 (s, 3H), 3.33 (s, 3H).

[0328] Step 2: 5-Bromo-3-iodo-4-methoxy-1 -methylpyridin-2(1 H)-one

[0329] To compound 5-bromo-4-methoxy-l-methylpyridin-2(lH)-one (218.05, 20.9 g, 95.850 mmol, 1 eq), NIS (224.98, 25.88 g, 115.032 mmol, 1.2 eq) was bubbled, 330 mL dry acetonitrile was added, after stirring well, trifluoroacetic acid (114.02, 2.1 mL, 28.273 mmol, 0.3 eq, 1.535 g / mL) was added, and the reaction was carried out at room temperature for 15 h. After the reaction was detected to be complete, the solvent was removed by rotary evaporation, diluted with a large amount of ethyl acetate, washed with saturated sodium thiosulfate 3 times, saturated NaCl 1 time, dried over anhydrous sodium sulfate, and rotary evaporated. The product was precipitated by adding an appropriate amount of dichloromethane, and the solid product was obtained by suction filtration; the mother liquor was column chromatographed (petroleum ether: ethyl acetate = 2: 1) to obtain 5-bromo-3-iodo-4-methoxy-l-methylpyridin-2(lH)-one (343.95, 17.1 g, 49.717 mmol, 52%). 1 H NMR (500 MHz, CDC13): δ 7.54 (s, 1H), 3.95 (s, 3H), 3.62 (s, 3H).

[0330] Step 3: 7-bromo-2-(2,4-dimethyl-lH-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0331] The reactants were pre-evacuated and dried in a sealed tube, compound 5-bromo-3-iodo-4-methoxy-l-methylpyridin-2(lH)-one (343.95, 600 mg, 1.744 mmol, 1 eq), CuI (190.45, 33 mg, 0.173 mmol, 0.1 eq), PdCl2(PPh3)2 (701.9, 60 mg, 0.0855 mmol, 0.05 eq), 5-ethynyl-2,4-dimethyl-lH-imidazole (120.16, 419 mg, 3.483 mmol, 2 eq) were added, and the oil pump was strictly bubbled. Meanwhile, 24 mL of chromatographic grade triethylamine and 8 mL of dry DMF were added to a double-mouth bottle, and after strict bubbling, the Et3N-DMF solution was quickly added to the reaction system, and treated with strict bubbling for 15 min. The reaction was carried out at 80°C for 48 h. After the reaction was detected to be complete, it was diluted with ethyl acetate, the solid impurities were removed with diatomite, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, rotary evaporated, and column chromatographed (dichloromethane:methanol = 10:1) to obtain 7-bromo-2-(2,4-dimethyl-lH-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one (322.16, 290 mg, 0.900 mmol, 52%). 1H NMR (500 MHz, DMSO-d6): δ 11.93 (s, 1H), 7.97 (s, 1H), 6.78 (s, 1H), 3.51 (s, 3H), 2.43 (s, 3H), 2.27 (s, 3H).

[0332] Step 4: 2-(2,4-Dimethyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0333] Double-mouth flask was added 7-bromo-2-(2,4-dimethyl-lH-imidazol-5-yl)-5- methylfuro[3,2-c]pyridin-4(5H)-one (322.16, 89 mg, 0.276 mmol, 1 eq), K3PO4 (212.27, 425 mg, 2 mmol, 7.25 eq), catalyst PdCl2(dppf) CH2Cl2(816.65, 18 mg, 0.0220 mmol, 0.08 eq), and air was exchanged. Another double-mouth flask was added with compound 2-(3-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)propan-2-ol (386.27, 320 mg, 0.828 mmol, 3 eq), dioxane 3 mL, and water phase 1 mL, and air was exchanged for 45 min. Then the dioxane / water solution of 2-(3-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)propan-2-ol was added into the reaction system, and air was exchanged. The reaction was refluxed at 85 °C for 8 h. After the reaction was detected to be complete, ethyl acetate was added for dilution, and the mixture was washed with saturated sodium chloride solution twice, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (dichloromethane:methanol = 500:30) twice to obtain the crude product. The crude product was re-purified by column chromatography (ethyl acetate:methanol = 500:20) to obtain pure 2-(2,4-dimethyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one (515.59, 42 mg, 0.0815 mmol, 30%). 1H NMR (500 MHz, CD3OD): δ 7.71 (s, 1H), 7.70 (d, 1H, J = 2.3 Hz), 7.40 (dd, 1H, J = 8.6, 2.3 Hz), 7.01 (s, 1H), 6.84 (d, 2H, J = 9.0 Hz), 6.41 (d, 1H, J = 8.6 Hz), 3.76 (s, 3H), 2.35 (s, 3H), 2.34 (s, 3H), 2.04 (s, 6H), 1.57 (s, 6H).

[0334] Example 22: 2-(2-Ethyl-4-methyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0335]

[0336] Synthesis as in Example 21, 75% yield. 1 H NMR (500 MHz, CD3OD): δ 7.71 (s, 1H), 7.70 (d, 1H, J = 2.3 Hz), 7.40 (dd, 1H, J = 8.6, 2.3 Hz), 7.01 (s, 1H), 6.84 (d, 2H, J = 9.0 Hz), 6.41 (d, 1H, J = 8.6 Hz), 3.76 (s, 3H), 2.35 (s, 3H), 2.34 (s, 3H), 2.04 (s, 6H), 1.57 (s, 6H).

[0337] Example 23: 7-(2-(4-Fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)- 2-(2-isopropyl-4-methyl-lH-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0338]

[0339] Synthesis as in Example 21, 51% yield. 1 H NMR (500 MHz, CD3OD): δ 7.71 (s, 1H), 7.70 (d, 1H, J = 2.3 Hz), 7.40 (dd, 1H, J = 8.6, 2.3 Hz), 7.01 (s, 1H), 6.84 (d, 2H, J = 9.0 Hz), 6.41 (d, 1H, J = 8.6 Hz), 3.76 (s, 3H), 2.35 (s, 3H), 2.34 (s, 3H), 2.04 (s, 6H), 1.57 (s, 6H).

[0340] Example 24: 2-(2-cyclopropyl-4-methyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0341]

[0342] Synthesis as in Example 21, yield 60%. 1 H NMR (500 MHz, DMSO-d6): δ 11.83 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H, 6.30 (d, 1H, J = 8.6 Hz), 5.00 (s, 1H), 3.60 (s, 3H), 2.27 (s, 3H), 2.01 (s, 6H), 1.84-1.91 (m, 1H), 1.45 (s, 6H), 0.75-0.91 (m, 4H).

[0343] Example 25: 2-(2-cyclobutyl-4-methyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0344]

[0345] Synthesis as in Example 21, yield 33%. 1 H NMR (500 MHz, CD3OD): δ 7.68-7.74 (m, 2H), 7.40 (d, 1H, J = 8.6 Hz), 7.04 (s, 1H), 6.83 (d, 2H, J = 8.6 Hz), 6.40 (d, 1H, J = 8.7 Hz), 3.76 (s, 3H), 3.55-3.62 (m, 1H), 2.33-2.41 (m, 7H), 2.07-2.11 (m, 1H), 2.04 (s, 6H), 1.89-1.96 (m, 1H), 1.58 (s, 6H).

[0346] Example 26: 2-(4-ethyl-2-methyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0347]

[0348] Synthesis as in Example 21, yield 70%. 1H NMR (500 MHz, DMSO-d6): δ 11.80 (s, 1H), 7.71 (s, 1H), 7.58 (d, 1H, J = 1.7 Hz), 7.37 (dd, 1H, J = 8.6, 2.0 Hz), 6.97 (d, 2H, J = 9.1 Hz), 6.74 (s, 1H), 6.31 (d, 1H, J = 8.6 Hz), 5.01 (s, 1H), 3.60 (s, 3H), 2.68 (q, 2H, J = 6.8 Hz), 2.24 (s, 3H), 2.00 (s, 6H), 1.45 (s, 6H), 1.06 (t, 3H, J = 7.4 Hz).

[0349] Example 27: 2-(2,4-Dimethyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0350]

[0351] Synthesis as in Example 21, yield 67%. 1 H NMR (500 MHz, CDCl3): δ 7.91 (d, 1H, J = 1.6 Hz), 7.58 (s, 1H), 7.19 (dd, 1H, J = 8.6, 2.1 Hz), 6.94 (s, 1H), 6.79 (d, 2H, J = 8.7 Hz), 6.35 (d, 1H, J = 8.6 Hz), 3.69 (s, 3H), 2.74 (q, 2H, J = 7.5 Hz), 2.64 (q, 2H, J = 7.6 Hz), 2.07 (s, 6H), 1.53 (s, 6H), 1.22 (t, 3H, J = 7.7 Hz), 1.18 (t, 3H, J = 7.6 Hz).

[0352] Example 27: 2-(2,4-Dimethyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0353]

[0354] Synthesis as in Example 21, yield 45%. 1H NMR (500 MHz, CDC13): δ 7.89 (s, 1H), 7.56 (s, 1H), 7.23 (d, 1H, J = 8.4 Hz), 6.95 (s, 1H), 6.78 (d, 2H, J = 8.6 Hz), 6.37 (d, 1H, J = 8.6 Hz), 3.69 (s, 3H), 3.01-3.08 (m, 1H), 2.72-2.82 (m, 2H), 2.07 (s, 6H), 1.59 (s, 6H), 1.20-11.31 (m, 9H).

[0355] Example 29: 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5- methyl-2-(2-methyl-4-propyl-lH-imidazol-5-yl)furo[3,2-c]pyridin-4(5H)-one

[0356]

[0357] Synthesis as in Example 21, 37% yield. 1 H NMR (500 MHz, CDC13): δ 7.89 (s, 1H), 7.56 (s, 1H), 7.23 (d, 1H, J = 8.4 Hz), 6.95 (s, 1H), 6.78 (d, 2H, J = 8.6 Hz), 6.37 (d, 1H, J = 8.6 Hz), 3.69 (s, 3H), 3.01-3.08 (m, 1H), 2.72-2.82 (m, 2H), 2.07 (s, 6H), 1.59 (s, 6H), 1.20-11.31 (m, 9H).

[0358] Example 30: 2-(2-ethyl-4-propyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5- (2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0359]

[0360] Synthesis as in Example 21, 56% yield. 1H NMR (500 MHz, CD3OD): δ 7.68 (s, 1H), 7.66 (d, 1H, J = 2.4 Hz), 7.41 (dd, 1H, J = 8.6, 2.3 Hz), 7.04 (s, 1H), 6.83 (d, 2H, J = 9.0 Hz), 6.41 (d, 1H, J = 8.6 Hz, Ar-H), 3.76 (s, 3H), 2.67-2.77 (m, 4H), 2.04 (s, 6H), 1.53-1.57 (m, 8H), 1.30 (t, 3H, J = 7.6 Hz), 0.77 (t, 3H, J = 7.4 Hz).

[0361] Example 31 : 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(4- isopropyl-2-methyl-1H-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0362]

[0363] Synthesis as in Example 21, yield 29%. 1 H NMR (500 MHz, CD3OD): δ 7.70 (s, 1H), 7.66 (d, 1H, J = 2.0 Hz), 7.41 (dd, 1H, J = 8.6, 2.0 Hz), 7.02 (s, 1H), 6.83 (d, 2H, J = 9.0 Hz), 6.40 (d, 1H, J = 8.7 Hz), 3.76 (s, 3H), 3.36-3.40 (m, 1H), 2.36 (s, 3H), 2.03 (s, 6H), 1.57 (s, 6H), 1.22 (d, 6H, J = 7.0 Hz).

[0364] Example 32: 2-(2-ethyl-4-isopropyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5- (2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0365]

[0366] Synthesis as in Example 21, yield 34%. 1H NMR (500 MHz, CD3OD): δ 7.73 (s, 1H), 7.69 (d, 1H, J = 2.3 Hz), 7.41 (dd, 1H, J = 8.7, 2.4 Hz), 7.16 (s, 1H), 6.83 (d, 2H, J = 9.0 Hz), 6.41 (d, 1H, J = 8.7 Hz), 4.54 (s, 2H), 3.76 (s, 3H), 3.22 (s, 3H), 2.74 (q, 2H, J = 7.6 Hz), 2.03 (s, 6H), 1.58 (s, 6H), 1.32 (t, 3H, J = 7.6 Hz).

[0367] Example 33: 2-(2-ethyl-4-(methoxymethyl)-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0368]

[0369] Synthesis as in Example 21, 64% yield. 1 H NMR (500 MHz, CD3OD): δ 7.73 (s, 1H), 7.69 (d, 1H, J = 2.3 Hz), 7.41 (dd, 1H, J = 8.7, 2.4 Hz), 7.16 (s, 1H), 6.83 (d, 2H, J = 9.0 Hz), 6.41 (d, 1H, J = 8.7 Hz), 4.54 (s, 2H), 3.76 (s, 3H), 3.22 (s, 3H), 2.74 (q, 2H, J = 7.6 Hz), 2.03 (s, 6H), 1.58 (s, 6H), 1.32 (t, 3H, J = 7.6 Hz).

[0370] Example 34: 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2- (2-isopropyl-4-(methoxymethyl)-1H-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0371]

[0372] Synthesis as in Example 21, 64% yield. 1H NMR (500 MHz, CD3OD): δ 7.73 (s, 1H), 7.69 (d, 1H, J = 2.3 Hz, Ar-H), 7.41 (dd, 1H, J = 8.6, 2.3 Hz), 7.17 (s, 1H), 6.83 (d, 2H, J = 8.9 Hz), 6.41 (d, 1H, J = 8.6 Hz), 4.53 (s, 2H), 3.76 (s, 3H), 3.22 (s, 3H), 3.05-3.10 (m, 1H), 2.03 (s, 6H), 1.58 (s, 6H), 1.34 (d, 6H, J = 7.0 Hz).

[0373] Example 35: 2-(2-cyclopropyl-4-(methoxymethyl)-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0374]

[0375] Synthesis as in Example 21, 77% yield. 1 H NMR (500 MHz, CD3OD): δ 7.73 (s, 1H), 7.69 (d, 1H, J = 2.3 Hz, Ar-H), 7.41 (dd, 1H, J = 8.6, 2.3 Hz), 7.17 (s, 1H), 6.83 (d, 2H, J = 8.9 Hz), 6.41 (d, 1H, J = 8.6 Hz), 4.53 (s, 2H), 3.76 (s, 3H), 3.22 (s, 3H), 3.05-3.10 (m, 1H), 2.03 (s, 6H), 1.58 (s, 6H), 1.34 (d, 6H, J = 7.0 Hz).

[0376] Example 36: 2-(2-cyclobutyl-4-(methoxymethyl)-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0377]

[0378] Synthesis as in Example 21, 77% yield. 1H NMR (500 MHz, CD3OD): δ 7.73 (s, 1H), 7.69 (d, 1H, J = 2.2 Hz), 7.41 (dd, 1H, J = 8.6, 2.3 Hz), 7.17 (s, 1H), 6.83 (d, 2H, J = 8.9 Hz), 6.41 (d, 1H, J = 8.7 Hz), 4.54 (s, 2H), 3.76 (s, 3H), 3.59-3.66 (m, 1H), 3.21 (s, 3H), 2.32-2.44 (m, 4H), 2.07-2.14 (m, 1H), 2.03 (s, 6H), 1.90-1.98 (m, 1H), 1.58 (s, 6H).

[0379] Example 37: 2-(2,4-Dimethyl-lH-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0380]

[0381] Synthesis as in Example 21, yield 44%. 1 H NMR (500 MHz, CD3OD): δ 7.83 (d, 1H, J = 9.0 Hz), 7.70 (s, 1H), 7.01 (s, 1H), 6.87 (d, 2H, J = 8.9 Hz), 6.13 (d, 1H, J = 13.0 Hz), 3.75 (s, 3H), 2.37 (s, 3H), 2.35 (s, 3H), 2.06 (s, 6H), 1.61 (s, 6H).

[0382] Example 38: 2-(2-Ethyl-4-methyl-lH-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0383]

[0384] Synthesis as in Example 21, yield 44%. 1H NMR (500 MHz, CD3OD): δ 7.83 (d, 1H, J = 9.0 Hz), 7.70 (s, 1H), 7.02 (s, 1H), 6.87 (d, 2H, J = 8.9 Hz), 6.13 (d, 1H, J = 13.0 Hz), 3.75 (s, 3H), 2.71 (q, 2H, J = 7.6 Hz), 2.38 (s, 3H), 2.06 (s, 6H), 1.61 (s, 6H), 1.30 (t, 3H, J = 7.6 Hz).

[0385] Example 39: 7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(2-isopropyl-4-methyl-1H-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0386]

[0387] Synthesis as in Example 21, yield 39%. 1 H NMR (500 MHz, CD3OD): δ 7.83 (d, 1H, J = 9.0 Hz), 7.70 (s, 1H), 7.04 (s, 1H), 6.86 (d, 2H, J = 8.8 Hz), 6.12 (d, 1H, J = 13.0 Hz), 3.75 (s, 3H), 3.00-3.09 (m, 1H), 2.38 (s, 3H), 2.06 (s, 6H), 1.61 (s, 6H), 1.33 (d, 6H, J = 7.0 Hz).

[0388] Example 40: 2-(2-cyclopropyl-4-methyl-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0389]

[0390] Synthesis as in Example 21, yield 51%. 1 H NMR (500 MHz, CD3OD): δ 7.82 (d, 1H, J = 9.0 Hz), 7.70 (s, 1H), 7.01 (s, 1H), 6.87 (d, 2H, J = 8.8 Hz), 6.12 (d, 1H, J = 13.0 Hz), 3.75 (s, 3H), 2.35 (s, 3H), 2.06 (s, 6H), 1.93-1.99 (m, 1H), 1.61 (s, 6H), 0.96-1.01 (m, 2H), 0.90-0.95 (m, 2H).

[0391] Example 41 : 2-(2-cyclobutyl-4-methyl-1 H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0392]

[0393] Synthesis as in Example 21, 82% yield. 1 H NMR (500 MHz, CD3OD): δ 7.82 (d, 1 H, J = 9.0 Hz), 7.71 (s, 1 H), 7.04 (s, 1 H), 6.87 (d, 2H, J = 8.9 Hz), 6.12 (d, 1 H, J = 13.0 Hz), 3.75 (s, 3H), 3.55-3.63 (m, 1 H), 2.39 (s, 3H), 2.34-2.37 (m, 4H), 2.07-2.13 (m, 1 H), 2.06 (s, 6H), 1.90-1.97 (m, 1 H), 1.61 (s, 6H).

[0394] Example 41 : 2-(2-cyclobutyl-4-methyl-1 H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0395]

[0396] Synthesis as in Example 21, 82% yield. 1 H NMR (500 MHz, CD3OD): δ 7.82 (d, 1 H, J = 9.0 Hz), 7.71 (s, 1 H), 7.04 (s, 1 H), 6.87 (d, 2H, J = 8.9 Hz), 6.12 (d, 1 H, J = 13.0 Hz), 3.75 (s, 3H), 3.55-3.63 (m, 1 H), 2.39 (s, 3H), 2.34-2.37 (m, 4H), 2.07-2.13 (m, 1 H), 2.06 (s, 6H), 1.90-1.97 (m, 1 H), 1.61 (s, 6H).

[0397] Example 41 : 2-(2-cyclobutyl-4-methyl-1 H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0398]

[0399] Synthesis as in Example 21, yield 32%. 1 H NMR (500 MHz, CD3OD): δ 7.81 (d, 1 H, J = 9.0 Hz), 7.70 (s, 1 H), 7.03 (s, 1 H), 6.87 (d, 2 H, J = 8.8 Hz), 6.13 (d, 1 H, J = 13.0 Hz), 3.75 (s, 3 H), 2.80 (q, 2 H, J = 7.4 Hz), 2.71 (q, 2 H, J = 7.6 Hz), 2.05 (s, 6 H), 1.61 (s, 6 H), 1.31 (t, 3 H, J = 7.6 Hz), 1.17 (t, 3 H, J = 7.5 Hz).

[0400] Example 44: 2-(4-Ethyl-2-isopropyl-1 H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0401]

[0402] Synthesis as in Example 21, yield 88%. 1 H NMR (500 MHz, CD3OD): δ 7.80 (d, 1 H, J = 9.0 Hz), 7.70 (s, 1 H), 7.04 (s, 1 H), 6.86 (d, 2 H, J = 8.8 Hz), 6.12 (d, 1 H, J = 13.0 Hz), 3.75 (s, 3 H), 3.02-3.09 (m, 1 H), 2.80 (q, 2 H, J = 8.8 Hz), 2.05 (s, 6 H), 1.61 (s, 6 H), 1.33 (d, 6 H, J = 7.0 Hz), 1.17 (t, 3 H, J = 7.5 Hz).

[0403] Example 45: 7-(4-Fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)- 5-methyl-2-(2-methyl-4-propyl-1 H-imidazol-5-yl)furo[3,2-c]pyridin-4(5H)-one

[0404]

[0405] Synthesis as in Example 21, yield 93%. 1H NMR (500 MHz, CD3OD): δ 7.79 (d, 1 H, J = 9.1 Hz), 7.68 (s, 1 H), 7.03 (s, 1 H), 6.87 (d, 2 H, J = 8.9 Hz), 6.13 (d, 1 H, J = 13.0 Hz), 3.75 (s, 3 H), 2.73 (t, 2 H, J = 7.4 Hz), 2.36 (s, 3 H), 2.05 (s, 6 H), 1.61 (s, 6 H), 1.53-1.59 (m, 2 H), 0.80 (t, 3 H, J = 7.4 Hz).

[0406] Example 46: 2-(2-Ethyl-4-propyl-lH-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0407]

[0408] Synthesis as in Example 21, 96% yield. 1 H NMR (500 MHz, CD3OD): δ 7.79 (d, 1 H, J = 9.1 Hz), 7.68 (s, 1 H), 7.03 (s, 1 H), 6.87 (d, 2 H, J = 8.9 Hz), 6.13 (d, 1 H, J = 13.0 Hz), 3.75 (s, 3 H), 2.73 (t, 2 H, J = 7.4 Hz), 2.36 (s, 3 H), 2.05 (s, 6 H), 1.61 (s, 6 H), 1.53-1.59 (m, 2 H), 0.80 (t, 3 H, J = 7.4 Hz).

[0409] Example 47: 7-(4-Fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2- yl)phenyl)-2-(4-isopropyl-2-methyl-lH-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0410]

[0411] Synthesis as in Example 21, 96% yield. 1H NMR (500 MHz, CD3OD): δ 7.79 (d, 1 H, J = 9.0 Hz, Ar-H), 7.69 (s, 1 H), 7.02 (s, 1 H), 6.87 (d, 2 H, J = 8.8 Hz), 6.13 (d, 1 H, J = 13.0 Hz), 3.75 (s, 3 H), 3.35-3.41 (m, 1 H), 2.37 (s, 3 H), 2.05 (s, 6 H), 1.61 (s, 6 H), 1.24 (d, 6 H, J = 7.0 Hz).

[0412] Example 48: 2-(2-Ethyl-4-isopropyl-1 H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0413]

[0414] Synthesis as in Example 21, yield 64%. 1 H NMR (500 MHz, CD3OD): δ 7.79 (d, 1 H, J = 9.0 Hz, Ar-H), 7.69 (s, 1 H), 7.02 (s, 1 H), 6.87 (d, 2 H, J = 8.8 Hz), 6.13 (d, 1 H, J = 13.0 Hz), 3.75 (s, 3 H), 3.35-3.41 (m, 1 H), 2.37 (s, 3 H), 2.05 (s, 6 H), 1.61 (s, 6 H), 1.24 (d, 6 H, J = 7.0 Hz).

[0415] Example 49: 2-(2-Ethyl-4-(methoxymethyl)-1 H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)- one

[0416]

[0417] Synthesis as in Example 21, yield 64%. 1H NMR (500 MHz, CD3OD): δ 7.79 (d, 1 H, J = 9.0 Hz), 7.71 (s, 1 H), 7.14 (s, 1 H), 6.85 (d, 2 H, J = 8.8 Hz), 6.12 (d, 1 H, J = 13.0 Hz), 4.54 (s, 2 H), 3.73 (s, 3 H), 3.23 (s, 3 H), 2.73 (q, 2 H, J = 7.6 Hz), 2.03 (s, 6 H), 1.59 (s, 6 H), 1.30 (t, 3 H, J = 7.6 Hz).

[0418] Example 50: 7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-2-(2-isopropyl-4-(methoxymethyl)-1 H-imidazol-5-yl)-5- methylfuro[3,2-c]pyridin-4(5H)-one

[0419]

[0420] Synthesis as in Example 21, yield 68%. 1 H NMR (500 MHz, CD3OD): δ 7.81 (d, 1 H, J = 9.0 Hz), 7.73 (s, 1 H), 7.17 (s, 1 H), 6.86 (d, 2 H, J = 8.9 Hz), 6.13 (d, 1 H, J = 13.0 Hz), 4.55 (s, 2 H), 3.76 (s, 3 H), 3.24 (s, 3 H), 3.04-3.12 (m, 1 H), 2.05 (s, 6 H), 1.61 (s, 6 H), 1.35 (d, 6 H, J = 7.0 Hz).

[0421] Example 51 : 2-(2-cyclopropyl-4-(methoxymethyl)-1 H-imidazol-5-yl)-7-(4-fluoro-2-(4- fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2- c]pyridin-4(5H)-one

[0422]

[0423] Synthesis as in Example 21, yield 79%. 1H NMR (500 MHz, CD3OD): δ 7.81 (d, 1 H, J = 9.0 Hz), 7.73 (s, 1 H), 7.17 (s, 1 H), 6.86 (d, 2 H, J = 8.9 Hz), 6.14 (d, 1 H, J = 13.0 Hz), 4.56 (s, 2 H), 3.76 (s, 3 H), 3.59-3.67 (m, 1 H), 3.24 (s, 3 H), 2.34-2.45 (m, 4 H), 2.09-2.14 (m, 1 H), 2.05 (s, 6 H), 1.91-1.98 (m, 1 H), 1.61 (s, 6 H).

[0424] Example 52: 2-(2-cyclobutyl-4-(methoxymethyl)-1 H-imidazol-5-yl)-7-(4-fluoro-2-(4- fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2- c]pyridin-4(5H)-one

[0425]

[0426] Synthesis as in Example 7, 19% yield. 1 H NMR (500 MHz, CD3OD): δ 7.81 (d, 1 H, J = 9.0 Hz), 7.73 (s, 1 H), 7.17 (s, 1 H), 6.86 (d, 2 H, J = 8.9 Hz), 6.14 (d, 1 H, J = 13.0 Hz), 4.56 (s, 2 H), 3.76 (s, 3 H), 3.59-3.67 (m, 1 H), 3.24 (s, 3 H), 2.34-2.45 (m, 4 H), 2.09-2.14 (m, 1 H), 2.05 (s, 6 H), 1.91-1.98 (m, 1 H), 1.61 (s, 6 H).

[0427] Example 53: 2-(2-(adamantan-1-yl)-1 H-imidazol-5-yl)-7-(3-fluoro-2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(4H)- one

[0428]

[0429] Synthesis as in Example 7, 19% yield. 1H NMR (500 MHz, DMSO-d6): δ 11.93 (s, 1H), 7.68 (s, 1H), 7.29-7.46 (m, 3H), 6.84 (s, 1H), 6.75 (d, 2H, J = 9.0 Hz), 5.19 (s, 1H), 3.56 (s, 3H), 1.98-2.08 (m, 9H), 1.93-1.98 (m, 6H), 1.69-1.78 (m, 6H), 1.47 (s, 6H).

[0430] 7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methyl-2-(2-phenyl-1H-imidazol-5-yl)furo[3,2-c]pyridin-4(5H)-one

[0431] Example 54: 7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methyl-2-(2-phenyl-1H-imidazol-5-yl)furo[3,2-c]pyridin-4(5H)-one

[0432]

[0433] Synthetic procedure as in Example 21, yield 25%. 1 H NMR (500 MHz, CD3OD): δ 7.94 (d, 2H, J = 7.4 Hz), 7.82 (d, 1H, J = 8.8 Hz), 7.71 (s, 1H), 7.49-7.56 (m, 3H), 7.43-7.46 (m, 1H), 7.30 (s, 1H), 6.88 (d, 2H, J = 8.8 Hz), 6.14 (d, 1H, J = 12.5 Hz), 3.76 (s, 3H), 2.12 (s, 6H), 1.63 (s, 6H).

[0434] Biological activity testing

[0435] 1. In vitro activity testing of compounds

[0436] Inhibition IC of compounds on the binding reaction of BET bromodomain 50 Values were performed using the homogeneous time-resolved fluorescence (HTRF) method. The C-terminal biotinylated H4KAc4 polypeptide sequence was: H-YSGRGK(Ac)GGK(Ac)GLGK(Ac)GGAK(Ac)RHRK-Biotin-OH. Europium-labeled streptavidin (Eu- SA) was used as a donor and Alexa647-labeled anti-His antibody was used as an acceptor. The final concentration of the polypeptide was 0.5 nM, the final concentration of Eu-SA was 0.5 nM, and the final concentration of Alexa647-labeled anti-His antibody was 0.5 nM. The final concentration of the test compound was 10 mM. 3+A cryptate-lable anti-His antibody was purchased from Thermo Fisher; Streptavidin-XL-665 was purchased from PerkinElmer; 384-well plates were purchased from PerkinElmer. Reaction buffer: 20 mM HEPES, 150 mM NaCl, 5 mM DTT, 0.005% Tween 20 and 100 μg / mL BSA, pH adjusted to 7.5. All bromodomain proteins used were His-tagged.

[0437] Compounds were serially diluted in DMSO, and 20 nL of each concentration was added to a 384-well plate. Subsequently, 10 μL of a mixture containing His-tagged bromodomain proteins (final concentration 2 nM) and biotin-labeled polypeptides (final concentration 20 nM) was added, and incubated for 1 hour at room temperature. 10 μL of a mixture containing Eu 3+ cryptate-lable anti-His antibody and Streptavidin-XL-665 was added, and incubated for 1 hour at room temperature. Fluorescence values were read on an EnVision (PerkinElmer) (excitation at 320 nm, emission at 620 nm and 665 nm). HTRF binding signal = 665 nm signal intensity / 620 nm signal intensity; the binding strength of each compound to the protein was determined at 10 concentrations, and the IC 50 values of the compounds were calculated using GraphPad Prism software.

[0438] The test results of some of the above compounds are shown in Table 1.

[0439] Table 1 In vitro activity results of compounds

[0440]

[0441]

[0442] As can be seen from Table 1, all the compounds have strong BRD4 bromodomain binding activity and BD2 bromodomain selectivity, and some of the compounds exhibit better BRD4 BD2 subtype selectivity.

[0443] 2. Proliferation inhibition activity of compounds on cancer cells

[0444] In this application, the Cell Titer-Glo reagent was used to determine the ability of the compounds to inhibit the proliferation of cancer cells. The MV4-11 cells were suspended in RPMI1640 medium containing 10% FBS and cultured at 37°C in a 5% CO2 incubator. After recovery, the cells were subcultured for at least two generations before use. When used, the cells were seeded in a 384-well plate at 500-1000 cells per well. The suspension cells were seeded at the same time as the cells and directly added with the test compound without culture for 12 hours. The test was performed after the compound was incubated with the cells for 120 hours. When tested: 25 μL of Cell Titer-GLO reagent (Promega) was added, and the fluorescence signal was measured using a GLOMAX microplate luminometer (Promega) according to the manufacturer's instructions. The maximum half-inhibitory concentration (IC 50 ) value was calculated using GraphPad Prism 6 software.

[0445] The results of the cancer cell proliferation inhibition activity of the selected part of the examples are shown in Table 2.

[0446] Table 2 In vitro anticancer activity of the compounds

[0447]

[0448] As can be seen from Table 2, most of the selected examples of the present application have strong anticancer activity on acute myeloid leukemia cells MV4-11, indicating that this series of BET inhibitors has good cell activity effect.

[0449] The present application is illustrated by the above examples, but the present application is not limited to the above examples, i.e. it does not mean that the present application must rely on the above examples to be implemented. It should be understood by those skilled in the art that any improvement of the present application, equivalent replacement of the selected raw materials of the present application, addition of auxiliary ingredients, selection of specific modes, etc. fall within the protection scope and disclosure scope of the present application.

Claims

1. A compound having the structure of Formula I: or a pharmaceutically acceptable salt thereof, wherein: M1and M2are independently selected from N, NH, O, S; X1, X2, and X3are independently selected from N, C; R1is selected from hydrogen, halogen, C1-C7alkyl, C1-C7alkoxy, C1-C7cycloalkyl, C1-C7alkyl substituted cycloalkyl, C1-C7oxygen-containing alkyl, C1-C7nitrogen-containing alkyl, C1-C7sulfur-containing alkyl, oxygen-containing 3- to 5-membered saturated ring, nitrogen-containing 3- to 5-membered saturated ring, or sulfur-containing 3- to 5-membered saturated ring; R2is selected from hydrogen, C1-C7alkyl, C1-C7cycloalkyl, C1-C7alkyl substituted cycloalkyl, C1-C7oxygen-containing alkyl, C1-C7nitrogen-containing alkyl, C1-C7sulfur-containing alkyl, oxygen-containing 3- to 5-membered saturated ring, sulfur-containing 3- to 5-membered saturated ring, or nitrogen-containing 3- to 5-membered saturated ring; R3is independently selected from H, halogen, C1-C6alkyl, C1-C6alkoxy; R4, R5, and R6are each independently selected from H, halogen; R7is selected from C1-C10alkoxy, and / or R8is selected from methyl. M1is selected from N, and M2is selected from NH, or M1is selected from NH, and M2is selected from N. the compound has the structure of Formula II: R1 is selected from hydrogen, C1-C15 alkyl, C1-C15 cycloalkyl, C1-C15 alkyl-substituted cycloalkyl, C1-C15 oxygen-containing alkyl, C1-C15 nitrogen-containing alkyl, C1-C15 sulfur-containing alkyl, oxygen-containing 3- to 7-membered saturated ring, sulfur-containing 3- to 7-membered saturated ring or nitrogen-containing 3- to 7-membered saturated ring, unsubstituted or R i Substituted C6-C15 aryl groups; said R i selected from hydrogen, C1-C10alkyl, C1-C10alkoxy or -0(C1-C5alkyl)OH; X1, X2, and X3are independently selected from N, C; R3, R9and R 10 each independently is selected from H, halogen, Ci-C6alkyl, Ci-C6alkoxy; R7is selected from C1-C10alkoxy, -(R a )2OH, -(R b )2OCR c , -CH2S(O)2R d , -NHS(O)2R e , -NHC(O)R f or -S(O)2NR g R h ; R a , R b , R c , R d , R e , R f , R g and R h are each independently selected from H or C1-C10alkyl; R2is selected from hydrogen, C1-C7alkyl, C1-C7cycloalkyl, C1-C7alkyl substituted cycloalkyl, C1-C7oxygen-containing alkyl, C1-C7nitrogen-containing alkyl, C1-C7sulfur-containing alkyl, oxygen-containing 3- to 5-membered saturated ring, sulfur-containing 3- to 5-membered saturated ring, or nitrogen-containing 3- to 5-membered saturated ring; R4, R5, and R6are each independently selected from H, halogen.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, R7is selected from C1-C3alkoxy.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein, the compound has the structure of Formula III: X1, X2, and X3are independently selected from N, C; R1 is selected from hydrogen, C1-C15 alkyl, C1-C15 cycloalkyl, C1-C15 alkyl-substituted cycloalkyl, C1-C15 oxygen-containing alkyl, C1-C15 nitrogen-containing alkyl, C1-C15 sulfur-containing alkyl, oxygen-containing 3- to 7-membered saturated ring, sulfur-containing 3- to 7-membered saturated ring or nitrogen-containing 3- to 7-membered saturated ring, unsubstituted or R i Substituted C6-C15 aryl groups; said R i selected from hydrogen, C1-C10alkyl, C1-C10alkoxy or -0(C1-C5alkyl)OH; R2is selected from hydrogen, C1-C7alkyl, C1-C7cycloalkyl, C1-C7alkyl substituted cycloalkyl, C1-C7oxygen-containing alkyl, C1-C7nitrogen-containing alkyl, C1-C7sulfur-containing alkyl, oxygen-containing 3- to 5-membered saturated ring, sulfur-containing 3- to 5-membered saturated ring, or nitrogen-containing 3- to 5-membered saturated ring; R3, R9and R 10 each independently selected from H, halogen, Ci-C6alkyl, Ci-C6alkoxy; R7is selected from C1-C10alkoxy, -(R a )2OH, -(R b )2OCR c , -CH2S(O)2R d , -NHS(O)2R e , -NHC(O)R f or -S(O)2NR g R h ; R a , R b , R c , R d , R e , R f , R g and R h are each independently selected from H, C1-C10alkyl; R3is independently selected from H, halogen, C1-C6alkyl, C1-C6alkoxy; 4. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein, R4, R5, and R6are each independently selected from H, halogen.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein, R7is selected from C1-C3alkoxy.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from hydrogen, C1-C15 alkyl, C1-C15 cycloalkyl, C1-C15 alkyl-substituted cycloalkyl, C1-C15 oxygen-containing alkyl, C1-C15 nitrogen-containing alkyl, C1-C15 sulfur-containing alkyl, oxygen-containing 3- to 7-membered saturated ring, sulfur-containing 3- to 7-membered saturated ring or nitrogen-containing 3- to 7-membered saturated ring, unsubstituted or R i Substituted C6-C15 aryl groups; said R i selected from hydrogen, C1-C10alkyl, C1-C10alkoxy or -0(C1-C5alkyl)OH; R2is selected from hydrogen, C1-C7alkyl, C1-C7cycloalkyl, C1-C7alkyl substituted cycloalkyl, C1-C7oxygen-containing alkyl, C1-C7nitrogen-containing alkyl, C1-C7sulfur-containing alkyl, oxygen-containing 3- to 5-membered saturated ring, sulfur-containing 3- to 5-membered saturated ring, or nitrogen-containing 3- to 5-membered saturated ring. R3is independently selected from H, halogen. R4, R5, and R6are each independently selected from H, halogen; X2is selected from C. R2is selected from hydrogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, cyclopropyl, C1-C5oxygen-containing alkyl, oxygen-containing 3-membered saturated ring, oxygen-containing 4-membered saturated ring, oxygen-containing 5-membered saturated ring. the compound is any one of: R1 is selected from hydrogen, C1-C15 alkyl, C1-C15 cycloalkyl, C1-C15 alkyl-substituted cycloalkyl, C1-C15 oxygen-containing alkyl, oxygen-containing 3- to 7-membered saturated rings, unsubstituted or R i Substituted C6-C15 aryl groups; said R i selected from hydrogen, C1-C6alkyl, C1-C6alkoxy or -0(C1-C5alkyl)OH; 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(2-((3,5-dimethylpyridin-4-yl)oxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(3-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein ​ R1is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, unsubstituted or by R i substituted C6-C15aryl; said R i is selected from hydrogen, C1-C6alkyl, C1-C6alkoxy or -0(C1-C5alkyl)OH. ​ 8. The compound or pharmaceutically acceptable salt thereof according to claims 1-7, wherein ​ ​ ​ 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclopentyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclohexyl-4-ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclohexyl-4-ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclohexyl-4-ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclohexyl-4-ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclohexyl-4-ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclohexyl-4-ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclohexyl-4-ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclohexyl-4-ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclohexyl-4-ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclohexyl-4-ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclohexyl-4-ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclohexyl-4-ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(4-ethyl-2-methyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2,4-dimethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(4-ethyl-2-isopropyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methyl-2-(2- methyl-4-propyl-1H-imidazol-5-yl)furo[3,2-c]pyridin-4(5H)-one 2-(2-ethyl-4-propyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(4-isopropyl-2- methyl-1H-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-ethyl-4-isopropyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-ethyl-4-(methoxymethyl)-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5- (2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(2-isopropyl-4- (methoxymethyl)-1H-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclopropyl-4-(methoxymethyl)-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)- 5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclobutyl-4-(methoxymethyl)-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)- 5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2,4-Dimethyl-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxyprop-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-Ethyl-4-methyl-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxyprop-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 7-(4-Fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxyprop-2-yl)phenyl)-2-(2- isopropyl-4-methyl-1H-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-Cyclopropyl-4-methyl-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)- 5-(2-hydroxyprop-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-Cyclobutyl-4-methyl-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)- 5-(2-hydroxyprop-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(4-Ethyl-2-methyl-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxyprop-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2,4-Diethyl-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxyprop-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(4-Ethyl-2-isopropyl-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5- (2-hydroxyprop-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 7-(4-Fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxyprop-2-yl)phenyl)-5-methyl-2- (2-methyl-4-propyl-1H-imidazol-5-yl)furo[3,2-c]pyridin-4(5H)-one 2-(2-Ethyl-4-propyl-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxyprop-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 7-(4-Fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxyprop-2-yl)phenyl)-2-(4-isopropyl- 2-methyl-1H-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-ethyl-4-isopropyl-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-ethyl-4-isopropyl-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(2- isopropyl-4-(methoxymethyl)-1H-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclopropyl-4-(methoxymethyl)-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-cyclobutyl-4-(methoxymethyl)-1H-imidazol-5-yl)-7-(4-fluoro-2-(4-fluoro-2,6- dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one 2-(2-(adamantan-1-yl)-1H-imidazol-5-yl)-7-(3-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2- hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(4H)-one 7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methyl- 2-(2-phenyl-1H-imidazol-5-yl)furo[3,2-c]pyridin-4(5H)-one.

9. A bromodomain protein inhibitor, characterized in that, The bromodomain protein inhibitor comprises at least one of the compounds or pharmaceutically acceptable salt thereof according to any one of claims 1-8; Preferably, the bromodomain protein inhibitor is an inhibitor that selectively inhibits BET family bromodomain 1 and bromodomain 2; Preferably, the bromodomain protein inhibitor is an inhibitor that selectively inhibits BET family bromodomain 2. Preferably, the bromodomain protein inhibitor is an inhibitor that selectively inhibits BRD4 family bromodomain 2.

10. A pharmaceutical composition, characterized by, The pharmaceutical composition comprises at least one of the compounds or pharmaceutically acceptable salt thereof according to any one of claims 1-8, and at least one pharmaceutically acceptable carrier and / or at least one other therapeutically active agent.

11. Use of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-8 or a bromodomain protein inhibitor according to claim 9 or a pharmaceutical composition according to claim 10 in the manufacture of a medicament for a disease or condition mediated by a BET protein. Preferably, the disease or disorder mediated by BET proteins comprises cancer, inflammation, autoimmune disease, non-alcoholic fatty liver disease, cardiovascular disease, diabetes, pulmonary fibrosis, myelofibrosis, or chronic obstructive pulmonary disease.

12. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8 or a bromodomain protein inhibitor according to claim 9 or a pharmaceutical composition according to claim 10 for the manufacture of a medicament for antiviral, antibacterial or antiparasitic treatment by inhibition of BET protein bromodomain receptors or for male contraception.

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