Compounds having bromodomain inhibitory activity and use thereof

Abstract

Provided are compounds having bromodomain inhibitory activity and the use thereof. The compounds have structures shown as formula I. The compounds can selectively inhibit the BD2 bromodomain of the BET family, and can be used as new-generation bromodomain inhibitors for treating BET-related diseases such as cancers and inflammations.

Description

Compounds with bromodomain inhibitory activity and uses thereof TECHNICAL FIELD

[0001] The present application belongs to the field of chemical medicine, and relates to compounds with bromodomain inhibitory activity and uses thereof, in particular to a kind of furanopyrimidinone compounds as BET bromodomain inhibitors and uses thereof. BACKGROUND

[0002] Dysfunction of epigenetic regulation is a common feature of cancer initiation and progression. 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 has become a hot new target with promising drug development prospects in the field of cancer treatment.

[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 the 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, 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.

[0008] SUMMARY

[0009] 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.

[0010] In order to achieve the purpose of the present application, the following technical solutions are adopted:

[0011] In one aspect, the present application provides a kind of compound, the compound has the structure shown in the following formula I:

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

[0013] X1, X2 and X3 are independently selected from N, 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 R i substituted C6-C15 aryl;

[0015] said R i selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, or -O(C1-C5 alkyl)OH;

[0016] R2is selected from hydrogen, C1-C7 alkyl, C1-C7 cycloalkyl, C1-C7 alkyl substituted cycloalkyl, C1-C7 oxygen-containing alkyl, C1-C7 nitrogen-containing alkyl, C1-C7 sulfur-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, R9and R 10 are each independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy;

[0018] R7is selected from C1-C10 alkoxy, -(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-C10 alkyl.

[0019] R4, R5and R6are each independently selected from H, halogen;

[0020] R8is selected from C1-C4 alkyl or deuterated C1-C4 alkyl.

[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, the compound has a structure according to Formula II:

[0023] X1, X2and X3are independently selected from being N, C;

[0024] 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;

[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 C1-C10alkyl, C1-C10alkoxy, or -O(C1-C5alkyl)OH;

[0026] 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;

[0027] R3, R9, and R 10 are each independently selected from H, halogen, C1-C6alkyl, C1-C6alkoxy;

[0028] 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.

[0029] R4, R5, and R6are each independently H, halogen.

[0030] In some preferred embodiments, R7is selected from C1-C10alkoxy.

[0031] In some preferred embodiments, R8is selected from methyl.

[0032] In another embodiment, the compound has the structure shown in Formula III:

[0033] X1, X2and X3are independently selected from N, C;

[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; i unsubstituted or substituted C6-C15aryl;

[0035] said R i is selected from hydrogen, C1-C10alkyl, C1-C10alkoxy, or -O(C1-C5alkyl)OH;

[0036] 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;

[0037] R3is each independently selected from H, halogen, C1-C6alkyl, C1-C6alkoxy;

[0038] R4, R5, and R6are each independently selected from H, halogen;

[0039] R7is selected from C1-C3alkoxy.

[0040] In some preferred embodiments, R3is each independently selected from H, halogen.

[0041] 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; and 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

[0042] In some preferred embodiments, X2is selected from C.

[0043] In some preferred embodiments, R4, R5, and R6are each independently selected from H, fluorine, chlorine.

[0044] ​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.

[0045] In a preferred embodiment, the compound of the present invention is any one of the following compounds:

[0046] 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

[0047] 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

[0048] 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

[0049] 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

[0050] 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

[0051] 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

[0052] 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

[0053] 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

[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] 2-(2-cyclopentyl-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

[0056] 2-(2-cyclohexyl-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

[0057] 2-(2-(adamantan-1-yl)-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

[0058] 2-(2-cyclopropyl-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

[0059] 2-(2-cyclobutyl-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

[0060] 2-(2-cyclopentyl-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

[0061] 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

[0062] 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

[0063] 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

[0064] 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

[0065] 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

[0066] 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

[0067] 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

[0068] 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

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

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

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

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

[0073] 7-(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

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

[0075] 7-(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

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

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

[0078] 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

[0079] 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

[0080] 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

[0081] 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

[0082] 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

[0083] 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

[0084] 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

[0085] 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

[0086] 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

[0087] 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

[0088] 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

[0089] 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

[0090] 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

[0091] 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

[0092] 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

[0093] 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

[0094] 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

[0095] 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

[0096] 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

[0097] 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

[0098] 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

[0099] In another aspect, the present application provides pharmaceutically acceptable salts of the compounds as described above.

[0100] 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.

[0101] 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.

[0102] In the present application, the synthetic route of the compound is as follows:

[0103] Scheme 1

[0104] 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.

[0105] Scheme 2

[0106] 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.

[0107] The application compounds can be prepared according to the synthetic route described in Scheme 1 or Scheme 2. Each product obtained in the reaction of 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.

[0108] 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 of formula (I).

[0109] 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 of formula (I).

[0110] In another aspect, the present application provides a bromodomain protein inhibitor, which comprises at least one of the compounds as described above.

[0111] Preferably, the bromodomain protein inhibitor is an inhibitor that selectively inhibits the bromodomain 2 (BD2) of the BET family.

[0112] Preferably, the bromodomain protein inhibitor is an inhibitor that selectively inhibits the bromodomain 2 (BD2) of the BRD4 family.

[0113] 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.

[0114] 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.

[0115] The pharmaceuticals prepared from the BET protein inhibitors of the present application, and the pharmaceutical compositions, 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 injection, intramuscular injection, subcutaneous, intradermal injection, intraperitoneal, intrathecal, surgical implantation), etc.

[0116] The pharmaceutical compositions of the present application 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, pastes, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres, or aerosols, etc.

[0117] The pharmaceutical compositions of the present application 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.

[0118] The pharmaceutical compositions for oral administration can be solid, gel, or liquid. Examples of solid preparations include, but are not limited to, tablets, capsules, granules, and bulk powders. These preparations can optionally contain binding agents, diluents, disintegrating agents, lubricants, glidants, sweeteners, and flavoring agents, etc. Examples of binding agents include, but are not limited to, microcrystalline cellulose, dextrose solution, acacia paste, gelatin solution, sucrose, and starch paste; examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate, and 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 disintegrating agents include, but are not limited to, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, and carboxymethyl cellulose.

[0119] For parenteral administration of the pharmaceutical composition of the present application, injection is generally preferred, including subcutaneous, intramuscular or intravenous injection. The injectable preparation can be in any conventional form, such as a liquid solution or suspension, a solid form suitable for dissolving or suspending in liquid prior to injection, or an emulsion. Examples of pharmaceutically acceptable carriers that can be used in the injectable preparation of the present application include, but are not limited to, aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, 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 glucose injection, sterile water injection, glucose and lactic acidified Ringer's injection; examples of non-aqueous carriers include fixed oils of plant origin, cottonseed oil, corn oil, sesame oil, and peanut oil; examples of antimicrobial agents include m-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride, etc.; examples of isotonic agents include sodium chloride and glucose; buffers include phosphate and citrate.

[0120] The pharmaceutical composition of the present application can also be prepared as a sterile lyophilized powder for injection, by dissolving the compound in a sodium phosphate buffer solution containing glucose or other suitable excipients, and then sterile filtering the solution under standard conditions known to those skilled in the art, followed by freeze-drying to obtain the desired preparation.

[0121] In another aspect, the present application provides the use of the compound or its pharmaceutically acceptable salt as described above or the bromodomain protein inhibitor or the pharmaceutical composition in the preparation of a medicament for a disease or disorder mediated by BET protein.

[0122] 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 fertility.

[0123] Preferably, the cancer is selected from solid tumors or hematological tumors.

[0124] More preferably, the solid tumor is selected from breast cancer or prostate cancer.

[0125] More preferably, the hematological tumor is selected from acute myeloid leukemia, multiple myeloma, or diffuse large B-cell lymphoma.

[0126] Compared with the prior art, the present application has the following beneficial effects:

[0127] 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 the treatment of BET-related diseases such as cancer, inflammation, etc. DETAILED DESCRIPTION

[0128] The technical solutions of the present application are further illustrated below by specific embodiments. 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 on the present application.

[0129] Unless otherwise indicated, temperatures are in degrees Celsius. Commercially available reagents were used without further purification unless otherwise indicated.

[0130] Unless otherwise indicated, the following reactions were carried out under anhydrous conditions, under a positive pressure of nitrogen or argon, or using a dry tube; the reaction vessel was closed with a rubber septum to allow the addition of substrates and reagents by syringe; and glassware was heated after drying.

[0131] NMR data were recorded using CDCl3, DMSO-d6, etc. as the solvent, with tetramethylsilane (0.00 ppm) or the residual solvent peak as the reference (CDCl3: 7.26 ppm, DMSO-d6: 2.50 ppm). When peak patterns were annotated, the following abbreviations were used to indicate different peak patterns: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets). The coupling constants given are in Hertz (Hz).

[0132] Preparation of intermediates:

[0133] The synthesis methods of the intermediates used in the following preparation examples are as follows:

[0134] Intermediate 1: 4-ethyl-5-ethynyl-2-methyl-1H-imidazole

[0135] Step 1: 5-ethyl-2-methyl-1H-imidazole

[0136] 5-ethynyl-2-methyl-1H-imidazole (106.13, 2.85 g, 27.480 mmol, 1 eq) was dissolved in 50 mL of methanol solution, 280 mg of 5% palladium-carbon was added, and the solution was stirred at room temperature under an atmosphere of hydrogen for 12 h. The reaction was detected to be complete, and the solution was filtered with diatomite and rotary evaporated to dryness. The product 5-ethyl-2-methyl-1H-imidazole (110.16, 1.6 g, 14.524 mmol, 53%) was obtained by dissolving in ethyl acetate / methanol and column chromatography on a sand core. 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).

[0137] Step 2: 4-ethyl-5-iodo-2-methyl-1H-imidazole

[0138] To compound 5-ethyl-2-methyl-lH-imidazole (110.16, 1.6 g, 14.524 mmol, 1 eq) was dissolved in 26 mL of chloroform, and 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), and stirring at room temperature for 18 h. After confirming completion of the reaction, it was extracted with ethyl acetate three times, washed with saturated sodium thiosulfate, dried over anhydrous sodium sulfate, and column chromatographed on a silica gel to obtain 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).

[0139] Step 3: 4-ethyl-2-methyl-5-((trimethylsilyl)ethynyl)-lH-imidazole

[0140] A two-necked flask was dried, and compound 4-ethyl-5-iodo-2-methyl-lH-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, and after strictly purging with air, 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 sequentially added through a needle, and the reaction was performed at 40°C in an oil bath for 3 h. After confirming completion of the reaction, it was diluted with a large amount of ethyl acetate, sequentially extracted with water and saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain 4-ethyl-2-methyl-5-((trimethylsilyl)ethynyl)-lH-imidazole (206.36, 1.5 g, 7.269 mmol, 64%) as a solid. 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).

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

[0142] To 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, potassium carbonate (138.21, 2.8 g, 20.259 mmol, 3 eq) was added, stirred at room temperature for 3 h. 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 = 1:1) to give the product 4-ethyl-5-ethynyl-2-methyl-1H-imidazole (134.18, 500 mg, 3.726 mmol, 51%). 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).

[0143] Intermediate 2: 2,4-diethyl-5-ethynyl-1H-imidazole

[0144] Synthetic method as Intermediate 1, yield 75%. 1 H 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).

[0145] Intermediate 3: 4-ethyl-5-ethynyl-2-isopropyl-1H-imidazole

[0146] Synthetic method as 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).

[0147] Intermediate 4: 2-cyclopropyl-5-ethyl-4-ethynyl-1H-imidazole

[0148] Synthetic method as 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).

[0149] Intermediate 5: 2-cyclobutyl-5-ethyl-4-ethynyl-lH-imidazole

[0150] Synthetic procedure 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).

[0151] Intermediate 6: 2-cyclopentyl-5-ethyl-4-ethynyl-lH-imidazole

[0152] Synthetic procedure as for Intermediate 1, yield 75%. 1 H 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).

[0153] Intermediate 7: 2-cyclohexyl-5-ethyl-4-ethynyl-lH-imidazole

[0154] Synthetic procedure 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).

[0155] Intermediate 8: 2-cycloheptyl-5-ethyl-4-ethynyl-lH-imidazole

[0156] Synthetic procedure as for Intermediate 1, yield 76%. 1H 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).

[0157] Intermediate 9: 2-(Bicyclo[2.2.1]heptan-2-yl)-5-ethyl-4-ethynyl-1H-imidazole

[0158] 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).

[0159] Intermediate 10: 2-(Adamantan-1-yl)-5-ethyl-4-ethynyl-1H-imidazole

[0160] Synthesis 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).

[0161] Intermediate 11: 5-Ethynyl-2-isopropyl-4-methyl-1H-imidazole

[0162] Step 1: 2-Isopropyl-4-methyl-1H-imidazole

[0163] To a solution of compound 40% methylglyoxal in water (72.06, 27 mL, 178.351 mmol, 1.08 eq, 1.19 g / mL) in 50 mL of methanol, 100 mL of water was added, followed by isobutyraldehyde (72.11, 15 mL, 164.332 mmol, 1 eq, 0.79 g / mL) in an ice bath. Then 28% ammonia water (35.05, 82 mL, 655.064 mmol, 4 eq) was added slowly dropwise. After the addition was completed, the reaction was allowed to react for 1 h in an ice bath, and then at room temperature overnight. After the reaction was detected to be complete, saturated sodium chloride solution was added, and ethyl acetate was back-extracted several times, dried over anhydrous sodium sulfate, and the product 2-isopropyl-4-methyl-1H-imidazole (124.19, 15.5 g, 124.809 mmol, 76%) was obtained by rotary evaporation. 1 H NMR (500 MHz, DMSO-d6): δ 11.27 (s, 1H), 6.61 (s, 1H), 2.82-2.90 (m, 1H), 2.05 (s, 3H), 1.19 (d, 6H, J = 6.9 Hz).

[0164] Step 2: 5-Iodo-2-isopropyl-4-methyl-1H-imidazole

[0165] To a solution of compound 2-isopropyl-4-methyl-1H-imidazole (124.19, 15.5 g, 124.809 mmol, 1 eq) in 225 mL of chloroform, iodine (253.18, 30.9 g, 122.048 mmol, 0.98 eq) was added, followed by 2M NaOH solution (225 mL, 450 mmol, 3.6 eq) dropwise. After stirring at room temperature overnight, the reaction was detected to be complete, and the product 5-iodo-2-isopropyl-4-methyl-1H-imidazole (250.08, 29 g, 115.963 mmol, 93%) was obtained by extraction with ethyl acetate three times, washing with saturated sodium thiosulfate, drying over anhydrous sodium sulfate, and column chromatography on a sand core, followed by rotary evaporation. 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).

[0166] Step 3: 2-Isopropyl-4-methyl-5-((trimethylsilyl)ethynyl)-1H-imidazole

[0167] Double-necked flask was dried, and 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) were added successively under strict air exchange, and then dry diethylamine 110 mL, dry DMF 55 mL, trimethylsilyl acetylene (98.22, 33 mL, 233.506 mmol, 2 eq, 0.695 g / mL) were added successively under strict air exchange. The reaction was carried out at 40 °C in an oil bath for 3 h. After the completion of the reaction was checked, it was diluted with a large amount of ethyl acetate, and then extracted with water and saturated NaCl aqueous solution successively, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the product 2-isopropyl-4-methyl-5-((trimethylsilyl)ethynyl)-1H-imidazole (220.39, 10.8 g, 49.004 mmol, 42%). 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).

[0168] Step 4: 5-ethynyl-2-isopropyl-4-methyl-1H-imidazole

[0169] 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, and potassium carbonate (138.21, 21.7 g, 157.007 mmol, 3 eq) was added. The mixture was stirred at room temperature overnight. After dilution with ethyl acetate, it was filtered through diatomite, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give 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).

[0170] Intermediate 12: 5-ethynyl-2,4-dimethyl-1H-imidazole

[0171] The synthesis method was the same as that of Intermediate 11, and the yield was 25%. 1H NMR (500 MHz, DMSO-d6): δ 11.75 (s, 1H), 3.92 (s, 1H), 2.18 (s, 6H).

[0172] Intermediate 13: 2-ethyl-5-ethynyl-4-methyl-1H-imidazole

[0173] Synthesis as for 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).

[0174] Intermediate 14: 2-cyclopropyl-5-ethynyl-4-methyl-1H-imidazole

[0175] Synthesis as for 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).

[0176] Intermediate 15: 2-cyclobutyl-5-ethynyl-4-methyl-1H-imidazole

[0177] 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).

[0178] Intermediate 16: 2-cyclopentyl-5-ethynyl-4-methyl-1H-imidazole

[0179] 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).

[0180] Intermediate 17: 2-cyclohexyl-5-ethynyl-4-methyl-1H-imidazole

[0181] 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).

[0182] Intermediate 18: 2-(adamantan-l-yl)-5-ethynyl-4-methyl-lH-imidazole

[0183] 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).

[0184] Intermediate 19: 5-ethynyl-2-methyl-4-propyl-lH-imidazole

[0185] Synthesis as for intermediate 11, yield 59%. 1 H NMR (500 MHz, DMSO-d6): 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).

[0186] Intermediate 20: 2-ethyl-5-ethynyl-4-propyl-lH-imidazole

[0187] Synthesis as for intermediate 11, yield 36%. 1 H NMR (500 MHz, DMSO-d6): 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).

[0188] Intermediate 21 : 5-ethynyl-4-isopropyl-2-methyl-lH-imidazole

[0189] Synthesis as for intermediate 11, yield 20%. 1H NMR (500 MHz, DMSO-d6): 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).

[0190] Intermediate 22: 2-Ethyl-5-ethynyl-4-isopropyl-lH-imidazole

[0191] Synthesis as for Intermediate 11, yield 52%. 1 H NMR (500 MHz, DMSO-d6): 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).

[0192] Intermediate 23: 2-Ethyl-5-ethynyl-4-(methoxymethyl)-lH-imidazole

[0193] 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).

[0194] Intermediate 23: 5-Ethynyl-2-isopropyl-4-(methoxymethyl)-lH-imidazole

[0195] Synthesis 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).

[0196] Intermediate 24: 2-Cyclopropyl-5-ethynyl-4-(methoxymethyl)-lH-imidazole

[0197] Synthesis 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).

[0198] Intermediate 25: 2-Cyclobutyl-5-ethynyl-4-(methoxymethyl)-lH-imidazole

[0199] Synthetic procedure as for intermediate 11, yield 48%. 1 HNMR (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).

[0200] Example 1 : 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

[0201] Step 1 : 3,5-dimethyl-4-nitropyridine 1 -oxide

[0202] Compound 3,5-dimethylpyridine 1 -oxide (123.16, 2 g, 16.239 mmol, 1 eq) was dissolved in 5 mL concentrated sulfuric acid, dropwise added concentrated nitric acid 1.7 mL under ice bath, stirred for 15 min under ice bath, then 90 °C oil bath overnight. The reaction was detected to be completed, cooled in ice bath, 10 M sodium hydroxide solution was added to adjust the pH value to neutral, diluted with water, then extracted with dichloromethane for three times, dried over anhydrous sodium sulfate, column chromatography (pure dichloromethane) to remove impurities, then (pure ethyl acetate) to obtain 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).

[0203] Step 2: 4-methoxy-3,5-dimethylpyridine 1 -oxide

[0204] The reactants were 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 methanol solution. At this time, the reactants were not very soluble, and the temperature was increased to 70 °C to reflux. After the reactants were completely dissolved, 30% sodium methoxide in methanol solution (1.4 mL, 7 mmol, 1.18 eq, 5 mmol / mL) was added dropwise through a dropping funnel. After the addition was completed, the reaction was carried out under argon protection at 65 °C oil bath for 12 hours. After the reaction was detected to be completed, it was cooled to room temperature, and the pH value was adjusted to neutral with acetic acid. Ethyl acetate was added for dilution, and anhydrous sodium sulfate was added for drying. After rotary evaporation, yellow crude product 4-methoxy-3,5-dimethylpyridine 1 -oxide (153.18, 800 mg, 5.223 mmol, 88%) was obtained. 1H NMR (500 MHz, DMSO-d6): δ 8.00 (s, 2H), 3.72 (s, 3H), 2.15 (s, 6H).

[0205] Step 3: 4-methoxy-3, 5-dimethylpyridine

[0206] Take the zirconium tetrachloride (233.04, 27.4g, 117.576mmol, 1.02eq), sodium borohydride (37.83, 23g, 607.983mmol, 5.2eq) in a dry flask, add 300mL of dry tetrahydrofuran solution, ice bath cooling. At the same time, take compound 4-methoxy-3, 5-dimethylpyridine 1-oxide (153.18, 18g, 117.509mmol, 1eq) dissolved in 300mL of dry tetrahydrofuran solution, then dropwise added to the reaction system, dropwise addition is completed, room temperature reaction for 24h. Detect the completion of the reaction, the reaction solution is ice-bath, dropwise add dilute hydrochloric acid to terminate the reaction. Then the Buchner funnel is filtered, the filter residue is diluted with a large amount of ethyl acetate, stirred and filtered again, and the solvent is removed by rotary evaporation to obtain the crude product. Repeat 2-3 times until there is no product in the filter residue; the filter liquor is rotary evaporated to remove tetrahydrofuran, then diluted with saturated sodium chloride solution, and extracted with ethyl acetate 2-3 times until there is no product point, and dried with anhydrous sodium sulfate. Spin dry, 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, 10.8g, 78.729mmol, 67%). 1 H NMR (500 MHz, DMSO-d6): δ 8.25 (s, 2H), 3.89 (s, 3H), 2.25 (s, 6H).

[0207] Step 4: 3, 5-dimethylpyridin-4-ol

[0208] Take compound 4-methoxy-3, 5-dimethylpyridine (137.18, 10.8g, 78.729mmol, 1eq) and dissolve it in 150mL of toluene, slowly drop 11mL of concentrated hydrochloric acid 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 18h. Detect the completion of the reaction, neutralize part of the acid with sodium hydroxide, keep the solution acidic, spin dry to obtain the crude compound 3, 5-dimethylpyridin-4-ol, which is directly used in the next step without purification.

[0209] Step 5: methyl 3-bromo-4-((3, 5-dimethylpyridin-4-yl) oxy) benzoate

[0210] Into a flask, 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 for 3-5 h in an oil bath. After the reaction is completed, dilute with ethyl acetate, and filter with diatomite. Dry the filtrate at 80 °C, dissolve in ethyl acetate / methylene chloride / methanol, and purify by column chromatography on silica gel to obtain the crude product. Concentrate by rotary evaporation to obtain a large amount of solid, and let the solid precipitate. After the solid precipitates, filter with a Buchner funnel to obtain the solid product. Purify the filtrate by column chromatography on silica gel (methylene chloride: 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).

[0211] Step 6: 2-(3-bromo-4-((3,5-dimethylpyridin-4-yl)oxy)phenyl)propan-2-ol

[0212] Into a flask, add compound methyl 3-bromo-4-((3,5-dimethylpyridin-4-yl)oxy)benzoate (336.18, 5 g, 14.873 mmol, 1 eq), and dissolve in dry THF (100 mL) after aeration. Cool in an ice bath, then add 3M methyl magnesium bromide in tetrahydrofuran (15 mL, 45 mmol, 3 eq) dropwise through a dropping funnel. Stir in the ice bath for 1 h, then add 50 mL of dry dioxane to assist dissolution. Stir at room temperature for 3 h. After the reaction is completed, quench by dropwise addition of 20 mL of methanol. Remove solid impurities by column chromatography on silica gel, concentrate the filtrate, then dilute with ethyl acetate / water, extract with ethyl acetate 3 times, dry over anhydrous sodium sulfate, and purify by column chromatography on silica gel (methylene chloride: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).

[0213] Step 7: 2-(3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-((3,5-dimethylpyridin-4- yl)oxy)phenyl)propan-2-ol

[0214] 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).

[0215] 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

[0216] 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).

[0217] 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

[0218] 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).

[0219] 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

[0220] 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).

[0221] 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

[0222] Step 1: Methyl 3-bromo-5-fluoro-4-(4-fluoro-2,6-dimethylphenoxy)benzoate

[0223] 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).

[0224] Step 2: 2-(3-bromo-5-fluoro-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)propan-2-ol

[0225] 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 stirred under strict aeration, cooled in an ice bath, and 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 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%) was obtained by diluting with ethyl acetate / water, and extracting with ethyl acetate three times, drying the organic phase over anhydrous sodium sulfate, and column chromatography (petroleum ether: ethyl acetate = 4:1). 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).

[0226] 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

[0227] 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).

[0228] 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

[0229] 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).

[0230] 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

[0231] 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).

[0232] 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

[0233] 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 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, saturated sodium chloride solution in turn, concentrated and purified by silica gel column chromatography (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).

[0234] 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

[0235] Synthetic method as Example 2, 50% yield. 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).

[0236] 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-methylfuran[3,2-c]pyridin-4(5H)- one

[0237] Synthetic procedure as 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).

[0238] Example 5: 2-(2-cyclopentyl-lH-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)- 5-(hydroxymethyl)phenyl)-5-methylfuran[3,2-c]pyridin-4(5H)-one

[0239] Step 1: 3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)benzaldehyde

[0240] Take compound 4-fluoro-2,6-dimethylphenol (140.16, 6g, 42.808 mmol, 1 eq), 3-bromo-4-fluorobenzaldehyde (203.01, 9.74g, 47.978 mmol, 1.12 eq), dissolved in 50 mL DMF, then add cesium carbonate (325.82, 42g, 128.906 mmol, 3 eq), react at room temperature overnight. After detecting the completion of the reaction, add enough ethyl acetate to dissolve, wash with water, saturated sodium chloride solution in turn, dry with anhydrous sodium sulfate, rotary evaporation, and column chromatography (pure dichloromethane) to obtain the product 3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)benzaldehyde (323.16, 12g, 37.133 mmol, 88%). 1 H 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).

[0241] Step 2: (3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)methanol

[0242] 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 checked to be completed, the reaction was diluted with ethyl acetate, washed with water, saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and concentrated. 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 HNMR (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).

[0243] Step 3: ((3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)benzyl)oxy)(tert-butyl)dimethylsilane

[0244] 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) were added in a flask, and the reaction was stirred at room temperature overnight after being aerated with dry DMF (75 mL). After the reaction was checked to be completed, the reaction was diluted with ethyl acetate, washed with water, saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 45: 1) to give ((3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)benzyl)oxy)(tert-butyl)dimethylsilane (439.44, 8.1 g, 18.433 mmol, 92%). 1H 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).

[0245] Step 4: tert-Butyl ((3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-(4-fluoro-2,6- dimethylphenoxy)phenyl)oxy)dimethylsilane

[0246] The flask was oven dried, ((3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)benzyl)oxy)(tert- butyldimethylsilyl)dimethylsilane (439.44, 8.1 g, 18.433 mmol, 1 eq), neopentyl glycol bisboronic acid (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), finally oven dried environment, anhydrous potassium acetate (98, 5.42 g, 55.306 mmol, 3 eq) was added quickly, strict oil pump ventilation for 30 min. After that, oven dried dioxane (110 mL) was added to the reaction system, strict ventilation, oil bath 80 °C for 24 h. After the reaction was detected to be completed, the silica gel was extracted by filtration, diluted with a large amount of ethyl acetate, then extracted with water and saturated NaCl aqueous solution successively, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to give 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, 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).

[0247] Step 5: 5-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)- 3-iodo-4-methoxy-1-methylpyridin-2(1H)-one

[0248] A two-necked flask was dried and 3,5-diiodo-4-methoxy-l-methylpyridin-2(lH)-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 nitrogen for 45 min. Meanwhile, another two-necked flask was added with tert-butyl ((3-(5,5-dimethyl-l,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 nitrogen for 45 min. Then the dioxane / water solution of tert-butyl ((3-(5,5-dimethyl-l,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-l-methylpyridin-2(lH)-one (623.58, 870 mg, 1.395 mmol, 9%). 1 HNMR (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).

[0249] Step 6: 5-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)-3-((2-cyclopentyl-lH-imidazol-5-yl)ethynyl)-4-methoxy-l-methylpyridin-2(lH)-one

[0250] 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).

[0251] 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

[0252] 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, saturated sodium chloride solution in turn, 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).

[0253] 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

[0254] 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).

[0255] 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

[0256] Synthetic method as example 5, yield 30%. 1HNMR (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).

[0257] 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

[0258] Step 1: Cycloheptanecarboxaldehyde

[0259] 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.

[0260] Step 2: 2-Cycloheptyl-lH-imidazole

[0261] 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%). 1H NMR (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).

[0262] Step 3: 2-Cycloheptyl-4,5-diiodo-1H-imidazole

[0263] 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).

[0264] Step 4: 2-Cycloheptyl-5-iodo-1H-imidazole

[0265] 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).

[0266] Step 5: 2-cycloheptyl-5-((trimethylsilyl)ethynyl)-1H-imidazole

[0267] The flask was dried and charged with 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), and the reaction was stirred under a strict atmosphere of nitrogen. Dry diethylamine (28 mL) and dry tetrahydrofuran (14 mL) were added via syringe, followed by trimethylsilylacetylene (98.22, 9.75 mL, 68.991 mmol, 1.978 eq, 0.695 g / mL) via syringe. The reaction was stirred at 45 °C in an oil bath for 3 h. Upon completion of the reaction, the reaction was diluted with ethyl acetate, washed with water and saturated aqueous NaCl, dried over anhydrous sodium sulfate, and purified by column chromatography on silica gel to give 2-cycloheptyl-5-((trimethylsilyl)ethynyl)-1H-imidazole (260.46, 8.0 g, 30.715 mmol, 89%). 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).

[0268] Step 6: 2-cycloheptyl-5-ethynyl-1H-imidazole

[0269] 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. The reaction was stirred at room temperature for 3 h. The reaction was diluted with ethyl acetate, filtered through celite, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, and concentrated. The product 2-cycloheptyl-5-ethynyl-1H-imidazole (188.27, 1.8 g, 9.561 mmol, 28%) was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 3: 1). 1HNMR (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).

[0270] 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

[0271] 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 left in an oil bath at 40 °C 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).

[0272] 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

[0273] 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).

[0274] 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

[0275] Synthetic procedure as Example 7, yield 23%. 1HNMR (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).

[0276] 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

[0277] Synthesis as in Example 7, yield 26%. 1 HNMR (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).

[0278] Example 10: 2-(2-(Bicyclo[2.2. l]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

[0279] Synthesis as in Example 7, yield 33%. 1HNMR (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).

[0280] 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

[0281] Synthetic procedure as for Example 7, step 7 and step 8, yield 13%. 1 HNMR (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).

[0282] 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

[0283] 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).

[0284] 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

[0285] Synthetic procedure as for Example 7, step 7 and step 8, yield 21%. 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).

[0286] 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

[0287] Synthetic procedure as for Example 7, step 7 and step 8, yield 16%. 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).

[0288] 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

[0289] Synthetic procedure as for Example 7, step 7 and step 8 in 41% yield. 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).

[0290] 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

[0291] Synthetic procedure as for Example 7, step 7 and step 8 in 41% yield. 1HNMR (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).

[0292] 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]pyridine- 4(5H)-one

[0293] Synthetic procedure as for Example 7, step 7 and step 8 in 38% yield. 1 HNMR (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).

[0294] Example 18: 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]pyridine- 4(5H)-one

[0295] Synthetic procedure as for Example 7, step 7 and step 8 in 23% yield. 1HNMR (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).

[0296] 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

[0297] Synthetic procedure as for Example 7, step 7 and step 8 in 42% yield. 1 HNMR (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).

[0298] 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

[0299] Synthetic procedure as for Example 7, step 7 and step 8 in 44% yield. 1HNMR (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).

[0300] 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

[0301] Step 1 : 5-Bromo-4-methoxy-1-methylpyridin-2(1H)-one

[0302] To compound 5-bromo-4-chloro-1-methylpyridin-2(1H)-one (220.47, 1 g, 4.536 mmol, 1 eq) in a 2-neck flask, 20 mL of dioxane was added to dissolve, then 5.4 M sodium methoxide in methanol solution (32.04, 4.5 mL, 24.36 mmol, 5.3 eq) was added, gas exchange, oil bath 50 °C for 3 h. The reaction was detected to be complete, enough ethyl acetate was added, washed with saturated NaCl aqueous solution for 2 times, dried with anhydrous sodium sulfate, rotary evaporation to get the crude product 5-bromo-4-methoxy-1-methylpyridin-2(1H)-one (218.05, 600 mg, 2.752 mmol, 60%). 1 HNMR (500 MHz, DMSO-d6): δ 8.03 (s, 1H), 5.93 (s, 1H), 3.81 (s, 3H), 3.33 (s, 3H).

[0303] Step 2: 5-Bromo-3-iodo-4-methoxy-1-methylpyridin-2(1H)-one

[0304] 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).

[0305] Step 3: 7-bromo-2-(2,4-dimethyl-lH-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one

[0306] 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).

[0307] 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

[0308] 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, 1 H), 7.70 (d, 1 H, J = 2.3 Hz), 7.40 (dd, 1 H, J = 8.6, 2.3 Hz), 7.01 (s, 1 H), 6.84 (d, 2 H, J = 9.0 Hz), 6.41 (d, 1 H, J = 8.6 Hz), 3.76 (s, 3 H), 2.35 (s, 3 H), 2.34 (s, 3 H), 2.04 (s, 6 H), 1.57 (s, 6 H).

[0309] Example 22: 2-(2-Ethyl-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

[0310] Synthetic procedure as Example 21, yield 75%. 1 H NMR (500 MHz, CD3OD): δ 7.71 (s, 1 H), 7.70 (d, 1 H, J = 2.3 Hz), 7.40 (dd, 1 H, J = 8.6, 2.3 Hz), 7.01 (s, 1 H), 6.84 (d, 2 H, J = 9.0 Hz), 6.41 (d, 1 H, J = 8.6 Hz), 3.76 (s, 3 H), 2.35 (s, 3 H), 2.34 (s, 3 H), 2.04 (s, 6 H), 1.57 (s, 6 H).

[0311] Example 23: 7-(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

[0312] Synthetic procedure as Example 21, yield 51%. 1 H NMR (500 MHz, CD3OD): δ 7.71 (s, 1 H), 7.70 (d, 1 H, J = 2.3 Hz), 7.40 (dd, 1 H, J = 8.6, 2.3 Hz), 7.01 (s, 1 H), 6.84 (d, 2 H, J = 9.0 Hz), 6.41 (d, 1 H, J = 8.6 Hz), 3.76 (s, 3 H), 2.35 (s, 3 H), 2.34 (s, 3 H), 2.04 (s, 6 H), 1.57 (s, 6 H).

[0313] 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

[0314] Synthetic procedure as in Example 21, yield 60%. 1 HNMR (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).

[0315] 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

[0316] Synthetic procedure 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).

[0317] 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

[0318] Synthetic procedure as in Example 21, yield 70%. 1HNMR (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).

[0319] 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

[0320] Synthetic procedure as for Example 21, yield 67%. 1 HNMR (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).

[0321] 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

[0322] Synthetic procedure as for Example 21, yield 67%. 1HNMR (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).

[0323] 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

[0324] Synthetic procedure as Example 21, yield 37%. 1 HNMR (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).

[0325] 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

[0326] Synthetic procedure as Example 21, yield 56%. 1H NMR (500 MHz, CD3OD): δ 7.68 (s, 1 H), 7.66 (d, 1 H, J = 2.4 Hz), 7.41 (dd, 1 H, J = 8.6, 2.3 Hz), 7.04 (s, 1 H), 6.83 (d, 2 H, J = 9.0 Hz), 6.41 (d, 1 H, J = 8.6 Hz, Ar-H), 3.76 (s, 3 H), 2.67-2.77 (m, 4 H), 2.04 (s, 6 H), 1.53-1.57 (m, 8 H), 1.30 (t, 3 H, J = 7.6 Hz), 0.77 (t, 3 H, J = 7.4 Hz).

[0327] Example 31 : 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

[0328] Synthetic procedure as Example 21, yield 29%. 1 H NMR (500 MHz, CD3OD): δ 7.68 (s, 1 H), 7.66 (d, 1 H, J = 2.4 Hz), 7.41 (dd, 1 H, J = 8.6, 2.3 Hz), 7.04 (s, 1 H), 6.83 (d, 2 H, J = 9.0 Hz), 6.41 (d, 1 H, J = 8.6 Hz, Ar-H), 3.76 (s, 3 H), 2.67-2.77 (m, 4 H), 2.04 (s, 6 H), 1.53-1.57 (m, 8 H), 1.30 (t, 3 H, J = 7.6 Hz), 0.77 (t, 3 H, J = 7.4 Hz).

[0329] Example 32: 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

[0330] Synthetic procedure as Example 21, yield 34%. 1HNMR (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).

[0331] 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

[0332] Synthesis as in Example 21, 64% yield. 1 HNMR (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).

[0333] 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

[0334] Synthesis as in Example 21, 64% yield. 1H NMR (500 MHz, CD3OD): δ 7.73 (s, 1 H), 7.69 (d, 1 H, J = 2.3 Hz, Ar-H), 7.41 (dd, 1 H, J = 8.6, 2.3 Hz), 7.17 (s, 1 H), 6.83 (d, 2 H, J = 8.9 Hz), 6.41 (d, 1 H, J = 8.6 Hz), 4.53 (s, 2 H), 3.76 (s, 3 H), 3.22 (s, 3 H), 3.05-3.10 (m, 1 H), 2.03 (s, 6 H), 1.58 (s, 6 H), 1.34 (d, 6 H, J = 7.0 Hz).

[0335] Example 35: 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

[0336] Synthesis as in Example 21, yield 65%. 1 H NMR (500 MHz, CD3OD): δ 7.73 (s, 1 H), 7.69 (d, 1 H, J = 2.3 Hz, Ar-H), 7.41 (dd, 1 H, J = 8.6, 2.3 Hz), 7.17 (s, 1 H), 6.83 (d, 2 H, J = 8.9 Hz), 6.41 (d, 1 H, J = 8.6 Hz), 4.53 (s, 2 H), 3.76 (s, 3 H), 3.22 (s, 3 H), 3.05-3.10 (m, 1 H), 2.03 (s, 6 H), 1.58 (s, 6 H), 1.34 (d, 6 H, J = 7.0 Hz).

[0337] Example 36: 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

[0338] Synthesis as in Example 21, yield 77%. 1HNMR (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).

[0339] 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]pyridine- 4(5H)-one

[0340] Synthetic procedure as Example 21, yield 14%. 1 HNMR (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).

[0341] 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]pyridine- 4(5H)-one

[0342] Synthetic procedure as Example 21, yield 44%. 1 HNMR (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).

[0343] Example 39: 7-(4-fluoro-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

[0344] Synthetic procedure as for Example 21, yield 39%. 1 HNMR (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).

[0345] Example 40: 2-(2-cyclopropyl-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

[0346] Synthetic procedure as for Example 21, yield 51%. 1 HNMR (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).

[0347] Example 41: 2-(2-cyclobutyl-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

[0348] Synthetic procedure as for Example 21, yield 82%. 1H 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, 2 H, J = 8.9 Hz), 6.12 (d, 1 H, J = 13.0 Hz), 3.75 (s, 3 H), 3.55-3.63 (m, 1 H), 2.39 (s, 3 H), 2.34-2.37 (m, 4 H), 2.07-2.13 (m, 1 H), 2.06 (s, 6 H), 1.90-1.97 (m, 1 H), 1.61 (s, 6 H).

[0349] Example 42: 2-(4-Ethyl-2-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]pyridine- 4(5H)-one

[0350] Synthetic procedure as for Example 21, yield 30%. 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).

[0351] Example 43: 2-(2,4-Diethyl-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]pyridine- 4(5H)-one

[0352] Synthetic procedure as for 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).

[0353] Example 44: 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

[0354] Synthetic procedure as for Example 21, yield 88%. 1 H NMR (500 MHz, CD3OD): δ 7.80 (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), 3.02-3.09 (m, 1H), 2.80 (q, 2H, J = 8.8 Hz), 2.05 (s, 6H), 1.61 (s, 6H), 1.33 (d, 6H, J = 7.0 Hz), 1.17 (t, 3H, J = 7.5 Hz).

[0355] Example 45: 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

[0356] Synthetic procedure as for Example 21, yield 93%. 1 H NMR (500 MHz, CD3OD): δ 7.79 (d, 1H, J = 9.1 Hz), 7.68 (s, 1H), 7.03 (s, 1H), 6.87 (d, 2H, J = 8.9 Hz), 6.13 (d, 1H, J = 13.0 Hz), 3.75 (s, 3H), 2.73 (t, 2H, J = 7.4 Hz), 2.36 (s, 3H), 2.05 (s, 6H), 1.61 (s, 6H), 1.53-1.59 (m, 2H), 0.80 (t, 3H, J = 7.4 Hz).

[0357] Example 46: 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

[0358] Synthetic procedure as for Example 21, yield 72%. 1HNMR (500 MHz, CD3OD): δ 7.78 (d, 1H, J = 9.0 Hz), 7.68 (s, 1H), 7.04 (s, 1H), 6.86 (d, 2H, J = 8.9 Hz), 6.13 (d, 1H, J = 13.0 Hz), 3.75 (s, 3H), 2.69-2.76 (m, 4H), 2.05 (s, 6H), 1.61 (s, 6H), 1.54-1.58 (m, 2H), 1.31 (t, 3H, J = 7.6 Hz), 0.80 (t, 3H, J = 7.4 Hz).

[0359] Example 47: 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

[0360] Synthetic procedure as Example 21, yield 96%. 1 HNMR (500 MHz, CD3OD): δ 7.79 (d, 1H, J = 9.0 Hz), 7.69 (s, 1H), 7.02 (s, 1H), 6.86 (d, 2H, J = 8.8 Hz), 6.13 (d, 1H, J = 13.0 Hz), 3.75 (s, 3H), 3.36-3.40 (m, 1H), 2.71 (q, 2H, J = 7.6 Hz), 2.05 (s, 6H), 1.61 (s, 6H), 1.30 (t, 3H, J = 7.7 Hz), 1.24 (d, 6H, J = 7.0 Hz,).

[0361] Example 48: 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

[0362] Synthetic procedure as Example 21, yield 70%. 1 HNMR (500 MHz, CD3OD): δ 7.79 (d, 1H, J = 9.0 Hz), 7.69 (s, 1H), 7.02 (s, 1H), 6.86 (d, 2H, J = 8.8 Hz), 6.13 (d, 1H, J = 13.0 Hz), 3.75 (s, 3H), 3.36-3.40 (m, 1H), 2.71 (q, 2H, J = 7.6 Hz), 2.05 (s, 6H), 1.61 (s, 6H), 1.30 (t, 3H, J = 7.7 Hz), 1.24 (d, 6H, J = 7.0 Hz,).

[0363] Example 49: 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

[0364] Synthetic procedure as for Example 21, yield 64%. 1 HNMR (500 MHz, CD3OD): δ 7.79 (d, 1H, J = 9.0 Hz), 7.71 (s, 1H), 7.14 (s, 1H), 6.85 (d, 2H, J = 8.8 Hz), 6.12 (d, 1H, J = 13.0 Hz), 4.54 (s, 2H), 3.73 (s, 3H), 3.23 (s, 3H), 2.73 (q, 2H, J = 7.6 Hz), 2.03 (s, 6H), 1.59 (s, 6H), 1.30 (t, 3H, J = 7.6 Hz).

[0365] Example 50: 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

[0366] Synthetic procedure as for Example 21, yield 68%. 1 HNMR (500 MHz, CD3OD): δ 7.81 (d, 1H, J = 9.0 Hz), 7.73 (s, 1H), 7.17 (s, 1H), 6.86 (d, 2H, J = 8.9 Hz), 6.13 (d, 1H, J = 13.0 Hz), 4.55 (s, 2H), 3.76 (s, 3H), 3.24 (s, 3H), 3.04-3.12 (m, 1H), 2.05 (s, 6H), 1.61 (s, 6H), 1.35 (d, 6H, J = 7.0 Hz).

[0367] Example 51: 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

[0368] Synthetic procedure as for Example 21, yield 79%. 1HNMR (500 MHz, CD3OD): δ 7.81 (d, 1 H, J = 9.0 Hz), 7.72 (s, 1 H), 7.14 (s, 1 H), 6.87 (d, 2 H, J = 8.9 Hz), 6.14 (d, 1 H, J = 13.0 Hz), 4.53 (s, 2 H), 3.75 (s, 3 H), 3.23 (s, 3 H), 2.05 (s, 6 H), 1.98-2.02 (m, 1 H), 1.61 (s, 6 H), 1.00-1.04 (m, 2 H), 0.96-1.00 (m, 2 H).

[0369] 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

[0370] Synthetic procedure as Example 21, yield 76%. 1 HNMR (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).

[0371] 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

[0372] Synthetic procedure as Example 7, yield 19%. 1 HNMR (500 MHz, DMSO-d6): δ 11.93 (s, 1 H), 7.68 (s, 1 H), 7.29-7.46 (m, 3 H), 6.84 (s, 1 H), 6.75 (d, 2 H, J = 9.0 Hz), 5.19 (s, 1 H), 3.56 (s, 3 H), 1.98-2.08 (m, 9 H), 1.93-1.98 (m, 6 H),

[0373] 1.69-1.78 (m, 6H), 1.47 (s, 6H).

[0374] 7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methyl-2-(2-phenyl-1H-imi dazol-5-yl)furo[3,2-c]pyridin-4(5H)-one

[0375] Example 54: 7-(4-fluoro-2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methyl-2-(2-phenyl-1H-imi dazol-5-yl)furo[3,2-c]pyridin-4(5H)-one

[0376] Synthetic procedure as 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).

[0377] Biological activity testing

[0378] 1. In vitro activity testing of compounds

[0379] 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 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 pg / mL BSA, pH adjusted to 7.5. Bromodomain proteins used all bear a His tag. 3+ Europium 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 pg / mL BSA, pH adjusted to 7.5. Bromodomain proteins used all bear a His tag.

[0380] 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 protein (final concentration 2 nM) and biotin-labeled polypeptide (final concentration 20 nM) was added and incubated for 1 h at room temperature. 10 μL of a mixture containing Eu 3+ cryptate-labeled anti-His antibody and Streptavidin-XL-665 was added and incubated for 1 h 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 data were used to calculate the IC 50 value of the compound using GraphPad Prism software.

[0381] The test results of some of the above compounds are shown in Table 1.

[0382] Table 1 In vitro activity results of compounds

[0383] 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.

[0384] 2. Proliferation inhibition activity of compounds on cancer cells

[0385] In this application, the Cell Titer-Glo reagent was used to determine the proliferation inhibition ability of the compounds on 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. For suspension cells, the test compounds were added directly after the cells were seeded for 12 hours without culture. The compounds were incubated with the cells for 120 hours before testing. When testing: 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.

[0386] The results of the cancer cell proliferation inhibition activity of some of the selected examples are shown in Table 2.

[0387] In vitro anticancer activity of compounds in Table 2

[0388] As can be seen from Table 2, most of the examples selected in 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.

[0389] 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 raw materials selected by 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: ###0001### or a pharmaceutically acceptable salt thereof, characterized in that: wherein: M1and M2are independently selected from N, NH, O, S; 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 rings, sulfur-containing 3- to 7-membered saturated rings or nitrogen-containing 3- to 7-membered saturated rings, 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 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; R4, R5, and R6are each independently selected from H, halogen; R8is selected from C1-C4alkyl or deuterated C1-C4alkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, M1is selected from N and M2is selected from NH, or M1is selected from NH and M2is selected from N.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein, The compounds have a structure according to Formula II: 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 rings, sulfur-containing 3- to 7-membered saturated rings or nitrogen-containing 3- to 7-membered saturated rings, 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; R4, R5, and R6are each independently selected from H, halogen.

4. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein, R7is selected from C1-C10alkoxy, and / or R8is selected from methyl.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein, The compounds have a structure according to 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 rings, sulfur-containing 3- to 7-membered saturated rings or nitrogen-containing 3- to 7-membered saturated rings, 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, C1-C6alkyl, C1-C6alkoxy; R4, R5, and R6are each independently selected from H, halogen; 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, 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; 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.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein, R4, R5, and R6are each independently selected from H, halogen. 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 -O(C1-C5alkyl)OH. 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.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein, The compound is any one of the following compounds: 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 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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