WO2019149205A1

WO2019149205A1 - Benzoheteroaryl derivative and preparation method and medical application thereof

Info

Publication number: WO2019149205A1
Application number: PCT/CN2019/073815
Authority: WO
Inventors: 杨方龙; 张羚; 韩吉慧; 贺峰; 陶维康
Original assignee: 江苏恒瑞医药股份有限公司; 上海恒瑞医药有限公司
Priority date: 2018-01-31
Filing date: 2019-01-30
Publication date: 2019-08-08
Also published as: TW201934558A; CN111094300A; CN111094300B

Abstract

The present invention relates to a benzoheteroaryl derivative and a preparation method and medical application thereof. In particular, the present invention relates to a novel benzoheteroaryl derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition comprising the derivative, and a use of the same as a therapeutic agent, especially as a PAR-4 antagonist. The definition of each substituent in general formula (I) is the same as the definition in the specification.

Description

Benzo-heteroaryl derivative, preparation method thereof and application thereof in medicine

Technical field

The present invention belongs to the field of medicine, and relates to a novel benzoheteroaryl derivative represented by the formula (I), a process for preparing the same, and a pharmaceutical composition containing the same, and as a therapeutic agent, particularly as a PAR Use of the -4 antagonist.

Background technique

Protease-activated receptors (PARs), a G-protein-coupled receptor on the cell surface, are members of the G-protein coupled receptor superfamily. Like other types of G protein-coupled receptors, protease-activated receptors also have the property of single-stranded seven-pass transmembrane. As one of the major receptors on the surface of platelets, a total of four protease-activated receptors have been discovered in the family to date, named PAR-1, PAR-2, PAR-3 and PAR-4. Human platelets express PAR-1 and PAR-4, while murine platelets express PAR-3 and PAR-4, but not PAR-1.

Researchers discovered PAR-4 in 1998 and further cloned the PAR-4 gene and obtained its sequence from lymphoma cells, with a total length of 4.9 kb (eg, Wenfeng, W. et al., Proc. Natl. Acad). .Sci. 95:6642-6646 (1998)). Structurally, the N-terminal and C-terminal amino acid sequences of PAR-4 differ from other PARs. PAR-4 consists of 385 amino acids and contains a signal peptide and an extracellular N-terminal Arg/Gly serine protease binding site. The genes for PAR-1, PAR-2 and PAR-3 are located on human chromosome 5q13, and fluorescence in situ hybridization experiments show that the human PAR-4 gene is located on chromosome 19p12. Unlike the PAR-1 and PAR-3 binding sites, PAR-4 has no thromboplastin-binding hirudin binding site and has a lower affinity for thrombin than PAR-1 and PAR-3. Therefore, in order to activate PAR-4, a higher concentration of thrombin is required.

The activation principle of PAR-4 is: first, thrombin binds to the extracellular N-terminus of PAR-4, and cleaves the N-terminal 47 arginine/48-glycine to produce a new N-terminal, tyrosin ligand GYPGQV, which is The second extracellular domain binds to and activates the receptor causing a series of signal transductions. In addition, the polypeptide fragment GYPGQV (hPAR-4) or AYPGKF (mPAR-4) at the end of the synthetic tethered ligand can also directly activate PAR-4 (eg, Tatjana, F. et al., J. Biol. Chem. 275: 19728). -19734 (2000)).

Human platelet-expressed PAR-1 and PAR-4 two thrombin receptors are one of the targets of antithrombotic drugs. In May 2014, PAR-1 small molecule antagonist Vorapaxar was approved by the FDA for the prevention of thrombosis and is currently the only drug that treats thrombus by antagonizing thrombin receptor activity (eg, French, S. Etc., Blood Reviews. 29: 179-189 (2015)). However, antithrombotic drugs targeting the PAR-1 receptor often cause bleeding, so Vorapaxar cannot be used in patients with cerebral hemorrhage. In recent years, studies have found that PAR-4 small molecule antagonists are considered to be potentially more safe and effective antithrombotic drugs compared to antagonizing PAR-1, which has a relatively low risk of antagonizing PAR-4.

PAR-4 is mainly expressed in the lung, pancreas, thyroid, testis and small intestine, and is moderately expressed in the digestive tract. In addition to thrombosis, PAR-4 is involved in other important aspects such as regulating vasoactivity, mediating cytokines, releasing inflammatory mediators, and regulating the immune system. The main coupling pathway for signal transduction between PAR-4 and G protein subunits is the activation of phospholipase C (PLC) by the G protein Gq, resulting in the production of inositol triphosphate (IP3) and diglycerylglycerol (DAG). Causes intracellular Ca ²⁺ mobilization and activation of protein kinase C (PKC). At the same time, PAR-4 is activated by a variety of serine proteases, which regulate edema (via the kallikrein-kinin system) and recruit granulocytes in the inflammatory response.

It is therefore desirable to develop antagonists of PAR-4 to prevent and/or treat thrombosis or patients with a history of myocardial infarction or a history of peripheral arterial disease for reducing thrombotic cardiovascular events. The disclosed antagonists of PAR-4 receptors include WO2013163241, WO2013163244, WO2013163279, WO2016134450, WO2016138199, WO2017019828, WO2017066661, WO2017066683 and WO2017184520, and the like.

In order to achieve a better therapeutic effect and better meet market demand, the present invention will provide a novel structure of a highly potent PAR-4 receptor antagonist for prophylactic and therapeutic use in suffering from thrombosis (thromboses) ), a population of patients associated with embolism, hypercoagulability, or fibrotic alteration.

Summary of the invention

It is an object of the present invention to provide a compound of the formula (I):

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

X is an O atom or an S atom;

W is an O atom or an S atom;

Ring A is selected from the group consisting of cycloalkyl, aryl and heteroaryl;

Ring B is a heteroaryl group;

R ^{1 is the} same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, and a hetero group. a cycloalkyl, aryl and heteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halo, alkyl, alkoxy, haloalkyl Substituting one or more substituents of a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R ^{2 is} selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl base;

R ^{3 are the} same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, and a hetero group. a cyclic group, an aryl group and a heteroaryl group;

R ⁴ and R ^{5 are the} same or different and are each independently a hydrogen atom or an alkyl group;

R ^{6 is} selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl a group wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyanide Base, amino, nitro, -CONR ⁹ R ¹⁰ , -CH ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ , -S(O) ₂ R ¹¹ , -COR ¹¹ , -COOR ¹² , -OR ¹² , naphthenic Substituted by one or more substituents in the group, heterocyclic group, aryl group and heteroaryl group;

Or R ⁶ is

Wherein J is a covalent bond or an alkylene group, wherein the alkylene group is optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cyclo Substituted by one or more substituents of an alkyl group, a heterocyclic group, an aryl group and a heteroaryl group, the ring C is selected from the group consisting of an aryl group, a heteroaryl group, a cycloalkyl group and a heterocyclic group, and R ^{8 is the} same or different, and Each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, -CONR ⁹ R ¹⁰ , -CH ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ , -S(O) ₂ R ¹¹ , -COR ¹¹ , -COOR ¹² , -OR ¹² , cycloalkyl, heterocyclic, aryl and heteroaryl;

R ^{7 are the} same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, and a hetero group. a cycloalkyl, aryl and heteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halo, alkyl, alkoxy, haloalkyl Substituting one or more substituents of a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R ⁹ and R ^{10 are the} same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

Or R ⁹ and R ¹⁰ together with the attached nitrogen atom form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different selected from N atom, O in addition to 1 nitrogen atom. a hetero atom of an atom and an S atom, and the heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, -COR ¹¹ Substituting one or more substituents of a cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl and heteroaryl group;

R ^{11 is} selected from the group consisting of alkyl, haloalkyl, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^{12 is} selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

n is 0, 1, 2 or 3;

s is 0, 1, 2, 3 or 4;

p is 0, 1, 2 or 3;

t is 0, 1, 2 or 3.

In some preferred embodiments of the present invention, the compound of the formula (I), wherein the R ⁶ is

Wherein J is a covalent bond, and ring C is selected from the group consisting of an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclic group, and R ^{8 are the} same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, Haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, -CONR ⁹ R ¹⁰ , -CH ₂ NR ⁹ R ¹⁰ , -S(O) ₂ R ¹¹ , -COR ¹¹ and -COOR ¹² , and R ⁹ to R ¹² are as defined in the formula (I).

In some preferred embodiments of the present invention, the compound of the formula (I), wherein the ring B is a 5- to 10-membered heteroaryl group, preferably selected from the group consisting of

Or a pyrimidinyl group, wherein: G is an N atom, CR ³ or CH; Y is selected from the group consisting of an S atom, an O atom, CH=CH, CH=N and N=CH, and R ^{3 is} as defined in the general formula (I).

In some preferred embodiments of the invention, the compound of formula (I) is a compound of formula (II):

among them:

G is N atom, CR ³ or CH;

Y is selected from the group consisting of an S atom, an O atom, CH=CH, CH=N, and N=CH;

Ring C is selected from the group consisting of an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclic group;

R ^{8 are the} same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, -CONR ⁹ R ¹⁰ , -CH ₂ NR ⁹ R ¹⁰ , -S(O) ₂ R ¹¹ , -COR ¹¹ and -COOR ¹² ;

W, ring A, R ¹ to R ⁵ , R ⁷ , R ⁹ to R ¹² , X, n, s, p and t are as defined in the formula (I).

In some preferred embodiments of the invention, the compound of the formula (I) is a compound of the formula (IIcc):

among them:

G is N atom, CR ³ or CH;

Z is selected from the group consisting of O atoms, NR ¹⁶ and CH ₂ ;

Ring C is selected from the group consisting of heterocyclic groups, aryl groups and heteroaryl groups;

R ^{b is the} same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, and an amino group;

R ^{16 is} selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, -S(O) ₂ R ¹¹ , -COR ¹¹ , cycloalkyl And cycloalkylalkyl;

q is 0 or 1;

r is 0, 1, 2 or 3;

W, ring A, R ¹ to R ⁵ , R ⁷ , R ¹¹ , X, n, s, p and t are as defined in the formula (I).

In some preferred embodiments of the invention, the compound of the formula (I) is a compound of the formula (IIaa):

among them:

G is N atom, CR ³ or CH;

W, ring C, R ¹ to R ⁵ , R ⁷ , R ⁹ to R ¹² , X, n, s, p and t are as defined in the formula (I).

In some preferred embodiments of the present invention, the compound of the formula (I), wherein the Y is an S atom or CH=CH.

In some preferred embodiments of the invention, the compound of the formula (I) is a compound of the formula (III), formula (IV) or formula (V):

among them:

Ring A, R ¹ to R ⁵ , R ⁷ , R ⁹ to R ¹² , X, n, s, p and t are as defined in the formula (I).

In some preferred embodiments of the invention, the compound of formula (I) wherein W is O.

In some preferred embodiments of the invention, the compound of the formula (I), wherein the ring A is selected from the group consisting of phenyl, C _3-6 cycloalkyl or 5 to 6 Heteroaryl, the heteroaryl optionally containing 1 to 3 heteroatoms the same or different selected from the group consisting of a N atom, an O atom and an S atom; the ring A is preferably selected from the group consisting of phenyl, pyridyl, thiazolyl, pyrimidine And pyrazolyl and imidazolyl; more preferably selected from the group consisting of phenyl, pyridyl and thiazolyl.

In some preferred embodiments of the invention, the compound of the formula (I) is a compound of the formula (III'), the formula (IV') or the formula (V') :

Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

R ¹ to R ⁵ , R ⁷ , R ⁹ to R ¹² , X, n, s, p and t are as defined in the formula (I).

In some preferred embodiments of the invention, the compound of formula (I) is a compound of formula (IIbb):

among them:

G is N atom, CR ³ or CH;

W, ring A, R ¹ to R ⁵ , R ⁷ , R ¹¹ , X, n, s and p are as defined in the formula (I).

In some preferred embodiments of the present invention, the compound of the formula (I) wherein the ring C is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, C _3-8 cycloalkyl And a 3 to 8 membered heterocyclic group, each of the heteroaryl and heterocyclic groups optionally containing 1 to 3 hetero atoms which are the same or different from the N atom, the O atom and the S atom; the ring C is preferably selected from the group consisting of benzene Base, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, piperidinyl, piperazinyl, 1,2,3,6-tetrahydropyridyl, 1,2,3,4-tetrahydro Pyridyl and morpholine.

In some preferred embodiments of the present invention, the compound of the formula (I), wherein the R ^{1 is} selected from the group consisting of a hydrogen atom, an alkyl group and an alkoxy group, preferably an alkoxy group, more preferably Is a methoxy group; n is 0 or 1.

In some preferred embodiments of the present invention, the compound of the formula (I), wherein the R ² is a hydrogen atom or an alkyl group; R ^{3 are the} same or different and are each independently selected from hydrogen Atom, alkyl and alkoxy.

In some preferred embodiments of the invention, the compound of formula (I) wherein X is O.

In some preferred embodiments of the invention, the compound of the formula (I), wherein R ⁴ and R ^{5 are the} same or different, and each independently is a hydrogen atom.

In some preferred embodiments of the present invention, the compound of the formula (I), wherein the R ^{7 is} selected from a hydrogen atom, a halogen or an alkyl group.

Typical compounds of the invention include, but are not limited to:

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof.

Another aspect of the invention relates to a compound of the formula (IA):

Or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, which is a formula (I) Intermediates,

among them:

M is selected from halogen, -OH or -OS(O) ₂ R ¹³ ;

X is an O atom or an S atom;

Ring B is a heteroaryl group;

R ¹³ is alkyl, amino, -NR ¹⁴ R ¹⁵ or cycloalkyl;

R ¹⁴ and R ^{15 are the} same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

Or R ¹⁴ and R ¹⁵ together with the attached nitrogen atom form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different selected from N atom, O in addition to 1 nitrogen atom. a hetero atom of an atom and an S atom, and said heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl Substituting one or more substituents in a heterocyclic group, an aryl group, and a heteroaryl group;

n is 0, 1, 2 or 3;

s is 0, 1, 2, 3 or 4.

Another preferred embodiment of the present invention relates to a compound of the formula (IA) wherein the ring B is a 5- to 10-membered heteroaryl group, preferably selected from the group consisting of

Or pyrimidinyl, wherein: G is an N atom, CR ³ or CH; Y is selected from the group consisting of an S atom, an O atom, CH=CH, CH=N and N=CH.

Another preferred embodiment of the invention relates to a compound of the formula (IA) which is of the formula (IIA):

among them:

G is N atom, CR ³ or CH;

Y is an S atom, an O atom or CH=CH;

M, X, R ¹ to R ⁵ , n and s are as defined in the formula (IA).

Another preferred embodiment of the invention relates to a compound of the formula (IA), or a tautomer, a mesogen, a racemate, an enantiomer, a non-pair a conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is of the formula (IIIA), formula (IVA) or formula (VA):

among them:

M, X, R ¹ to R ⁵ , n and s are as defined in the formula (IA).

Typical intermediates of the invention include, but are not limited to:

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention relates to a process for the preparation of a compound of formula (I), which process comprises:

A compound of the formula (IA) is reacted with a compound of the formula (IB) to give a compound of the formula (I),

among them:

M is selected from the group consisting of halogen, -OH and -OS(O) ₂ R ¹³ ;

R ^{13 is} selected from the group consisting of alkyl, amino, NR ¹⁴ R ¹⁵ and cycloalkyl;

Ring A, Ring B, W, X, R ¹ to R ⁷ , n, s and p are as defined in the general formula (I).

Another aspect of the invention relates to a process for the preparation of a compound of formula (II), the process comprising:

The compound of the formula (IIA) and the compound of the formula (IIB) are reacted to obtain a compound of the formula (II).

among them:

M is selected from the group consisting of halogen, -OH and -OS(O) ₂ R ¹³ ;

R ¹³ is alkyl, amino, NR ¹⁴ R ¹⁵ and cycloalkyl;

Ring A, Ring C, W, X, G, Y, R ¹ to R ⁵ , R ⁷ , R ⁸ , n, s, p and t are as defined in the formula (II).

Another aspect of the invention relates to a process for the preparation of a compound of the formula (IIbb) which comprises:

A compound of the formula (IIA) is reacted with a compound of the formula (IIb) to give a compound of the formula (IIbb),

among them:

M is selected from the group consisting of halogen, -OH and -OS(O) ₂ R ¹³ ;

R ^{13 is} selected from the group consisting of alkyl, amino, -NR ¹⁴ R ¹⁵ and cycloalkyl;

Ring A, Ring C, W, X, G, Y, R ¹ to R ⁵ , R ⁷ , R ⁹ , R ¹⁰ , n, s and p are as defined in the formula (II).

Another aspect of the invention relates to a process for the preparation of a compound of formula (III), formula (IV) or formula (V), the process comprising:

The compound of the formula (IIIA) and the compound of the formula (IIB) are reacted to obtain a compound of the formula (III).

The compound of the formula (IVA) is reacted with a compound of the formula (IIB) to give a compound of the formula (IV).

A compound of the formula (VA) is reacted with a compound of the formula (IIB) to give a compound of the formula (V),

among them:

M is selected from the group consisting of halogen, -OH and -OS(O) ₂ R ¹³ ;

R ¹³ is alkyl, amino, -NR ¹⁴ R ¹⁵ or cycloalkyl;

Ring A, Ring C, W, X, R ¹ to R ⁵ , R ⁷ , R ⁸ , n, s, p and t are as defined in Formula (III), Formula (IV) or Formula (V) .

Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, an enantiomer a form, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent and excipient.

Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a medicament.

Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof A form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for antagonizing PAR-4.

Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a PAR-4 antagonist.

Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof Use of a form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment or prevention of a disease of platelet aggregation.

Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof Use of a form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating or preventing a thromboembolic disease, preferably, the thromboembolic disease is selected from the group consisting of arterial cardiovascular thromboembolism Disease, venous cardiovascular thromboembolic disease, cerebrovascular thromboembolic disease, and thromboembolic disease in the heart or peripheral circulation.

Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof A form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment or prevention of a disease of platelet aggregation.

Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment or prevention of a thromboembolic disease, preferably, the thromboembolic disease is selected from the group consisting of an arterial cardiovascular thromboembolic disease, venous cardiovascular Thromboembolic disease, cerebrovascular thromboembolic disease, and thromboembolic disease in the heart or peripheral circulation.

Another aspect of the invention relates to a method of antagonizing PAR-4 comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, a mesogen, racemic Or a pharmaceutically acceptable salt or a pharmaceutical composition comprising the same, or an enantiomer, a diastereomer or a mixture thereof.

Another aspect of the invention relates to a method of treating or preventing a disease of platelet aggregation comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen thereof, A racemic form, enantiomer, diastereomer or mixture thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.

Another aspect of the invention relates to a method of treating or preventing a thromboembolic disease comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen thereof, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, preferably, the thromboembolic disease is selected from the group consisting of Arterial cardiovascular thromboembolic disease, venous cardiovascular thromboembolic disease, cerebrovascular thromboembolic disease, and thromboembolic disease in the heart chamber or peripheral circulation.

The dosage of the compound or composition used in the methods of treatment described herein will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound. However, as a general guide, a suitable unit dose may be from 0.1 to 1000 mg.

The pharmaceutical composition of the present invention may contain, in addition to the active compound, one or more excipients selected from the group consisting of fillers (diluents), binders, wetting agents, disintegrating agents or Shape agent, etc. The composition may contain from 0.1 to 99% by weight of active compound, depending on the method of administration.

The active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture. These excipients can be inert excipients, granulating agents, disintegrating agents, binders, and lubricants. These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.

Oral formulations can also be provided in soft gelatine capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient in admixture with a water-soluble vehicle or an oil vehicle.

The aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending, dispersing or wetting agents. The aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

The oil suspension can be formulated by suspending the active ingredient in vegetable oil, or mineral oil. The oil suspension may contain a thickening agent. The above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an antioxidant.

The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, and emulsions can also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.

The pharmaceutical compositions of the invention may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase. The injection or microemulsion is injected into the bloodstream of the patient by topical injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.

The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile fixed oils may conveniently be employed as a solvent or suspension medium.

The compounds of the invention may be administered in the form of a suppository for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug. Such materials include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

As is well known to those skilled in the art, the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient. , the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment modality such as the mode of treatment, the daily dosage of the compound of formula (I) or the pharmaceutically acceptable salt The type can be verified according to traditional treatment options.

Detailed description of the invention

Terms used in the specification and claims have the following meanings unless stated to the contrary.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons. The alkyl group of the atom. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 , 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-B Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-B Base, 2, 2 2-Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, which is independently optionally selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy. , haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, decyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl Substituted by one or more substituents of a cycloalkoxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, and an oxo group.

The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon radical having two residues derived from the removal of two hydrogen atoms from the same carbon atom of the parent alkane or two different carbon atoms. A linear or branched group having 1 to 20 carbon atoms, preferably having 1 to 12 carbon atoms, more preferably an alkylene group having 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH ₂ -), 1,1-ethylene (-CH(CH ₃ )-), 1,2-ethylene (-CH _{2 )} CH ₂ )-, 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylene (-CH ₂ CH(CH ₃ )-), 1,3-propylene (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), and the like. The alkylene group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, which is independently optionally selected from the group consisting of halogen, alkyl, haloalkyl, alkane. Oxyl, haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, decyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl Substituted by one or more substituents in the group, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, which is independently optionally selected from halogen, alkyl, haloalkyl. , alkoxy, haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, decyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, Substituted by one or more substituents of a heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo group.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom, most preferably from 5 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene A polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.

The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring includes the above cycloalkyl (eg, monocyclic, fused, spiro, and bridged cycloalkyl) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the parent structure is attached The ring together is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like; preferably phenylcyclopentyl, tetrahydronaphthyl. The cycloalkyl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment, which is independently optionally selected from the group consisting of halogen, alkyl, haloalkyl. , alkoxy, haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, decyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, Substituted by one or more substituents of a heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo group.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O). A hetero atom of _m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; most preferably from 3 to 8 (eg 3, 4, 5, 6, 7 or 8) ring atoms, of which 1 to 3 (eg 1, 2 or 3) are heteroatoms; most preferably 5 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like are preferably tetrahydropyranyl, piperidinyl or pyrrolidinyl. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) _m (where m is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group. Non-limiting examples of spiroheterocyclyl groups include:

The term "fused heterocyclyl" refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), and the remaining rings The atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

The term "bridge heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total A π-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridge heterocyclic groups include:

The heterocyclyl ring includes the above heterocyclic group (for example, a monocyclic ring, a fused ring, a spiro ring, and a bridged heterocyclic group) fused to an aryl group, a heteroaryl group or a cycloalkyl ring, wherein the structure is bonded to the parent structure. The ring together is a heterocyclic group, non-limiting examples of which include:

Wait.

The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, which is independently optionally selected from the group consisting of halogen, alkyl, haloalkyl , alkoxy, haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, decyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, Substituted by one or more substituents of a heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo group.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. The aryl ring includes the above aryl group fused to a heteroaryl group, a heterocyclic group or a cycloalkyl ring, wherein the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, which is independently optionally selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy , haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, decyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl Substituted by one or more substituents of a cycloalkoxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, and an oxo group.

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 members, and has 1 to 3 hetero atoms; more preferably 5 or 6 members, and 1 to 2 hetero atoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridyl Azyl, oxazolyl, pyrrolyl, 1H-1,2,3-triazolyl, 4H-1,2,4-triazolyl, 4H-1,2,3-triazolyl, 1H-tetrazole a group, 2H-tetrazolyl, 5H-tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl or the like, preferably imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or Imidazolyl. The heteroaryl ring includes a heteroaryl group as defined above fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:

The heteroaryl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment, which is independently optionally selected from the group consisting of halogen, alkyl, haloalkyl. , alkoxy, haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, decyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, Substituted by one or more substituents of a heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo group.

The term "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" means that the alkoxy group is substituted by one or more halogens, wherein alkoxy is as defined above.

The term "cycloalkylalkyl" refers to an alkyl group substituted by one or more cycloalkyl groups, wherein alkyl and cycloalkyl are as defined above.

The term "hydroxy" refers to an -OH group.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

The term "halogen" means fluoro, chloro, bromo or iodo.

The term "amino" means -NH _2.

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "oxo" refers to =0.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.

The present invention provides a novel PAR-4 antagonist having the structure of the general formula (I), which has a marked improvement in solvent solubility and a drug-absorbable property as compared with the prior art compound.

Method for synthesizing the compound of the present invention

In order to accomplish the object of the present invention, the present invention adopts the following technical solutions:

Option One

a compound of the formula (I) of the present invention or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or A method for preparing a medicinal salt, comprising the steps of:

M is selected from halogen, -OH or -OS(O) ₂ R ¹³ ;

Ring A, Ring B, W, X, R ¹ to R ⁷ , n, s and p are as defined in the general formula (I). When M is halogen or -OS(O) ₂ R ¹³ , the compound of the formula (IA) and the compound of the formula (IB) undergo nucleophilic substitution reaction under basic conditions to give a compound of the formula (I) ;

When both M and W are -OH, the compound of the formula (IA) and the compound of the formula (IB) undergo a Mitsunobu etherification reaction to give a compound of the formula (I).

The reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, potassium acetate, sodium t-butoxide, potassium t-butoxide and sodium n-butoxide, said inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, Potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide, preferably cesium carbonate;

Reagents that provide Mitsunobu etherification reaction conditions include, but are not limited to, tri-n-butylphosphoric acid and azodiyldipiperidine, tri-n-butylphosphine, and N,N,N',N'-tetramethylazo Amide or triphenylphosphine and diethyl azodicarboxylate;

The above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 , 4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.

Option II

a compound of the formula (II) of the present invention or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or A method for preparing a medicinal salt, comprising the steps of:

M is selected from halogen, -OH or -OS(O) ₂ R ¹³ ;

When M is halogen or -OS(O) ₂ R ¹³ , the compound of the formula (IIA) and the compound of the formula (IIB) undergo nucleophilic substitution reaction under basic conditions to obtain a compound of the formula (II) ,

When both M and W are -OH, the compound of the formula (IIA) and the compound of the formula (IIB) undergo a Mitsunobu etherification reaction to give a compound of the formula (II).

third solution

a compound of the formula (III) of the present invention or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or A method for preparing a medicinal salt, comprising the steps of:

among them:

M is selected from halogen, -OH or -OS(O) ₂ R ¹³ ;

Ring A, Ring C, W, X, R ¹ to R ⁵ , R ⁷ , R ⁸ , n, s, p and t are as defined in the formula (III).

When M is halogen or -OS(O) ₂ R ¹³ , the compound of the formula (IIIA) and the compound of the formula (IIB) undergo nucleophilic substitution reaction under basic conditions to obtain a compound of the formula (III) ,

When both M and W are -OH, the compound of the formula (IIIA) and the compound of the formula (IIB) undergo a Mitsunobu etherification reaction to give a compound of the formula (III).

Option four

a compound of the formula (IV) of the present invention or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or A method for preparing a medicinal salt, comprising the steps of:

among them:

M is selected from halogen, -OH or -OS(O) ₂ R ¹³ ;

Ring A, Ring C, W, X, R ¹ to R ⁵ , R ⁷ , R ⁸ , n, s, p and t are as defined in the general formula (IV).

When M is halogen or -OS(O) ₂ R ¹³ , the compound of the formula (IVA) and the compound of the formula (IIB) undergo nucleophilic substitution reaction under basic conditions to give a compound of the formula (IV) ;

When both M and W are -OH, the compound of the formula (IVA) and the compound of the formula (IIB) undergo a Mitsunobu etherification reaction to give a compound of the formula (IV).

Option five

a compound of the formula (V) of the present invention or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or A method for preparing a medicinal salt, comprising the steps of:

among them:

M is selected from halogen, -OH or -OS(O) ₂ R ¹³ ;

Ring A, Ring C, W, X, R ¹ to R ⁵ , R ⁷ , R ⁸ , n, s, p and t are as defined in the formula (V).

When M is halogen or -OS(O) ₂ R ¹³ , the compound of the formula (VA) and the compound of the formula (IIB) undergo nucleophilic substitution reaction under basic conditions to give a compound of the formula (V) ,

When both M and W are -OH, the compound of the formula (VA) and the compound of the formula (IIB) undergo a Mitsunobu etherification reaction to give a compound of the formula (V).

Detailed ways

Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four. Methyl silane (TMS).

The measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

High performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200 DAD, an Agilent HPLC 1200 VWD and a Waters HPLC e2695-2489 high pressure liquid chromatograph.

Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.

High performance liquid phase preparations were performed using a Waters 2767, Waters 2767-SQ Detecor 2, Shimadzu LC-20AP and Gilson-281 preparative chromatograph.

Chiral preparation using a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash Rapid Preparer uses the Combiflash Rf200 (TELEDYNE ISCO).

Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.2mm. The specification for thin layer chromatography separation and purification is 0.4mm. ~0.5mm.

Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

The average value of ₅₀ measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).

The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.

Unless otherwise specified in the examples, the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.

An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

The pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.

The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.

The microwave reaction used a CEM Discover-S Model 908860 microwave reactor.

Unless otherwise stated in the examples, the solution means an aqueous solution.

There is no particular description in the examples, and the reaction temperature is room temperature and is 20 ° C to 30 ° C.

The progress of the reaction in the examples was monitored by thin layer chromatography (TLC), the developing agent used for the reaction, the column chromatography eluent system used for the purification of the compound, and the thin layer chromatography developing solvent system including: A: Methylene chloride/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: dichloromethane/ethyl acetate solvent volume ratio is adjusted according to the polarity of the compound, It can also be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid.

Example 1

2-methoxy-6-(6-methoxy-4-((3-(6-methylpyridin-3-yl)phenoxy)methyl)benzofuran-2-yl)imidazo[ 2,1-b][1,3,4]thiadiazole 1

first step

3-(6-methylpyridin-3-yl)phenol 1c

5-Bromo-2-methylpyridine 1a (344 mg, 2.0 mmol, Shanghai Haoyuan Reagent Co., Ltd.) was dissolved in 12 mL of a mixed solution of 1,4-dioxane and water (V: V = 5:1), and added. 3-hydroxyphenylboronic acid 1b (276 mg, 2.0 mmol, Shanghai Haoyuan Reagent Co., Ltd.), tetrakis(triphenylphosphine)palladium (231 mg, 0.2 mmol), sodium carbonate (424 mg, 4.0 mmol), heated to an argon atmosphere Stir at 90 ° C for 18 hours. The reaction was cooled, EtOAc EtOAc (EtOAc (EtOAc)EtOAc. Chromatography on eluent B afforded the title compound 1c (300 mg).

MS m/z (ESI): 185.9 [M+1]

Second step

1-(4-hydroxy-6-methoxybenzofuran-2-yl)ethanone 1e

1-(4-Benzyloxy-6-methoxybenzofuran-2-yl)ethanone 1d (10 g, 33.7 mmol, prepared by the method disclosed in the patent application "WO2013163244") dissolved in 200 mL of two In methyl chloride, it was cooled to -78 ° C, and pentamethylbenzene (35 g, 236.1 mmol) and a boron trichloride dichloromethane solution (1M, 50.6 mL) were added and reacted for 40 minutes. Saturated ammonium chloride (30 mL), EtOAc (EtOAc) The organic layer was concentrated under reduced pressure.

MS m/z (ESI): 207.1 [M+1]

third step

2-acetyl-6-methoxybenzofuran-4-yltrifluoromethanesulfonate 1f

Compound 1e (4.48g, 21.7mmol) was dissolved in 300mL of tetrahydrofuran, cooled to -20 ° C, added potassium tert-butoxide (2.92g, 26mmol), stirred at 0 ° C for 30 minutes, then cooled to -20 ° C, added N-phenylbis(trifluoromethanesulfonyl)imide (9.31 g, 26 mmol) was reacted for 30 minutes. After adding water (60 mL), EtOAc (EtOAc m. (5330 mg), yield: 72.5%.

the fourth step

2-acetyl-6-methoxybenzofuran-4-carboxylic acid methyl ester 1g

Compound 1f (1800 mg, 5.3 mmol) was dissolved in 20 mL of N,N-dimethylformamide, and palladium acetate (36 mg, 0.16 mmol) and 1,1'-bis(diphenylphosphino)ferrocene were sequentially added. (28 mg, 0.33 mmol), triethylamine (1200 mg, 11.9 mmol) and methanol (1.5 mL) were heated to 60 ° C for 3 hours under a carbon monoxide atmosphere. The reaction mixture was cooled to room temperature, and water (40 mL) was evaporated. Purification gave the title compound 1 g (1200 mg).

MS m/z (ESI): 249.1 [M+1]

the fifth step

Methyl 2-(2-bromoacetyl)-6-methoxybenzofuran-4-carboxylate 1h

A solution of 1 g (1.2 g, 4.8 mmol) of compound in 30 mL of dry tetrahydrofuran was slowly added dropwise at 40 ° C to dissolve 40 mL of N,N'-bis(trimethylsilyl)amide lithium (1M, After reacting for 1 hour in a dry tetrahydrofuran solution of 16.9 mL), trimethylchlorosilane (1830 mg, 16.8 mmol) was slowly added dropwise, and stirring was continued for 2 hours. 50 mL of saturated sodium hydrogencarbonate and ethyl acetate (80 mL) were added. The organic phase was dried over anhydrous sodium sulfate and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The reaction was stirred for 0.5 hours, 50 mL of saturated sodium bicarbonate solution was added, and ethyl acetate was added (80 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated, evaporated.

MS m/z (ESI): 327.0 [M+1]

Step 6

2-(2-bromoimidazo[2,1-b][1,3,4]thiadiazole-6-yl)-6-methoxybenzofuran-4-carboxylic acid methyl ester 1i

Compound 1h (1300 mg, 3.9 mmol) was dissolved in 30 mL of n-butanol, and 2-amino-5-bromo-1,3,4-thiadiazole (1100 mg, 6.1 mmol, Shanghai Bied Pharmaceutical Technology Co., Ltd.) was added. Heat to 90 ° C and react for 12 hours. The reaction was cooled to room temperature and then evaporated tolululululululu

MS m/z (ESI): 408.0 [M+1]

Seventh step

6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl)benzofuran-4-carboxylic acid methyl ester 1j

The crude compound 1i (1300 mg, 3.2 mmol) was dissolved in 15 mL of methanol and 12 mL of dichloromethane, and a solution of fresh sodium methoxide in methanol (2.1 M, 3 mL) was added and reacted for 3 hours. The organic layer was concentrated under reduced pressure.

MS m/z (ESI): 360.1 [M+1]

Eighth step

(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)methanol 1k

Compound 1j (260 mg, 0.72 mmol) was dissolved in 20 mL of tetrahydrofuran, cooled to 0 ° C under argon, and diisobutylaluminum hydride (1 M, 3.6 mL) was added dropwise, stirring was continued for 30 minutes; 10 mL of saturated chlorine was added. Aqueous ammonium chloride solution, EtOAc (EtOAc (EtOAc)EtOAc.

MS m/z (ESI): 331.8 [M+1]

Step 9

6-(4-(Chloromethyl)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole 1l

Compound 1k (130 mg, 0.4 mmol) was dissolved in dichloromethane (30 mL), and then filtered. 8 mL of water, and the organic phase was washed with water (8 mL, 3), dried over anhydrous sodium sulfate.

MS m/z (ESI): 350.1 [M+1]

Step 10

Compound 11 (30 mg, 86 μmol) and Compound 1c (20 mg, 108 μmol) were dissolved in 5 mL of N,N'-dimethylformamide, and cesium carbonate (150 mg, 450 μmol) was added, and the reaction was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure.

MS m/z (ESI): 499.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.73 (s, 1H), 7.89 (s, 1H), 7.82 (d, 1H), 7.39 (t, 1H), 7.27 (s, 1H), 7.21 (s, 1H), 7.17 (d, 1H), 7.11 (s, 1H), 7.04 (d, 2H), 6.98 (s, 1H), 5.32 (s, 2H), 4.21 (s, 3H), 3.88 (s, 3H) ), 2.64 (s, 3H).

Example 2

6-(3-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4- Methoxy)phenyl)nicotinonitrile 2

first step

6-(3-hydroxyphenyl)nicotinonitrile 2b

6-bromonicotinonitrile 2a (730 mg, 3.9 mmol, Shanghai Haoyuan Reagent Co., Ltd.) was dissolved in 12 mL of a mixed solution of 1,4-dioxane and water (V: V = 5:1), and then 1b ( 606 mg, 4.4 mmol, Saan Chemical Technology (Shanghai) Co., Ltd., tetrakis(triphenylphosphine)palladium (233 mg, 0.2 mmol) and sodium carbonate (847 mg, 7.9 mmol) were added to the above reaction system, under an argon atmosphere, oil bath Heat to 90 ° C and stir the reaction for 18 hours. The reaction was cooled, EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The obtained residue was purified to give the title compound 2b (500 mg).

MS m/z (ESI): 196.9 [M+1]

Second step

6-(3-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4 -yl)methoxy)phenyl)nicotinonitrile 2

The compound 11 (30 mg, 86 μmol) and the compound 2b (26 mg, 132 μmol) were dissolved in 5 mL of N,N'-dimethylformamide, and cesium carbonate (140 mg, 430 μmol) was added thereto, and the mixture was heated to 50 ° C, and the reaction was stirred for 1 hour. The reaction mixture was concentrated under reduced vacuo.

MS m/z (ESI): 510.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.94-8.94 (s, 1H), 8.01-7.98 (dd, 1H), 7.90 (s, 1H), 7.84-7.82 (d, 1H), 7.76 (s, 1H), 7.64-7.62 (d, 1H), 7.45-7.41 (t, 1H), 7.16-7.13 (m, 2H), 7.04-7.00 (m, 2H), 5.36 (s, 2H), 4.22 (s, 3H), 3.88 (s, 3H).

Example 3

2-methoxy-6-(6-methoxy-4-((3-(5-methoxypyrazin-2-yl)phenoxy)methyl)benzofuran-2-yl)imidazole And [2,1-b][1,3,4]thiadiazole 3

first step

3-(5-methoxypyrazin-2-yl)phenol 3b

2-Bromo-5-methoxypyrazine 3a (189 mg, 1.00 mmol, Suiyuan Technology (Shanghai) Co., Ltd.) was dissolved in 6 mL of a mixed solution of 1,4-dioxane and water (V: V=5) :1), 3-hydroxyphenylboronic acid 1b (138 mg, 1.00 mmol), tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol), sodium carbonate (212 mg, 2.00 mmol), under argon, 100 Stir at °C for 16 hours. After cooling to room temperature, water (10 mL), EtOAc (EtOAc)EtOAc. , Yield: 94%.

Second step

Compound 11 (30 mg, 86 μmol) and Compound 3b (21 mg, 103 μmol) were dissolved in 5 mL of N,N'-dimethylformamide, and cesium carbonate (140 mg, 430 μmol) was added thereto, and the reaction was stirred for 3 hours. The reaction mixture was concentrated under reduced vacuo.

MS m/z (ESI): 516.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ): δ8.51 (d, 1H), 8.30 (d, 1H), 7.89 (s, 1H), 7.64-7.63 (m, 1H), 7.52-7.50 (m, 1H) , 7.41-7.37 (t, 1H), 7.12 (s, 1H), 7.07-7.03 (m, 2H), 7.00 (m, 1H), 5.35 (s, 2H), 4.22 (s, 3H), 4.02 (s) , 3H), 3.88 (s, 3H).

Example 4

6-(4-(((2-(4-chlorophenyl)pyridin-4-yl)oxy)methyl)-6-methoxybenzofuran-2-yl)-2-methylimidazolium [2,1-b][1,3,4]thiadiazole 4

first step

2-(4-chlorophenyl)pyridin-4-ol 4c

2-Chloro-4-hydroxypyridine 4a (500 mg, 3.86 mmol, Adamars Reagent Co., Ltd.) was dissolved in 15 mL of dioxane under argon atmosphere, 3 mL of water was added, and stirring was carried out, and 4-chlorophenylboronic acid 4b was added. (603 mg, 3.86 mmol, Suiyuan Technology (Shanghai) Co., Ltd.), sodium carbonate (226 mg, 2.13 mmol), tetrakis(triphenylphosphine)palladium (41 mg, 0.04 mmol), and reacted at 100 ° C for 2 hours. The reaction mixture was concentrated to give crystal crystal crystal crystal crystal crystal crystal

MS m/z (ESI): 206.0 [M+1]

Second step

Methyl 6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazole-6-yl)benzofuran-4-carboxylate 4d

Compound 1h (3.5 g, 10.7 mmol) was dissolved in 150 mL of isopropanol, and 2-amino-5-methyl-1,3,4-thiadiazole (2.5 g, 21.7 mmol, 韶远科技 (Shanghai) was added. ))), heated to 100 ° C, reacted for 12 hours, and reacted at 130 ° C for 4 hours. After the reaction was cooled to room temperature, filtered, washed with EtOAc EtOAc EtOAc

MS m/z (ESI): 344.0 [M+1]

third step

(6-Methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)methanol 4e

Compound 4d (2.5 g, 7.28 mmol) was dissolved in 80 mL of tetrahydrofuran, and the reaction mixture was stirred, chilled to -20 ° C, diisobutylaluminum hydride (1.0 M, 36.82 mmol) was added dropwise, and the reaction was continued for 1 hour. The reaction was quenched by the dropwise addition of 10 mL of methanol at 20 ° C, and then, 1N hydrochloric acid, 70 mL, and 40 mL of water was added dropwise, and filtered to give the title compound 4e (2 g).

MS m/z (ESI): 315.6 [M+1]

the fourth step

Compound 4c (25.4 mg, 0.12 mmol) was dissolved in 12 mL of tetrahydrofuran under argon and stirred. Compound 4e (30 mg, 0.09 mmol), tri-n-butylphosphonium (57 mg, 0.28 mmol), and heated to 40 ° C, N, N, N', N'-tetramethylazodicarbonamide (49 mg, 0.28 mmol, Suiyuan Technology (Shanghai) Co., Ltd.) was added, and reacted at 40 ° C for 2 hours. 15 mL of water was added to the reaction mixture, and ethyl acetate (30 mL × 2) was evaporated. Compound 4 (35 mg), Yield: 73%.

MS m/z (ESI): 503.1 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.55 (d, 1H), 8.05 (s, 1H), 7.93 (d, 2H), 7.45 (d, 2H), 7.34 (s, 1H), 7.14 (s, 1H), 7.06 (s, 1H), 6.95 (d, 2H), 5.42 (s, 2H), 3.89 (s, 3H), 2.74 (s, 3H).

Example 5

2-methoxy-6-(6-methoxy-4-((4'-methoxy-[1,1'-biphenyl]-3-yl)oxy)methyl)benzo Furan-2-yl)imidazo[2,1-b][1,3,4]thiadiazole 5

first step

4'-methoxy-[1,1'-biphenyl]-3-phenol 5c

3-bromophenol 5a (500 mg, 2.89 mmol, 韶远 reagent (Shanghai) Technology Co., Ltd.) was dissolved in a 1,4-dioxane/water mixed solution under an argon atmosphere (V: V = 5:1). () 4-(methoxyphenyl)boronic acid 5b (440 mg, 2.90 mmol, sputum reagent (Shanghai) Technology Co., Ltd.), tetrakistriphenylphosphine palladium (167 mg, 0.15 mmol) and sodium carbonate (613 mg) , 5.78 mmol) was added to the above reaction system; the oil bath was heated to 90 ° C, and the reaction was stirred at this temperature for 18 hours. The reaction was cooled, and ethyl acetate (50 mL) was evaporated, evaporated, evaporated. Purification by column chromatography using EtOAc EtOAc (EtOAc)

MS m/z (ESI): 201.2 [M+1]

Second step

Compound 1k (30 mg, 0.09 mmol), compound 5c (28 mg, 0.14 mmol) and tri-n-butylphosphonium (28 mg, 0.14 mmol) were dissolved in 10 mL of tetrahydrofuran under argon. Piperidine (69 mg, 0.27 mmol) was added to the above reaction system, and the reaction was kept at room temperature for 1 hour. The reaction was quenched with EtOAc (EtOAc) (EtOAc m. Compound 5 (15 mg), Yield: 32.3%.

MS m/z (ESI): 514.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.88 (s, 1H), 7.52 (d, 2H), 7.30 (t, 1H), 7.22 (s, 1H), 7.14 (d, 1H), 7.03 (s, 1H), 6.99-6.95 (m, 5H), 5.31 (s, 2H), 4.21 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H).

Example 6

2-methoxy-6-(6-methoxy-4-((3-(2-methylthiazol-5-yl)phenoxy)methyl)benzofuran-2-yl)imidazo[ 2,1-b][1,3,4]thiadiazole 6

first step

3-(2-methylthiazol-5-yl)phenol 6b

Compound 6a (356 mg, 2.0 mmol, Suiyuan Technology (Shanghai) Co., Ltd.) and Compound 1b (276 mg, 2.00 mmol, Suiyuan Technology (Shanghai) Co., Ltd.) were dissolved in 10 mL of 1,4-two under an argon atmosphere. Tetrakis(triphenylphosphine)palladium (116 mg, 100.4 umol), potassium carbonate (424 mg, 4.00 mmol) was added to the hexacyclohexane and 2 mL of water, and the mixture was reacted at 100 ° C for 16 hours. To the reaction mixture was added 10 mL of water, EtOAc (EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Purification was used directly in the next step.

MS m/z (ESI): 192.1 [M+1]

Second step

Compound 1k (24 mg, 0.07 mmol), compound 6b (15 mg, 0.08 mmol) and tri-n-butylphosphonium (30 mg, 0.15 mmol) were dissolved in 4 mL of tetrahydrofuran under argon, and then azodicarboxylate Piperidine (37 mg, 0.15 mmol) was added to the above reaction system, and the reaction was kept at room temperature for 1 hour. The reaction was quenched by the addition of EtOAc (EtOAc) (EtOAc) Title Compound 6 (20 mg), Yield: 55.1%.

MS m/z (ESI): 505.1 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.88 (s, 1H), 7.78 (s, 1H), 7.29 (t, 1H), 7.16 (d, 1H), 7.11 (d, 2H), 7.02 (s, 1H), 6.95 (d, 2H), 5.28 (s, 2H), 4.20 (s, 3H), 3.87 (s, 3H), 2.73 (s, 3H).

Example 7

2-methoxy-6-(6-methoxy-4-((3-(5-methoxypyrimidin-2-yl)phenoxy)methyl)benzofuran-2-yl)imidazolium [2,1-b][1,3,4]thiadiazole 7

first step

3-(5-methoxypyrimidin-2-yl)phenol 7b

2-Bromo-5-methoxypyrimidine 7a (189 mg, 1.00 mmol, Shanghai Bied Pharmaceutical Technology Co., Ltd.) and Compound 1b (138 mg, 1.00 mmol) were dissolved in 5 mL of 1,4-dioxane under an argon atmosphere. To the ring and 1 mL of water, tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) and sodium carbonate (212 mg, 2.00 mmol) were added, and the mixture was reacted at 100 ° C for 18 hours. To the reaction mixture, 10 mL of water (3 mL, EtOAc, EtOAc) Yield: 89%.

MS m/z (ESI): 203.1 [M+1]

Second step

Compound 1k (24 mg, 0.072 mmol) and compound 7b (15 mg, 0.074 mmol) were dissolved in 4 mL of tetrahydrofuran, followed by tributylphosphine (29 mg, 0.14 mmol), azodiyldipiperidine (36 mg, 0.14 mmol) The reaction was stirred for 1 hour and stirred at 20 ° C for 1 hour. To the reaction mixture, 10 mL of water, EtOAc (EtOAc m. 27%.

MS m/z (ESI): 516.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.49 (s, 2H), 8.07-8.13 (m, 1H), 7.95-8.03 (m, 1H), 7.89 (s, 1H), 7.35-7.44 (m, 1H ), 7.15 (s, 1H), 7.08-7.13 (m, 1H), 7.03 (s, 2H), 5.37 (s, 2H), 4.21 (s, 3H), 3.97 (s, 3H), 3.88 (s, 3H).

Example 8

2-methoxy-6-(6-methoxy-4-((3-(2-methoxypyrimidin-5-yl)phenoxy)methyl)benzofuran-2-yl)imidazolium [2,1-b][1,3,4]thiadiazole 8

first step

3-(2-methoxypyrimidin-5-yl)phenol 8b

Compound 5a (453 mg, 2.62 mmol) was dissolved in a 1,4-dioxane/water mixed solvent (V:V = 5:1) under an argon atmosphere. (2-Methoxypyrimidin-5-yl)boronic acid 8a (467 mg, 3.0 mmol, Shanghai Bied Pharmaceutical Technology Co., Ltd.), tetrakis(triphenylphosphine)palladium (150 mg, 129.81 umol) and potassium carbonate (2M, 2.64 mL), the reaction was stirred at 90 ° C for 18 hours in an oil bath. The reaction was cooled, and ethyl acetate (50 mL) was evaporated, evaporated, evaporated. Purification by column chromatography on silica gel eluting with EtOAc (EtOAc)

MS m/z (ESI): 203.3 [M+1]

Second step

Compound 1k (29 mg, 0.09 mmol), compound 8b (30 mg, 0.15 mmol) and tri-n-butylphosphonium (60 mg, 0.30 mmol) were dissolved in 10 mL of tetrahydrofuran under argon, then azodicarboxylate Piperidine (70 mg, 0.28 mmol) was added to the above reaction system, and the reaction was kept at room temperature for 1 hour. The reaction was quenched by the addition of EtOAc (EtOAc) (EtOAc) Title Compound 8 (18 mg), Yield: 39.9%.

MS m/z (ESI): 516.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.71 (s, 2H), 7.89 (s, 1H), 7.40 (t, 1H), 7.16 (s, 1H), 7.13 (s, 1H), 7.12 (d, 1H), 7.05 (s, 1H), 7.03 (s, 1H), 6.98 (s, 1H), 5.32 (s, 2H), 4.22 (s, 3H), 4.07 (s, 3H), 3.88 (s, 3H) ).

Example 9

2-methoxy-6-(6-methoxy-4-((5-(4-methoxyphenyl)pyridin-3-yl)oxy)methyl)benzofuran-2-yl Imidazo[2,1-b][1,3,4]thiadiazole 9

first step

5-(4-methoxyphenyl)pyridin-3-ol 9b

5-Bromo-3-hydroxypyridine 9a (300 mg, 1.72 mmol, 韶远 reagent (Shanghai) Technology Co., Ltd.) was dissolved in a mixed solvent of 1,4-dioxane/water under an argon atmosphere (V:V) In the range of =5:1), compound 5b (263 mg, 1.73 mmol), tetrakistriphenylphosphine palladium (100 mg, 0.09 mmol) and sodium carbonate (366 mg, 3.45 mmol) were added to the above reaction system; the oil bath was heated to 90 ° C. The reaction was stirred at this temperature for 18 hours. The reaction was cooled, and ethyl acetate (50 mL) was evaporated, evaporated, evaporated. Purification by column chromatography using EtOAc EtOAc (EtOAc)

MS m/z (ESI): 202.2 [M+1]

Second step

Compound 1k (24 mg, 0.07 mmol), compound 9b (15 mg, 0.07 mmol) and tri-n-butylphosphonium (45 mg, 0.22 mmol) were dissolved in 15 mL of tetrahydrofuran under argon. Piperidine (56 mg, 0.22 mmol) was added to the above reaction system, and the reaction was kept at room temperature for 1 hour. The reaction was quenched by the addition of EtOAc (EtOAc) (EtOAc) Title Compound 9 (26 mg), Yield: 69.8%.

MS m/z (ESI): 515.0 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.44 (d, 1H), 8.35 (d, 1H), 7.89 (s, 1H), 7.50 (d, 2H), 7.44 (s, 1H), 7.10 (s, 1H), 7.04-6.97 (m, 4H), 5.36 (s, 2H), 4.22 (s, 3H), 3.88 (s, 3H), 3.86 (s, 3H).

Example 10

2-methoxy-6-(6-methoxy-4-((6'-methoxy-[2,3'-bipyridin]-4-yl)oxy)methyl)benzofuran -2-yl)imidazo[2,1-b][1,3,4]thiadiazole 10

first step

6'-methoxy-[2,3'-bipyridyl]-4-phenol 10c

2-Bromo-4-hydroxypyridine 10a (400 mg, 2.30 mmol, 韶远 reagent (Shanghai) Technology Co., Ltd.) was dissolved in a solvent mixture of 1,4-dioxane and water under an argon atmosphere (V=5). (1), further (6-methoxypyridin-3-yl)boronic acid 10b (387 mg, 2.53 mmol, 韶远 reagent (Shanghai) Technology Co., Ltd.), tetrakistriphenylphosphine palladium (133 mg, 0.12 mmol) Sodium carbonate (488 mg, 4.60 mmol) was added to the above reaction system; the oil bath was heated to 90 ° C, and the reaction was stirred at this temperature for 18 hours. The reaction was cooled, EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Purification with the developer system A gave the title compound 10c (200 mg).

MS m/z (ESI): 203.2 [M+1]

Second step

Compound 1k (25 mg, 0.07 mmol), compound 10c (16 mg, 0.08 mmol) and tri-n-butylphosphonium (46 mg, 0.22 mmol) were dissolved in 10 mL of tetrahydrofuran under an argon atmosphere, and then N, N, N' N'-Tetramethylazodicarbonamide (39 mg, 0.22 mmol) was added to the above reaction system, and the reaction was kept at room temperature for 1 hour. The reaction was quenched by the addition of EtOAc (EtOAc) (EtOAc) The title compound 10 (15 mg), yield: 38.6%.

MS m/z (ESI): 516.3 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ8.89 (d, 1H), 8.47 (d, 1H), 8.43 (s, 1H), 8.39 (dd, 1H), 7.66 (d, 1H), 7.21 ( s,1H),7.18(s,1H),7.07-6.05(m,2H),6.91(d,1H),5.53(s,2H),4.21(s,3H),3.91(s,3H),3.83 (s, 3H).

Example 11

2-methoxy-6-(6-methoxy-4-(((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)methyl)benzofuran-2 -yl)imidazo[2,1-b][1,3,4]thiadiazole 11

first step

2-(2-methylthiazol-5-yl)pyridin-4-phenol 11b

Compound 10a (120 mg, 0.69 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole 11a (156mg, 0.69mmol, Shanghai Bied Pharmaceutical Technology Co., Ltd.) was dissolved in a mixed solvent of 5mL of 1,4-dioxane and 1mL of water, and then added tetrakis(triphenylphosphine)palladium (40mg, 0.035mmol), carbonated Sodium (146 mg, 1.38 mmol) was sealed under argon atmosphere, and the reaction was sealed at 80 ° C for 16 hours. The TLC dot plate raw material was not reacted, and the temperature was raised to 100 ° C for 2 hours, and the reaction liquid turned brown. 20 mL of water was added to the reaction mixture, and dichloromethane (20 mL × 3) was evaporated. Compound 11b (35 mg), Yield: 26%.

MS m/z (ESI): 193.1 [M+1]

Second step

Compound 1k (52 mg, 0.15 mmol), compound 11b (30 mg, 0.15 mmol) was dissolved in 8 mL of tetrahydrofuran, and then tributylphosphine (158 mg, 0.78 mmol), N, N, N', N'-tetramethyl Nitroformamide (161 mg, 0.94 mmol, Suiyuan Technology (Shanghai) Co., Ltd.) was stirred at 35 ° C for 1 hour. 30 mL of water and dichloromethane (20 mL × 3) were added to the reaction mixture, and the combined organic layers were dried over anhydrous sodium sulfate. Compound 11 (30 mg), Yield: 38%.

MS m/z (ESI): 506.1 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ8.43 (s, 1H), 8.33-8.39 (m, 2H), 7.66-7.72 (m, 1H), 7.19-7.25 (m, 1H), 7.17 (s , 1H), 7.06-7.09 (m, 1H), 7.02 (dd, 1H), 5.51 (s, 2H), 4.21 (s, 3H), 3.84 (s, 3H), 2.67 (s, 3H).

Example 12

2-methoxy-6-(6-methoxy-4-((5-methyl-2-(5-methylpyridin-2-yl)thiazol-4-yl)oxy)methyl) Benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole 12

first step

5-methyl-2-(5-methylpyridin-2-yl)thiazole-4-phenol 12c

Add 5-methyl-2-cyanopyridine 12a (1.18g, 10.0mmol, Shanghai Bied Pharmaceutical Technology Co., Ltd.), thiolactic acid 12b (1.06g, 10.0mmol, Anikei Chemical Co., Ltd.), pyridine ( 198 mg, 2.50 mmol), which was reacted at 100 ° C for 2 hours, and a large amount of solid was evaporated to room temperature, and the mixture was filtered and evaporated to give the title compound 12c (950 mg).

MS m/z (ESI): 207.1 [M+1]

Second step

Compound 1k (24 mg, 0.072 mmol), compound 12c (16 mg, 0.078 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran, and then tributylphosphine (24 mg, 0.119 mmol), azodicarbonamide (20 mg, 0.116 mmol), The reaction was stirred for 1 hr, EtOAc (EtOAc)EtOAc. , Yield: 53%.

MS m/z (ESI): 520.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.39 (s, 1H), 7.98-8.07 (m, 1H), 7.88 (s, 1H), 7.50-7.67 (m, 1H), 7.18 (s, 1H), 7.01 (s, 2H), 5.61 (s, 2H), 4.21 (s, 3H), 3.87 (s, 3H), 2.38 (s, 3H), 2.31 (s, 3H).

Example 13

(3'-((6-Methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl) )methoxy)-[1,1'-biphenyl]-4-yl)(4-propylpiperazin-1-yl)methanone 13

first step

1-propylpiperazine 13d

Piperazine (9.68 g, 112.38 mmol) was dissolved in 50 mL of ethanol, and 1-bromopropane (3.07 g, 24.96 mmol, Shanghai Titan Technology Co., Ltd.) and triethylamine (2.53 g, 25.00 mmol) were added to the above reaction. The system was heated to 80 ° C in an oil bath and the reaction was stirred at this temperature for 18 hours. The reaction was cooled, EtOAc (3 mL, dry dry.

MS m/z (ESI): 129.3 [M+1]

Second step

3'-hydroxy-[1,1'-biphenyl]-4-carboxylic acid tert-butyl ester 13b

The compound (4-(tert-butoxycarbonyl)phenyl)boronic acid 13a (2.6 g, 11.71 mmol, 韶远 reagent (Shanghai) Technology Co., Ltd.) was dissolved in 1,4-dioxane/ under an argon atmosphere. In a mixed solvent of water (V: V = 100 mL / 20 mL), compound 5a (2 g, 11.56 mmol, Shanghai Bied Pharmaceutical Technology Co., Ltd.), tetrakistriphenylphosphine palladium (670 mg, 0.58 mmol) and sodium carbonate (2.5 g, 23.59 mmol) was added to the above reaction system; the oil bath was heated to 100 ° C, and the reaction was stirred at this temperature for 18 hours. The reaction was cooled, and 20 mL of water was added to the mixture, and the mixture was evaporated. Purification gave the title compound 13b (2.5 g).

MS m/z (ESI): 269.0 [M-1]

third step

3'-hydroxy-[1,1'-biphenyl]-4-carboxylic acid 13c

Compound 13b (1.95 g, 7.21 mmol) was dissolved in 20 mL of dichloromethane, and then trifluoroacetic acid (9 g, 78.93 mmol, saponin (Shanghai) Technology Co., Ltd.) was added to the above reaction system; the reaction was stirred at room temperature for 2 hours. . The title compound 13c (1.6 g) was obtained. MS m/z (ESI): 213.2 [M-1]

the fourth step

(3'-Hydroxy-[1,1'-biphenyl]-4-yl)(4-propylpiperazin-1-yl)methanone 13e

Compound 13c (120 mg, 0.56 mmol) and compound 13d (110 mg, 0.86 mmol) were dissolved in 10 mL of N,N'-dimethylformamide and then 1-ethyl-3(3-dimethylpropylamine) carbon Diimine (160 mg, 0.84 mmol, sputum reagent (Shanghai) Technology Co., Ltd.), 1-hydroxybenzotriazole (114 mg, 0.84 mmol) and triethylamine (170 mg, 1.68 mmol) were added to the above reaction system; The reaction was stirred for 18 hours. The solvent was removed under reduced pressure. EtOAc (EtOAc m. Purification gave the title compound 13e (110 mg).

MS m/z (ESI): 325.3 [M+1]

the fifth step

Compound 13e (32 mg, 0.1 mmol) was dissolved in 10 mL of tetrahydrofuran under argon and stirred. Compound 4e (30 mg, 0.09 mmol), tri-n-butylphosphonium (60 mg, 0.29 mmol), and heated to 40 ° C, Azodiyl dipiperidine (72 mg, 0.28 mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was reacted at 40 ° C for 2 hours. 15 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (30 mL×2), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A. The title compound 13 (10 mg), yield: 16.9%.

MS m/z (ESI): 622.3 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.03 (s, 1H), 7.62 (d, 2H), 7.47 (d, 2H), 7.45-7.38 (m, 1H), 7.24 (s, 1H), 7.20- 7.17 (m, 2H), 7.05-7.03 (m, 2H), 6.99 (s, 1H), 5.33 (s, 2H), 4.10-3.60 (m, 7H), 3.40-3.38 (m, 2H), 2.90- 2.46 (m, 7H), 1.29-1.23 (m, 2H), 0.94 (t, 3H).

Example 14

(4-ethylpiperazin-1-yl)(6-(3-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiophene) Diazol-6-yl)benzofuran-4-yl)methoxy)phenyl)pyridin-3-yl)methanone 14

first step

6-(3-hydroxyphenyl)nicotinate methyl ester 14b

Dissolve 6-bromonicotinic acid methyl ester 14a (500mg, 2.3mmol, 韶远 reagent (Shanghai) Technology Co., Ltd.) in 30mL 1,4-dioxane and water mixed solution (V:V=10:1) Add compound 1b (323 mg, 2.3 mmol, sputum reagent (Shanghai) Technology Co., Ltd.), tetrakis(triphenylphosphine)palladium (134 mg, 0.1 mmol), sodium carbonate (492 mg, 4.6 mmol), and heat under argon atmosphere. Stir to 4 ° C for 4 hours. The reaction was cooled, quenched with 20 mL of water, EtOAc (EtOAc) EtOAc (EtOAc) The residue was purified by silica gel chromatography eluting elut elut

MS m/z (ESI): 230.2 [M+1]

Second step

6-(3-hydroxyphenyl)nicotinic acid 14c

Compound 14b (400 mg, 1.7 mmol) was dissolved in 15 mL of a mixture of methanol, tetrahydrofuran and water (V:V:V = 1:1:1), and sodium hydroxide (209 mg, 5.2 mmol) was added and reacted for 2 hours. The reaction mixture was extracted with EtOAc (EtOAc m. The organic layer was concentrated under reduced pressure.

MS m/z (ESI): 214.2 [M+1]

third step

(4-ethylpiperazin-1-yl)(6-(3-hydroxyphenyl)pyridin-3-yl)methanone 14e

Compound 14c (100 mg, 0.46 mmol), 1-ethylpiperazine 14d (53 mg, 0.46 mmol, Titan Reagent (Shanghai) Technology Co., Ltd.), 1-(3-dimethylaminopropyl)-3-ethyl carbon Diimine hydrochloride (78 mg, 0.51 mmol), 1-hydroxybenzotriazole (98 mg, 0.51 mmol) and triethylamine (141 mg, 1.39 mmol) dissolved in 2 mL of N,N'-dimethylformamide In the reaction, 2 hours. The mixture was quenched with EtOAc (EtOAc)EtOAc.

MS m/z (ESI): 312.2 [M+1]

the fourth step

6-(4-(Chloromethyl)-6-methoxybenzofuran-2-yl)-2-methylimidazo[2,1-b][1,3,4]thiadiazole 14f

Compound 4e (302 mg, 0.96 mmol) was dissolved in 10 mL of dichloromethane, and then chlorosulfoxide (1.0 mL) was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 1.5 hours. The mixture was dried with EtOAc (EtOAc m.)

MS m/z (ESI): 334.1 [M+1]

the fifth step

The compound 14e (47 mg, 0.15 mmol) and the compound 14f (50 mg, 0.15 mmol) were dissolved in 3 mL of N,N'-dimethylformamide, and cesium carbonate (146 mg, 0.45 mmol) was added, and the reaction was stirred for 16 hours. After quenching with 5 mL of water, a mixed solution of ethyl acetate and methanol (V: V = 10:1, 10 mL × 3) was added, and the organic phase was combined, washed with 10 mL of brine, dried over anhydrous sodium sulfate and filtered. The residue was purified by silica gel chromatography eluting elut elut elut

MS m/z (ESI): 609.2 [M+1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (s, 1H), 8. s (s, 1H), 7.85 (d, 1H), 7.79 (d, 1H), 7.43 (s, 1H), 7.61 ( d,1H), 7.41(t,1H), 7.18(s,1H),7.11(dd,1H),7.03(s,1H),7.00(s,1H),5.36(s,2H),3.88(s , 3H), 3.57-3.62 (m, 4H), 2.73 (s, 3H), 2.52-2.63 (m, 6H), 1.13-1.16 (m, 3H).

Example 15

(S)-(3-(hydroxymethyl)morphinyl)(3'-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3, 4] thiadiazole-6-yl)benzofuran-4-yl)methoxy)-[1,1'-biphenyl]-4-yl)methanone 15

first step

(S)-(3'-hydroxy-[1,1'-biphenyl]-4-yl)(3-(hydroxymethyl)morphinolinyl)methanone 15b

Compound 13c (214 mg, 999.0 umol) and Compound 15a (120 mg, 1.02 mmol, Shanghai Qianyuan Pharmaceutical Technology Co., Ltd.), (1-ethyl-3(3-dimethylpropylamine)carbodiimide) (287 mg, 1.4971) Methyl), 1-hydroxybenzotriazole (228 mg, 1.50 mmol) and triethylamine (303 mg, 2.99, mmol) were dissolved in 5 mL of N,N-dimethylformamide. After stirring at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure. To the reaction mixture, 10 mL of water was added, and ethyl acetate (10 mL × 3) was evaporated. The rate is 67.1%.

MS m/z (ESI): 314.1 [M+1]

Second step

Compound 1k (33 mg, 0.10 mmol), compound 15b (33 mg, 0.11 mmol) and tri-n-butylphosphonium (60 mg, 0.30 mmol) were dissolved in 10 mL of tetrahydrofuran under argon, and then azodicarbonamide ( 51 mg, 0.30 mmol) was added to the above reaction system, and the mixture was heated to 40 ° C for 2 hours. The reaction was quenched by the addition of EtOAc (EtOAc) (EtOAc) The title compound 15 (10 mg), yield: 16.0%.

MS m/z (ESI): 627.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.88 (s, 1H), 7.61 (d, 2H), 7.48 (d, 2H), 7.36 (t, 1H), 7.24 (s, 1H), 7.18 (d, 2H), 7.06-6.97 (m, 3H), 5.32 (s, 2H), 4.22 (s, 3H), 4.23-3.60 (m, 9H), 3.87 (s, 3H).

Example 16

(4-ethylpiperazin-1-yl)(3'-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazole) -6-yl)benzofuran-4-yl)methoxy)-4'-methyl-[1,1'-biphenyl]-4-yl)methanone 16

first step

5-bromo-2-methylphenol 16b

4-Bromo-2-methoxy-1-methylbenzene 16a (1000mg, 4.97mmol, Shanghai Bied Pharmaceutical Technology Co., Ltd.) was dissolved in 20mL of dichloromethane, under the protection of argon, boron tribromide (12500 mg, 49.9 mmol) was dissolved in 50 mL of dichloromethane, and the above reaction system was added, and the reaction was stirred at room temperature for 1 hour. The reaction was cooled with ice-cooling, EtOAc EtOAc (EtOAc m. The mixture was filtered and evaporated to dryness crystals crystals

MS m/z (ESI): 185.1 [M-1], 187.1 [M-1]

Second step

3'-hydroxy-4'-methyl-[1,1'-biphenyl]-4-carboxylic acid tert-butyl ester 16c

Compound 16b (400 mg, 2.14 mmol) was dissolved in a 1,4-dioxane/water mixed solvent (V = 10 mL / 2 mL) under an argon atmosphere, and then 13a (475 mg, 2.14 mmol, pyridine reagent) (Shanghai) Technology Co., Ltd.), tetrakistriphenylphosphine palladium (124 mg, 0.11 mmol) and sodium carbonate (455 mg, 4.29 mmol) were added to the above reaction system; the oil bath was heated to 90 ° C, and the reaction was stirred at this temperature for 18 hours. . The reaction was cooled, EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Purification with the developer system A gave the title compound 16c (200 mg).

MS m/z (ESI): 229.2 [M-56+1]

third step

3'-((6-Methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl) Methoxy)-4'-methyl-[1,1'-biphenyl]-4-carboxylic acid tert-butyl ester 16d

The compound 16c (86 mg, 0.30 mmol) and the compound 14f (100 mg, 0.30 mmol) were dissolved in 8 mL of N,N'-dimethylformamide, and cesium carbonate (293 mg, 0.90 mmol) was added, and the reaction was stirred for 18 hours. After quenching with 5 mL of water, a mixed solution of ethyl acetate and methanol (V: V = 10:1, 10 mL × 3) was added, and the organic phase was combined, washed with 10 mL of brine, dried over anhydrous sodium sulfate and filtered. The residue was purified by silica gel column chromatography eluting elut elut MS m/z (ESI): 581.9 [M+1]

the fourth step

3'-((6-Methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl) Methoxy)-4'-methyl-[1,1'-biphenyl]-4-carboxylic acid 16e

Compound 16d (140 mg, 0.24 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2.74 g, 24.03 mmol) was added to the above system under ice-cooling, and the reaction was stirred for 2 hours under ice bath. The title compound 16e (150 mg) was obtained.

MS m/z (ESI): 526.2 [M+1]

the fifth step

Compound 16e (35 mg, 0.07 mmol) and compound 14d (10 mg, 0.09 mmol) were dissolved in 3 mL of N,N'-dimethylformamide, and the compound 2-(7-benzotriazole)- N,N,N',N'-tetramethyluronium hexafluorophosphate (20 mg, 0.09 mmol) and N,N'-diisopropylethylamine (23 mg, 0.18 mmol), sequentially added to the above system, room temperature The reaction was stirred for 18 hours. The residue was purified by EtOAcqqqqqqq

MS m/z (ESI): 622.3 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ8.03 (s, 1H), 7.59 (d, 2H), 7.46 (d, 2H), 7.24 (d, 1H), 7.16-7.14 (m, 3H), 7.03 (s, 2H), 5.35 (s, 2H), 3.88 (m, 5H), 3.60 (m, 2H), 2.73 (s, 3H), 2.56-2.50 (m, 6H), 2.35 (s, 3H) , 1.16-1.14 (m, 3H).

Example 17

(4-ethylpiperazin-1-yl)(4'-fluoro-3'-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3, 4]thiadiazole-6-yl)benzofuran-4-yl)methoxy)-[1,1'-biphenyl]-4-yl)methanone 17

first step

5-bromo-2-fluorophenol 17b

4-Bromo-1-fluoro-2-methoxybenzene 17a (430 mg, 2.10 mmol, sputum reagent (Shanghai) Technology Co., Ltd.) was dissolved in 10 mL of dichloromethane, and 22 mL of tribromide was added at 0 ° C under argon atmosphere. Boron (1M, Haoyuan Reagent (Shanghai) Technology Co., Ltd.), reacted at room temperature for 18 hours. Quenched by adding 5 mL of methanol at 0 ° C, and then adding 10 mL of water, dichloromethane (20 mL × 3), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified to give the title compound 17b (395 mg).

MS m/z (ESI): 189.1, 191.1 [M-1]

Second step

4'-Fluoro-3'-hydroxy-[1,1'-biphenyl]-4-carboxylic acid tert-butyl ester 17c

Compound 13a (384 mg, 1.73 mmol) and compound 17b (300 mg, 1.57 mmol) were dissolved in a mixture of 25 mL of anhydrous ethanol and toluene (V:V=2:3), and 3 mL of potassium carbonate aqueous solution (2M) was added and added. [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (57 mg, 0.08 mmol) was refluxed for 16 hours under an argon atmosphere. The reaction mixture was concentrated under reduced vacuo.

MS m/z (ESI): 287.0 [M-1]

third step

4'-Fluoro-3'-hydroxy-[1,1'-biphenyl]-4-carboxylic acid 17d

Compound 17c (190 mg, 0.66 mmol) was dissolved in 10 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added, and the reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced vacuo.

MS m/z (ESI): 231.1 [M-1]

the fourth step

(4-ethylpiperazin-1-yl)(4'-fluoro-3'-hydroxy-[1,1'-biphenyl]-4-yl)methanone 17e

Compound 17d (40 mg, 0.17 mmol) and compound 14d (24 mg, 0.17 mmol) were dissolved in 2 mL of N,N'-dimethylformamide, followed by 1-(3-dimethylaminopropyl)-3-ethyl The carbodiimide hydrochloride (40 mg, 0.21 mmol), 1-hydroxybenzotriazole (28 mg, 0.21 mmol) and triethylamine (52 mg, 0.51 mmol) were stirred for 16 hours. The reaction mixture was concentrated under reduced vacuo.

MS m/z (ESI): 329.2 [M+1]

the fifth step

The compound 17e (16 mg, 0.05 mmol) and the compound 14f (20 mg, 0.06 mmol) were dissolved in 2 mL of N,N'-dimethylformamide, and hydrazine carbonate (48 mg, 0.15 mmol) was added, and the reaction was stirred for 18 hours. The organic layer was concentrated under reduced pressure.

MS m/z (ESI): 626.2 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ8.47 (s, 1H), 7.69 (d, 2H), 7.61 (d, 1H), 7.40 (d, 2H), 7.32-7.25 (m, 3H), 7.17 (s, 1H), 7.02 (s, 1H), 5.52 (s, 2H), 3.79 (s, 3H), 3.57 (brs, 2H), 3.25 (brs, 2H), 2.71 (s, 3H), 2.31 -2.32 (m, 6H), 0.97 (t, 3H).

Example 18

(4-ethylpiperazin-1-yl)(2-(3-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiophene) Diazol-6-yl)benzofuran-4-yl)methoxy)phenyl)pyrimidin-5-yl)methanone 18

first step

(2-chloropyrimidin-5-yl)(4-ethylpiperazin-1-yl)methanone 18b

2-Chloropyrimidine-5-carboxylic acid 18a (800 mg, 5.04 mmol, Nanjing Stone Technology Co., Ltd.), compound 14e (576 mg, 5.04 mmol), 2-(7-azobenzotriazole)-N,N , N', N'-tetramethylurea hexafluorophosphate (2.5 g, 6.57 mmol), N,N-diisopropylethylamine (1.3 g, 10.06 mmol) dissolved in N,N-dimethyl The amide (30 mL) was stirred for 2 hours. Diluted with water (100 mL), dichloromethane (50 mL×3). The residue was purified by column chromatography eluting elut elut elut eluting

MS m/z (ESI): 255.1 [M+1]

Second step

(4-ethylpiperazin-1-yl)(2-(3-hydroxyphenyl)pyrimidin-5-yl)methanone 18c

Compound 18b (79 mg, 0.31 mmol), Compound 1b (43 mg, 0.31 mmol) was dissolved in 10 mL of a mixture of 1,4-dioxane and 2 mL of water, and then added tetrakis(triphenylphosphine)palladium (18 mg, 0.015) Methyl acetate (65 mg, 0.61 mmol) was stirred at 100 ° C for 18 hours under argon. After cooling, the residue was evaporated to dryness crystals crystals

MS m/z (ESI): 313.1 [M+1]

third step

The compound 14f (51 mg, 0.15 mmol) and the compound 18c (34 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (8 mL), and hydrazine carbonate (106 mg, 0.32 mmol) was added, and the reaction was stirred for 15 hours. To the reaction mixture were added 30 mL of EtOAc (EtOAc m.

MS m/z (ESI): 610.2 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ8.95 (s, 2H), 8.51 (s, 1H), 8.09 (s, 1H), 8.04 (d, 1H), 7.45-7.56 (m, 1H), 7.25-7.33 (m, 1H), 7.22 (s, 1H), 7.16-7.20 (m, 1H), 7.02-7.08 (m, 1H), 5.46 (s, 2H), 3.83 (s, 3H), 3.52- 3.71 (m, 2H), 3.35-3.52 (m, 2H), 2.74 (s, 3H), 2.25-2.48 (m, 6H), 1.01 (t, 3H).

Example 19

(4-ethylpiperazin-1-yl)(2-(3-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiophene) Diazol-6-yl)benzofuran-4-yl)methoxy)phenyl)thiazol-5-yl)methanone 19

first step

2-(3-hydroxyphenyl)thiazole-5-carboxylic acid methyl ester 19b

Methyl 2-bromothiazole-5-carboxylate 19a (200mg, 0.09mmol, sputum reagent (Shanghai) Technology Co., Ltd.) and compound 1b (186mg, 1.35mmol, 韶远 reagent (Shanghai) Technology under argon atmosphere Ltd.) was dissolved in a solvent mixture of ethylene glycol dimethyl ether/ethanol (V=5 mL/5 mL), and tetrakistriphenylphosphine palladium (105 mg, 0.09 mmol) and sodium carbonate (287 mg, 2.71 mmol) were added to the above reaction. The system was heated to 100 ° C in an oil bath and the reaction was stirred at this temperature for 16 hours. The reaction was cooled, the reaction was diluted with EtOAc EtOAc (EtOAc m. , Yield: 28.3%.

MS m/z (ESI): 236.1 [M+1]

Second step

2-(3-hydroxyphenyl)thiazole-5-carboxylic acid 19c

The compound 19b (60 mg, 0.26 mmol) was dissolved in 5 mL of methanol, and then sodium hydroxide (102 mg, 2.55 mmol) was dissolved in 2.5 mL of water, and then added to the above reaction system, and the reaction was stirred at room temperature for 2 hours. After removing most of the methanol under reduced pressure, 10 mL of water was added to the residue, and then 1 M hydrochloric acid was added until the pH of the reaction mixture was 2 to 3, and extracted with ethyl acetate (10 mL × 2). The residue was evaporated to dryness crystall

MS m/z (ESI): 222.1 [M+1]

third step

(4-ethylpiperazin-1-yl)(2-(3-hydroxyphenyl)thiazol-5-yl)methanone 19d

The compound 19c (40 mg, 0.18 mmol) and the compound 14d (21 mg, 0.18 mmol) were dissolved in 3 mL of N,N'-dimethylformamide, and the compound 2-(7-benzotriazole)- N,N,N',N'-tetramethyluronium hexafluorophosphate (83 mg, 0.22 mmol) and N,N'-diisopropylethylamine (117 mg, 0.09 mmol), sequentially added to the above system, room temperature The reaction was stirred for 2 hours. 50 ml of water was added to the reaction mixture, and the mixture was combined with EtOAc. Compound 19d (58 mg) was taken directly to the product without purification.

MS m/z (ESI): 318.2 [M+1]

the fourth step

The compound 19d (20 mg, 0.06 mmol) and the compound 14f (27 mg, 0.08 mmol) were dissolved in 2 mL of N,N'-dimethylformamide, and cesium carbonate (62 mg, 0.19 mmol) was added, and the reaction was stirred for 18 hours. After quenching with 5 mL of water, a mixed solution of ethyl acetate and methanol (V: V = 10:1, 10 mL × 3) was added, and the organic phase was combined, washed with 10 mL of brine, dried over anhydrous sodium sulfate and filtered. The residue was purified by silica gel column chromatography elut elut elut

MS m/z (ESI): 615.2 [M+1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (s, 1H), 7. 7. (s, 1H), 7.65 (s, 1H), 7.54 (d, 1H), 7.36 (t, 1H), 7.15 ( s,1H),7.11(d,1H),7.03(s,1H),6.98(s,1H),5.33(s,2H),3.88-3.83(m,7H),2.72(s,3H),2.56 -2.49 (m, 6H), 1.14 (t, 3H).

Example 20

(4-ethylpiperazin-1-yl)(5-(3-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiophene) Diazol-6-yl)benzofuran-4-yl)methoxy)phenyl)thiazol-2-yl)methanone 20

first step

(5-bromothiazol-2-yl)(4-ethylpiperazin-1-yl)methanone 20b

In a argon atmosphere, 5-bromothiazole-2-carboxylic acid 20a (250 mg, 1.20 mmol, Nanjing Pharmaceutical Co., Ltd.) was dissolved in 12 mL of N,N-dimethylformamide, stirred, and compound 14d was added at room temperature. (150 mg, 1.31 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (503 mg, 1.32 mmol, hydrazine) Yuan Technology (Shanghai) Co., Ltd., N,N-diisopropylethylamine (465mg, 3.59mmol), tetrakis(triphenylphosphine)palladium (41mg, 0.04mmol), stirred at room temperature for 4 hours, concentrated to give residue Purification by column chromatography using EtOAc EtOAc (EtOAc)

Second step

(4-ethylpiperazin-1-yl)(5-(3-hydroxyphenyl)thiazol-2-yl)methanone 20c

Compound 20b (200 mg, 0.65 mmol) was dissolved in 6 mL of 1,4-dioxane under argon, and 1.5 mL of water was added and stirred. Compound 1b (109 mg, 0.78 mmol), sodium carbonate (139 mg, 1.31) was added. Methyl) and tetrakis(triphenylphosphine)palladium (45 mg, 0.04 mmol), mp. : 48%.

MS m/z (ESI): 318.0 [M+1]

third step

(4-ethylpiperazin-1-yl)(5-(3-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiophene) Diazol-6-yl)benzo

Furan-4-yl)methoxy)phenyl)thiazol-2-yl)methanone 20

Compound 20b (30 mg, 0.094 mmol) was dissolved in 6 mL of N,N-dimethylformamide under argon, and stirred at room temperature. Compound 14f (35 mg, 0.105 mmol), cesium carbonate (93 mg, 0.28 mmol) The reaction was carried out at room temperature for 12 hr.

MS m/z (ESI): 615.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.03 (s, 1H), 7.96 (s, 1H), 7.32 (d, 1H), 7.24 (s, 1H), 7.19 (d, 1H), 7.15 (s, 1H), 7.03 (s, 2H), 6.97 (s, 1H), 5.30 (s, 2H), 4.45-4.55 (m, 2H), 3.67 (s, 3H), 2.73 (s, 3H), 2.55-2.65 (m, 4H), 1.58-1.60 (m, 4H), 1.20 (s, 3H).

Example 21

(4-ethylpiperazin-1-yl)(4-(4-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiophene) Diazol-6-yl)benzofuran-4-yl)methoxy)pyridin-2-yl)phenyl)methanone 21

first step

4-(4-Hydroxypyridin-2-yl)benzoic acid tert-butyl ester 21a

Compound 10a (400 mg, 2.30 mmol) was dissolved in a solvent of 1,4-dioxane and water mixture (V = 5:1) under argon, and then compound 13a (561 mg, 2.53 mmol), four Triphenylphosphine palladium (133 mg, 0.12 mmol) and sodium carbonate (488 mg, 4.60 mmol) were added to the above reaction system; the oil bath was heated to 90 ° C, and the reaction was stirred at this temperature for 18 hours. The reaction was cooled, EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Purification by the developer system A gave the title compound 21a (1.06 g).

MS m/z (ESI): 272.2 [M+1]

Second step

4-(4-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4- Tert-butyl ester of methoxy)pyridin-2-yl)benzoate 21b

The compound 21a (80 mg, 0.29 mmol) and the compound 14f (130 mg, 0.35 mmol) were dissolved in 6 mL of N,N'-dimethylformamide, and hydrazine carbonate (288 mg, 0.88 mmol) was added, and the reaction was stirred for 16 hours. The title compound 21b (148 mg) was obtained (yield: 88.3%).

MS m/z (ESI): 569.2 [M+1]

third step

4-(4-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4- Methoxy)pyridin-2-yl)benzoic acid 21c

Compound 21b (140 mg, 025 mmol) was dissolved in 5 mL of dichloromethane, and then trifluoroacetic acid (1.68 g, 14.73 mmol) was added to the above reaction system; and the reaction was stirred at room temperature for 2 hours. The title compound 21c (154 mg) was obtained.

MS m/z (ESI): 513.1 [M+1]

the fourth step

(4-ethylpiperazin-1-yl)(4-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]] Thiazol-6-yl)benzofuran-4-yl)methoxy)pyridin-2-yl)phenyl)methanone 21

The compound 21c (40 mg, 0.06 mmol) and the compound 14d (11 mg, 0.10 mmol) were dissolved in 3 mL of N,N'-dimethylformamide, and the compound 2-(7-benzotriazole)- N,N,N',N'-tetramethyluronium hexafluorophosphate (25 mg, 0.07 mmol) and N,N'-diisopropylethylamine (24 mg, 0.19 mmol), sequentially added to the above system, room temperature The reaction was stirred for 18 hours. The residue was purified by EtOAcjjjjjjjjj

MS m/z (ESI): 609.3 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.52 (d, 1H), 8.04 (s, 1H), 7.99 (d, 2H), 7.49 (d, 2H), 7.35 (d, 1H), 7.14 (s, 1H), 7.05 (d, 1H), 6.96 (d, 1H), 6.90 (dd, 1H), 5.38 (s, 2H), 3.88 (s, 7H), 2.74 (s, 9H), 1.27 (d, 3H) ).

Example 22

(4-(4-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4 -yl)methoxy)-5-methylthiazol-2-yl)phenyl)(4-propylpiperazin-1-yl)methanone 22

first step

Methyl 4-cyanobenzoate 22b

4-cyanobenzoic acid 22a (521 mg, 3.5411 mmol) was dissolved in 10 mL of methanol, chlorosulfoxide (842 mg, 7.08 mmol, 513.4 uL) was added dropwise, heated to reflux for 16 hours, and concentrated to give crude 22b (532 mg). It was directly used in the next step by purification.

Second step

Methyl 4-(4-hydroxy-5-methylthiazol-2-yl)benzoate 22c

Compound 22b (564 mg, 3.5 mmol), compound 12b (371 mg, 3.5 mmol), pyridine (755 mg, 9.5 mmol), and the reaction mixture was reacted at 100 ° C for 16 hours, and a large amount of solids were allowed to cool to room temperature, and then ethanol was added and filtered to obtain the title. Compound 22c (532 mg), Yield: 61.0%.

MS m/z (ESI): 250.1 [M+1]

third step

4-(4-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4- Methyl)-5-methylthiazol-2-yl)benzoate 22d

Compound 22c (59 mg, 0.24 mol) and compound 14f (80 mg, 0.24 mmol) were dissolved in 5 mL of N, N'-dimethylformamide, and cesium carbonate (234 mg, 0.72 mmol) and potassium iodide (79 mg, 0.48 mmol) ), heated to 60 ° C, and stirred for 20 minutes. The organic layer was concentrated under reduced pressure.

MS m/z (ESI): 547.1 [M+1]

the fourth step

4-(4-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4- Methoxy)-5-methylthiazol-2-yl)benzoic acid 22e

Compound 22d (100 mg, 0.18 mmol) was dissolved in a mixture of tetrahydrofuran/methanol/water (V:V:V=2:3:5, 10mL), and lithium hydroxide monohydrate (76 mg, 1.81 mmol) was added at room temperature. ), stirred at room temperature for 1 hour. The pH of the reaction mixture was adjusted to EtOAc (EtOAc m.

MS m/z (ESI): 533.1 [M+1]

the fifth step

Compound 22e (40 mg, 0.08 mmol) and compound 13d (19 mg, 0.15 mmol) were dissolved in 3 mL of N,N'-dimethylformamide and then O-(7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethyluronium hexafluorophosphate (21 mg, 0.09 mmol) and N,N'-diisopropylethylamine (97 mg, 0.75 mmol) were added to the above reaction system; The reaction was stirred at room temperature for 0.5 hours. To the reaction mixture, 100 mL of water was added, and dichloromethane (50 mL × 3) was evaporated. Purification by the developer system A gave the title compound 22 (40 mg).

MS m/z (ESI): 643.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.02 (s, 1H), 7.92 (d, 2H), 7.48-7.42 (m, 2H), 7.22 (d, 1H), 7.03-6.99 (m, 2H), 5.61 (s, 2H), 3.87 (s, 7H), 2.61-2.82 (m, 9H), 2.30 (s, 3H), 0.98 (t, 3H).

Example 23

4-((6-(3-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzo) Furan-4-yl)methoxy)phenyl)pyridin-3-yl)methyl)morpholine 23

first step

4-((6-bromopyridin-3-yl)methyl)morpholine 23c

2-Bromo-5-aldehyde pyridyl 23a (930 mg, 5 mmol, 韶远科技 (Shanghai) Co., Ltd.) was dissolved in 12 mL of dichloromethane under argon atmosphere, and morpholine 23b (436 mg, 5 mmol) was added at room temperature. Add sodium triacetoxyborohydride (36 mg, 0.17 mmol), react at room temperature for 5 hours, quench with 10 mL of ice water, dichloromethane (30 mL×3), and the organic phase washed with saturated aqueous sodium carbonate (15 mL) The residue was dried over EtOAc (EtOAc m.

MS m/z (ESI): 259.0, 256.0 [M+1]

Second step

3-(5-(morphinolinylmethyl)pyridin-2-yl)phenol 23d

Compound 23c (257 mg, 1 mmol) was dissolved in 10 mL of 1,4-dioxane under argon, 2 mL of water was added and stirred. Compound 1b (137 mg, 1 mmol), sodium carbonate (211 mg, 2 mmol) and Triphenylphosphine)palladium (70 mg, 0.06 mmol), mp EtOAc (EtOAc)

MS m/z (ESI): 271.2 [M+1]

third step

Compound 23d (22 mg, 0.081 mmol) was dissolved in 8 mL of N,N-dimethylformamide under argon, and stirred at room temperature. Compound 14f (38 mg, 0.113 mmol), cesium carbonate (80 mg, 0.25 mmol) The reaction was carried out for 12 hours at rt.

MS m/z (ESI): 568.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.64 (s, 1H), 8.03 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.58 (d, 1H), 7.40 (t, 1H), 7.16 (s, 1H), 7.09-7.12 (m, 2H), 7.02 (s, 1H), 6.99 (s, 1H), 5.35 (s, 2H), 3.95-4.33 (m, 4H), 3.87 (s, 3H), 3.31-3.39 (m, 2H), 2.85-2.91 (m, 2H), 2.73 (s, 3H), 1.57 (s, 2H).

Example 24

4-((3'-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran- 4-yl)methoxy)-[1,1'-biphenyl]-4-yl)methyl)morpholine 24

first step

4-(4-bromobenzyl)morpholine 24b

4-Bromobenzaldehyde 24a (800 mg, 4.32 mmol, Adamars Reagent Co., Ltd.), Compound 23b (377 mg, 4.32 mmol) was dissolved in 20 mL of dichloromethane, and argon was exchanged twice, and triacetoxy was added in two portions. Sodium borohydride (1.37 g, 6.46 mmol) was exothermic. The reaction was stirred for 2 hours. Add 100 mL of dichloromethane, dilute with a saturated sodium carbonate solution to adjust the pH of the reaction mixture to 8 to 10, dilute with dichloromethane (30 mL × 2), dry over anhydrous sodium sulfate, and then concentrate. The title compound 24b (150 mg) was obtained.

MS m/z (ESI): 257.6 [M+1]

Second step

4'-(morpholinemethyl)-[1,1'-biphenyl]-3-phenol 24c

Compound 24b (100 mg, 0.39 mmol) and compound 1b (54 mg, 0.39 mmol) were dissolved in a mixture solvent of 10 mL of 1,4-dioxane and 2 mL of water under argon, and tetrakis(triphenylphosphine) was added. Palladium (23 mg, 0.020 mmol) and sodium carbonate (83 mg, 0.78 mmol) were reacted with argon gas at 100 ° C for 18 hours. After cooling, the residue was concentrated to dryness. 24c (84 mg), yield: 80%.

MS m/z (ESI): 270.3 [M+1]

third step

Compound 14f (48 mg, 0.14 mmol), Compound 24c (35 mg, 0.13 mmol) was dissolved in 8 mL of N,N-dimethylformamide, and hydrazine carbonate (127 mg, 0.39 mol) was added, and the reaction was stirred for 15 hours, and 30 mL of water was added. The title compound (24 mg) was obtained (yield: 41%).

MS m/z (ESI): 567.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (s, 1H), 7.54 - 7.62 (m, 2H), 7.41 - 7.53 (m, 2H), 7.32 - 7.40 (m, 1H), 7.22 - 7.26 (m) , 1H), 7.14-7.19 (m, 2H), 6.97-7.06 (m, 3H), 5.33 (s, 2H), 3.59-4.04 (m, 9H), 2.46-2.80 (m, 7H).

Example 25

6-(6-Methoxy-4-((4'-(pyrrolidin-1-ylmethyl)-[1,1'-biphenyl]-3-yl)oxy)methyl)benzene And furan-2-yl)-2-methylimidazo[2,1-b][1,3,4]thiadiazole 25

first step

3'-hydroxy-[1,1'-biphenyl]-4-carbaldehyde 25a

Compound 24a (488 mg, 2.63 mmol) was dissolved in 15 mL of 1,4-dioxane under argon and stirred. Compound 1b (450 mg, 3.26 mmol), sodium carbonate (600 mg, 5.66 mmol) and Triphenylphosphine)palladium (200 mg, 0.07 mmol), mp EtOAc (EtOAc)

MS m/z (ESI): 199.2 [M+1]

Second step

3'-((6-Methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl) Methoxy

Base)-[1,1'-biphenyl]-4-carbaldehyde 25b

Compound 25a (121 mg, 0.61 mmol) was dissolved in 6 mL of N,N-dimethylformamide under argon and stirred at room temperature. Compound 14f (200 mg, 0.559 mmol) and cesium carbonate (586 mg, 1.79 mmol) The reaction was carried out at room temperature for 12 hr.

MS m/z (ESI): 496.1 [M+1]

third step

Compound 25b (20 mg, 0.04 mmol) was dissolved in 6 mL of dichloromethane under argon, pyrrolidine (4.3 mg, 0.06 mmol) was added, and sodium triacetoxyborohydride (12.8 mg, 0.06 mmol) was added at room temperature. The reaction was carried out for 12 hours, diluted with 40 mL of dichloromethane, added with 30 mL of saturated sodium carbonate solution and extracted with dichloromethane (30 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the solvent system A gave the title compound 25 (15 mg).

MS m/z (ESI): 551.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.02 (s, 1H), 7.53 (d, 2H), 7.40 (d, 2H), 7.32-7.34 (m, 1H), 7.19 (d, 1H), 7.16 ( s, 1H), 7.02 (s, 1H), 6.99 (d, 3H), 5.31 (s, 2H), 3.87 (s, 3H), 3.69 (s, 2H), 2.72 (s, 3H), 2.59-2.63 (m, 4H), 1.82-1.91 (m, 4H).

Example 26

1-(4-((3'-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzene) And furan-4-yl)methoxy)-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)propyl-1-one 26

first step

4-((3'-Hydroxy-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester 26b

Compound 25a (1000 mg, 5.0 mmol) and tert-butylpiperazine-1-carboxylate 26a (940 mg, 5.0 mmol) were dissolved in 60 mL of dichloromethane, and sodium triacetoxyborohydride was added portionwise at 0 °C. 1390 mg, 6.6 mmol), and the reaction was stirred at room temperature for 16 hours. The reaction was quenched by the addition of 20 mL of EtOAc (EtOAc) (EtOAc) The title compound 26b (1750 mg) was obtained, yield: 94.1%.

MS m/z (ESI): 369.3 [M+1]

Second step

4-((3'-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran- 4-yl)methoxy)-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester 26c

Compound 26b (166 mg, 0.45 m mol) and compound 14f (150 mg, 0.45 mmol) were dissolved in 5 mL of N,N'-dimethylformamide, and cesium carbonate (439 mg, 1.34 mmol) and potassium iodide (74 mg, 0.45 mmol) ), the reaction was stirred for 16 hours. Quenched with a mixed solution of 20 mL of water and a saturated ammonium chloride solution (V: V = 1:1), the solid precipitated, and the residue obtained by filtration was purified by silica gel column chromatography using eluent system A to give the title compound. 26c (240 mg), Yield: 80.2%.

MS m/z (ESI): 666.3 [M+1]

third step

6-(6-Methoxy-4-((4'-(piperazin-1-ylmethyl)-[1,1'-biphenyl]-3-yl)oxy)methyl)benzene And furan-2-yl)-2-methylimidazo[2,1-b][1,3,4]thiadiazole 26d

Compound 26c (36 mg, 0.05 mmol) was dissolved in 5 mL of dichloromethane, and then, 1.2 mL of trifluoroacetic acid was added, and the mixture was stirred at 0 ° C for 1 hour. The reaction was quenched by the addition of 3 mL of ice water, and the mixture was adjusted to pH 8 to 9 with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with dichloromethane (10 mL×3). The title compound 26d (30 mg) was obtained (yield: 98.1%).

MS m/z (ESI): 566.2 [M+1]

the fourth step

Compound 26d (30 mg, 0.05 mmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (28 mg, 0.22 mmol) and propionyl chloride 26 g (15 mg, 0.16 mmol). Reaction for 1 hour. The reaction was quenched by the addition of 3 mL of ice water, extracted with dichloromethane (10 mL×3), and the organic phase was combined, washed with 5 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, dried and evaporated. System A was prepared in the title compound 26 (20 mg).

MS m/z (ESI): 622.3 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ): δ8.01 (s, 1H), 7.54 (d, 2H), 7.41 (brs, 2H), 7.34 (t, 1H), 7.24 (s, 1H), 7.22-7.18 (m, 2H), 7.00 (d, 3H), 5.30 (s, 2H), 3.86 (s, 3H), 3.63 (brs, 6H), 2.71 (s, 3H), 2.31 (brs, 4H), 2.31 ( q, 2H), 1.12 (t, 3H).

Example 27

6-(6-Methoxy-4-((2-methyl-5-(4-propylpiperazin-1-yl)phenoxy)methyl)benzofuran-2-yl)-2- Methylimidazo[2,1-b][1,3,4]thiadiazole 27

first step

2-methyl-5-(4-propylpiperazin-1-yl)phenol 27a

Compound 16b (250 mg, 1.95 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 21.84 umol), 2-dicyclohexylphosphino-2'-(N,N-dimethyl) under an argon atmosphere Amine)-biphenyl (15 mg, 38.12 umol), bis-trimethylsilylamino lithium tetrahydrofuran (1 M, 5.98 mL) was added to the reaction flask, heated to reflux for 2 hours, cooled to room temperature, quenched with water, ethyl acetate The title compound 27a (128 mg) was obtained.

MS m/z (ESI): 235.3 [M+1]

Second step

The compound 27a (40 mg, 0.17 mmol) and the compound 14f (35 mg, 0.10 mmol) were dissolved in 5 mL of N,N'-dimethylformamide, and hydrazine carbonate (120 mg, 0.37 mmol) was added, and the reaction was stirred for 15 hours. The title compound 27 (34 mg) was obtained after EtOAc (3 mL). Yield:

61.0%.

MS m/z (ESI): 532.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.03 (s, 1H), 7.15 (d, 1H), 7.03 (d, 1H), 7.02 (s, 1H), 7.01 (s, 1H), 6.55 (s, 1H), 6.46 (d, 1H), 5.26 (s, 2H), 3.88 (s, 3H), 3.44 - 3.18 (m, 4H), 2.95-2.43 (m, 6H), 2.74 (s, 3H), 2.22 (s, 3H), 1.33-1.20 (m, 2H), 0.96 (t, 3H).

Example 28

2-methoxy-6-(6-methoxy-4-((3-(4-(methylsulfonyl)piperazin-1-yl)phenoxy)methyl)benzofuran-2-yl Imidazo[2,1-b][1,3,4]thiadiazole 28

first step

4-(3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester 28b

1-Bromo-3-methoxybenzene 28a (3.74 g, 20 mmol, Shunyuan Technology (Shanghai) Co., Ltd.) was dissolved in 100 mL of toluene under argon atmosphere, and compound compound 26a (2.74 g, 14.7 mmol) was added. Tri-tert-butylphosphine (30 mg, 0.14 mmol), tris(dibenzylideneacetone)dipalladium (150 mg, 0.16 mmol) and potassium t-butoxide (2.5 g, 22.2 mmol), heated at 100 ° C, stirred for 12 hours, cold To room temperature. 40 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2). Filtration, and the filtrate was concentrated under reduced pressure.

MS m/z (ESI): 293.2 [M+1]

Second step

1-(3-methoxyphenyl)piperazine 28c

Compound 28b (1.5 g, 4.56 mmol) was dissolved in EtOAc EtOAc (EtOAc m. Yield: 91%.

MS m/z (ESI): 193.0 [M+1]

third step

1-(3-methoxyphenyl)-4-(methylsulfonyl)piperazine 28d

Compound 28c (274 mg, 1.2 mmol) was dissolved in 15 mL of methylene chloride and stirred, triethylamine (1.09 g, 10.77 mmol) was added at 0 ° C, and methanesulfonyl chloride (205 mg, 1.79 mmol) was added dropwise at 0 ° C. Reaction for 2 hours. 30 mL of water and dichloromethane (30 mL) were added to the reaction mixture, and the mixture was evaporated. EtOAcjjjjjjjjjj , Yield: 58.6%.

MS m/z (ESI): 271.1 [M+1]

the fourth step

3-(4-(methylsulfonyl)piperazin-1-yl)phenol 28e

Compound 28d (190 mg, 0.70 mmol) was dissolved in 15 mL of dichloromethane, stirred, and boron tribromide (1 M, 3.50 mmol) was added at 0 ° C, and reacted at 0 ° C for 1 hour, reacted at room temperature for 12 hours, and added with 10 mL of methanol. The reaction was quenched and the reaction solution was concentrated. After adding 15 mL of a saturated sodium hydrogencarbonate solution, ethyl acetate (10 mL, 3) was evaporated.

MS m/z (ESI): 257.1 [M+1]

the fifth step

Compound 28e (30 mg, 0.12 mmol) was dissolved in 12 mL of tetrahydrofuran under argon and stirred. Compound 1k (30 mg, 0.09 mmol), tri-n-butylphosphonium (55 mg, 0.27 mmol), and stirred, azo Formyl dipiperidine (68 mg, 0.27 mmol, Suiyuan Technology (Shanghai) Co., Ltd.) was reacted at room temperature for 2 hours. 15 mL of water was added to the reaction mixture, and the mixture was evaporated. 20 mg), yield: 38%.

MS m/z (ESI): 570.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.89 (s, 1H), 7.11 (s, 1H), 7.01 (d, 1H), 6.94 (d, 1H), 6.81 (d, 2H), 6.71 (d, 2H), 5.25 (s, 2H), 4.21 (s, 3H), 3.87 (s, 3H), 3.53-3.54 (m, 4H), 3.36-3.37 (m, 4H), 2.84 (s, 3H).

Example 29

(S)-6-(6-methoxy-4-((3-(2-methyl-4-propylpiperazin-1-yl)phenoxy)methyl)benzofuran-2-yl )-2-methylimidazo[2,1-b][1,3,4]thiadiazole 29

first step

(S)-2-methyl-4-propylpiperazine-1-carboxylic acid tert-butyl ester 29b

The compound (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 29a (600 mg, 3.0 mmol) was dissolved in acetonitrile (8 mL), 1-bromopropane (442 mg, 3.5937 mmol) was added at room temperature, and N was added in ice bath. N-Diisopropylethylamine (580 mg, 4.49 mmol) was stirred at room temperature for 16 h. Water (100 mL) was added to the reaction mixture, and ethyl acetate (50 mL × 3) was evaporated.

MS m/z (ESI): 242.8 [M+1]

Second step

(S)-3-methyl-1-propylpiperazine 29c

Compound 29b (480 mg, 1.98 mmol), EtOAc (EtOAc) Concentrate to a crude 29c (260 mg).

third step

(S)-1-(3-methoxyphenyl)-2-methyl-4-propylpiperazine 29d

Compound 28a (315 mg, 1.68 mmol, 211.41 uL) was dissolved in toluene (10 mL), compound 29c (300 mg, 2.1091 mmol), tri-tert-butylphosphine (0.5M, 415.19 uL), tris(dibenzylideneacetone) Dipalladium (193 mg, 210.76 umol) and potassium t-butoxide (1.18 g, 10.52 mmol) were heated to 100 ° C and stirred for 16 hours. The organic layer was purified by EtOAc (EtOAc).

MS m/z (ESI): 249.3 [M+1]

the fourth step

(S)-3-(2-methyl-4-propylpiperazin-1-yl)phenol 29e

Compound 29d (180 mg, 724.7459 umol) was dissolved in dichloromethane (10 mL) under nitrogen atmosphere, and boron tribromide (1M, 7.1850 mL) was added at room temperature and stirred for 14 hours. The mixture was quenched with EtOAc (EtOAc)EtOAc.

MS m/z (ESI): 235.3 [M+1]

the fifth step

The compound 29e (23 mg, 0.10 mmol) and the compound 14f (39 mg, 0.12 mmol) were dissolved in 3 mL of N,N'-dimethylformamide, and hydrazine carbonate (159 mg, 0.49 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The organic layer was concentrated under reduced pressure.

MS m/z (ESI): 532.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (s, 1H), 7.19 (s, 1H), 7.14 (s, 1H), 7.01 (s, 1H), 6.96 (d, 1H), 6.85 (s, 1H), 6.58 (s, 2H), 5.23 (s, 2H), 3.87 (s, 5H), 3.12 (s, 2H), 2.89 (d, 2H), 2.73 (s, 3H), 2.57 (s, 3H) ), 1.45-1.19 (m, 5H), 0.98 (s, 3H).

Example 30

1-(4-(3-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzo) Furan-4-yl)methoxy)phenyl)piperazin-1-yl)propyl-1-one 30

first step

1-(4-(3-methoxyphenyl)piperazin-1-yl)propyl-1-one 30a

Compound 28c (274 mg, 1.2 mmol) was dissolved in 15 mL of methylene chloride, stirred, and then triethylamine (1.09 g, 10.77 mmol) was added at 0 ° C, propionyl chloride (166 mg, 1.79 mmol) was added dropwise, and the reaction was carried out at 0 ° C. 2 hours. 30 mL of water and dichloromethane (30 mL) were added to the reaction mixture, and the mixture was evaporated. , Yield: 97.4%.

MS m/z (ESI): 249.2 [M+1]

Second step

1-(4-(3-hydroxyphenyl)piperazin-1-yl)propyl-1-one 30b

Compound 30a (290 mg, 1.16 mmol) was dissolved in 20 mL of dichloromethane, stirred, and boron tribromide (1 M, 9.34 mmol) was added at 0 ° C, and reacted at 0 ° C for 1 hour, at room temperature for 12 hours, and then added with 10 mL of methanol. The reaction was quenched and the reaction solution was concentrated. After adding 20 mL of a saturated aqueous solution of sodium hydrogencarbonate, ethyl acetate (30 mL, 3) was evaporated to give the title compound 30b (160 mg).

MS m/z (ESI): 235.1 [M+1]

third step

Compound 30b (16 mg, 0.07 mmol) was dissolved in 8 mL of tetrahydrofuran under argon and stirred. Compound 1k (20 mg, 0.06 mmol), tri-n-butylphosphonium (61 mg, 0.30 mmol), and stirred, azo Formyl dipiperidine (52 mg, 0.30 mmol, Suiyuan Technology (Shanghai) Co., Ltd.) was reacted at room temperature for 2 hours. 15 mL of water was added to the reaction mixture, and ethyl acetate (30 mL × 2) was evaporated. 12 mg), yield: 36.3%.

MS m/z (ESI): 548.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.92 (s, 1H), 7.26 (d, 1H), 7.14 (s, 1H), 7.04 (d, 1H), 6.98 (d, 1H), 6.83-6.84 ( m, 2H), 6.73 (d, 1H), 5.28 (s, 2H), 4.24 (s, 3H), 3.93 (m, 2H), 3.90 (s, 3H), 3.78 (m, 2H), 3.26-3. (m, 4H), 2.40-2.42 (m, 2H), 1.18-1.20 (m, 3H).

Example 31

6-(6-Methoxy-4-((3-(1-propylpiperidin-4-yl)phenoxy)methyl)benzofuran-2-yl)-2-methylimidazo[ 2,1-b][1,3,4]thiadiazole 31

first step

4-(3-methoxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 31b

Compound 28a (3 g, 16 mmol) was dissolved in 75 mL of 1,4-dioxane under argon, 15 mL of water was added, stirred, and 4-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl)-5,6-dihydropyridine-1-(2H)-carboxylic acid tert-butyl ester 31a (6 g, 19.4 mmol, Suiyuan Technology (Shanghai) Co., Ltd., sodium carbonate (3.40 g, 32 mmol), tetrakis(triphenylphosphine)palladium (1.11 g, 0.96 mmol), reacted at 100 ° C for 12 hours, and concentrated to give a residue. The title compound 31b (4.6 g),yield: 99.1%. MS m/z (ESI): 234.1 [M-55]

Second step

4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine 31c

The compound 31b (4.6 g, 15.89 mmol) was dissolved in EtOAc EtOAc EtOAc. 31c (3.58g), yield: 99.7%

MS m/z (ESI): 190.2 [M+1]

third step

4-(3-methoxyphenyl)piperidine 31d

Compound 31c (450 mg, 1.99 mmol) was dissolved in 60 mL of methanol, and then a palladium carbon catalyst (dry) (90 mg, 0.845 mmol) was added, and the hydrogen balloon was replaced three times, and stirred at room temperature for 12 hours. The reaction mixture was filtered over EtOAc EtOAcjjjjjj

MS m/z (ESI): 192.2 [M+1]

the fourth step

4-(3-methoxyphenyl)-1-propylpiperidine 31e

Compound 31d (440 mg, 1.93 mmol) was dissolved in 15 mL of N,N-dimethylformamide and stirred. EtOAc (1. <RTI ID=0.0></RTI> </RTI> <RTIgt; 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjj : 51.0%.

MS m/z (ESI): 233.8 [M+1]

the fifth step

3-(1-propylpiperidin-4-yl)phenol 31f

Compound 31e (230 mg, 0.98 mmol) was dissolved in 12 mL of dichloromethane, stirred, and boron tribromide (1 M, 3.0 mmol) was added at 0 ° C, and reacted at 0 ° C for 1 hour, at room temperature for 12 hours, and then added with 10 mL of methanol. The reaction was quenched and the reaction solution was concentrated. After adding 20 mL of a saturated sodium hydrogencarbonate solution and ethyl acetate (40 mL × 3), the title compound 31f (200 mg)

MS m/z (ESI): 219.7 [M+1]

Step 6

Compound 31f (14 mg, 0.06 mmol) was dissolved in 10 mL of tetrahydrofuran under argon and stirred. Compound 4e (20 mg, 0.06 mmol), tri-n-butylphosphonate (64 mg, 0.31 mmol) was added and heated to 40 ° C. N, N, N', N'-tetramethylazodicarbonamide (54 mg, 0.31 mmol, Suiyuan Technology (Shanghai) Co., Ltd.), reacted at 40 ° C for 2 hours. 15 mL of water was added to the reaction mixture, and ethyl acetate (30 mL × 2) was evaporated. Compound 31 (8 mg), Yield: 24.4%.

MS m/z (ESI): 517.3 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.03 (s, 1H), 7..22 (d, 1H), 7.14 (s, 1H), 7.01 (d, 1H), 6.95 (d, 1H), 6.88 -6.89(m,2H), 6.87-6.88(m,1H), 5.24(s,2H),3.87(s,3H),3.53-3.54(m,2H),2.82-2.86(m,2H),2.73 (s, 3H), 2.68-2.70 (m, 2H), 2.44 - 2.45 (m, 2H), 1.99-2.00 (m, 2H), 1.93-1.95 (m, 1H), 1.87-1.91 (m, 2H) , 0.97-1.01 (t, 3H).

Example 32

1-(4-(3-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzo) Furan-4-yl)methoxy)phenyl)-5,6-dihydropyridine-1(2H)-yl)propyl-1-one 32

first step

4-(3-hydroxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 32a

Compound 5a (1.0 g, 5.78 mmol) was dissolved in 30 mL of 1,4-dioxane, 6 mL of water under argon and stirred. Compound 31a (2.68 g, 8.66 mmol), sodium carbonate (1.22 g, 11.5) Methyl), tetrakis(triphenylphosphine)palladium (667 mg, 0.58 mmol), mp. : 75.4%.

Second step

3-(1,2,3,6-tetrahydropyridin-4-yl)phenol 32b

The compound 32a (413 mg, 1.5 mmol) was dissolved in EtOAc EtOAc EtOAc. 32b (262 mg), Yield: 99.6%.

third step

3-(1-propionyl-1,2,3,6-tetrahydropyridin-4-yl)phenylpropionate 32c

Compound 32b (110 mg, 0.52 mmol) was dissolved in dichloromethane (5 mL), stirred, and triethylamine (210 mg, 2.0 mmol) was added at 0 ° C, propionyl chloride (120 mg, 1.29 mmol) was added dropwise, and the reaction was carried out at 0 ° C for 2 hours. . 30 mL of water was added to the reaction mixture, and 30 mL of dichloromethane was added, and the mixture was stirred and evaporated. Rate: 93.7%.

MS m/z (ESI): 288.3 [M+1]

the fourth step

1-(4-(3-hydroxyphenyl)-5,6-dihydropyridine-1(2H)-yl)propyl-1-one 32d

Compound 32c (110 mg, 0.52 mmol) was dissolved in 2 mL of dichloromethane and 5 mL of methanol, and 2M of 1 mL sodium hydroxide solution was added, and the mixture was stirred and reacted at room temperature for 2 hours. 2N Hydrochloric acid was added until the pH of the reaction mixture was 3-4, and concentrated under reduced pressure. After adding 10 mL of water, ethyl acetate (10 mL × 3) was evaporated. Column chromatography was carried out to give the title compound 32d (100 mg).

MS m/z (ESI): 232.2 [M+1]

the fifth step

Compound 32d (24 mg, 0.10 mmol) was dissolved in 5 mL of tetrahydrofuran under argon and stirred. Compound 1k (33 mg, 0.10 mmol), tri-n-butylphosphonium (60 mg, 0.29 mmol), and stirred, and azo Formyl dipiperidine (75 mg, 0.29 mmol, Suiyuan Technology (Shanghai) Co., Ltd.) was reacted at room temperature for 2 hours. After adding 15 mL of water to the reaction mixture, ethyl acetate (30 mL × 2) was evaporated. 20 mg), yield: 36.8%.

MS m/z (ESI): 545.3 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.88 (s, 1H), 7.22-7.26 (m, 2H), 7.12 (s, 1H), 6.90-9.98 (m, 4H), 6.04 (d, 1H), 5.26 (s, 2H), 4.21 (s, 3H), 3.81 (s, 3H), 2.54-2.55 (m, 2H), 2.36-2.42 (m, 2H), 1.55-1.57 (m, 2H), 1.17- 1.18 (m, 3H), 0.90-0.94 (m, 2H).

Example 33

4-((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl) Methoxy)-5',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylic acid tert-butyl ester 33

Compound 1k (33 mg, 0.10 mmol), compound 32a (33 mg, 0.12 mmol) and tri-n-butylphosphonium (60 mg, 0.30 mmol) were dissolved in 5 mL of tetrahydrofuran under argon. Piperidine (76 mg, 0.30 mmol) was added to the above reaction system, and the reaction was kept at room temperature for 1 hour. The reaction was quenched by the addition of EtOAc (EtOAc) (EtOAc) Title Compound 33 (15 mg), Yield: 25.5%.

MS m/z (ESI): 590.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.40-8.38 (m, 1H), 7.89 (s, 1H), 7.05-7.04 (m, 2H), 6.98 (s, 1H), 6.92-6.88 (m, 2H ), 6.81 (s, 1H), 5.31 (d, 2H), 4.21 (s, 3H), 4.15 - 4.10 (m, 1H), 3.87 (s, 3H), 3.65 - 3.62 (m, 2H), 2.59 ( s, 1H), 2.25-2.15 (m, 1H), 2.05-1.95 (m, 1H), 1.56-1.48 (m, 9H).

Example 34

2-methoxy-6-(6-methoxy-4-((3-(6-methoxypyridin-3-yl)phenoxy)methyl)benzofuran-2-yl)imidazolium [2,1-b][1,3,4]thiadiazole 34

Using the synthetic route of Example 5, the starting material compound 5b was replaced with compound 10a to give the title compound 34 (24 mg).

MS m/z (ESI): 515.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.39 (s, 1H), 7.88 (s, 1H), 7.78 (d, 1H), 7.36 (t, 1H), 7.18 (s, 1H), 7.12 (s, 2H), 7.03 (s, 1H), 7.00 (s, 2H), 6.81 (d, 1H), 5.32 (s, 2H), 4.21 (s, 3H), 3.99 (s, 3H), 3.88 (s, 3H) ).

Example 35

2-methoxy-6-(6-methoxy-4-((3-(5-methoxypyridin-2-yl)phenoxy)methyl)benzofuran-2-yl)imidazolium [2,1-b][1,3,4]thiadiazole 35

Using the synthetic route of Example 5, the starting material was replaced with compound 1b and 2-bromo-5-methoxypyridine 35a to give the title compound 35 (14 mg).

MS m/z (ESI): 515.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.41 (s, 1H), 7.89 (s, 1H), 7.69 (d, 2H), 7.54 (d, 1H), 7.43-7.30 (m, 2H), 7.12 ( s, 1H), 7.03 (dd, 3H), 5.36 (s, 2H), 4.21 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H).

Example 36

6-(4-((3-(5-ethoxypyridin-2-yl)phenoxy)methyl)-6-methoxybenzofuran-2-yl)-2-methoxyimidazole [2,1-b][1,3,4]thiadiazole 36

Using the synthetic route in Example 5, the first step of the starting material was replaced by the compound 1b and 2-bromo-5-ethoxypyridine (prepared by the method disclosed in the patent application "EP2752410 (A1)") to obtain the title. Compound 36 (7 mg).

MS m/z (ESI): 529.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.39 (d, 1H), 7.89 (s, 1H), 7.69-7.67 (m, 2H), 7.53 (d, 1H), 7.39-7.36 (m, 1H), 7.32-7.30 (m, 1H), 7.13 (s, 1H), 7.05-7.01 (m, 3H), 5.36 (s, 2H), 4.22 (s, 3H), 4.14 (dd, 2H), 3.88 (s, 3H), 1.43 (t, 3H).

Example 37

2-methoxy-6-(6-methoxy-4-((5-(5-methoxypyridin-2-yl)-2-methylphenoxy)methyl)benzofuran-2 -yl)imidazo[2,1-b][1,3,4]thiadiazole 37

Using the synthetic route in Example 5, the first step was replaced by 2-methoxy-5-bromopyridine and 2-methyl-5-(4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl)phenol 37a (prepared by the method disclosed in the patent application "WO2016203400 (A1)") gave the title compound 37 (15 mg).

MS m/z (ESI): 528.8 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.41-8.49 (m, 1H), 7.90 (s, 1H), 7.75-7.89 (m, 2H), 7.52-7.65 (m, 1H), 7.38-7.45 (m) , 1H), 7.28-7.32 (m, 1H), 7.19 (s, 1H), 7.09-7.14 (m, 1H), 7.01-7.05 (m, 1H), 5.52 (s, 2H), 4.22 (s, 3H) ), 3.98 (s, 3H), 3.89 (s, 3H), 2.35 (s, 3H).

Example 38

2-methoxy-6-(6-methoxy-4-((3-(5-methylpyridin-2-yl)phenoxy)methyl)benzofuran-2-yl)imidazo[ 2,1-b][1,3,4]thiadiazole 38

The title compound 38 (48 mg) was obtained from the title compound (b).

MS m/z (ESI): 499.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.54 (s, 1H), 7.88 (s, 1H), 7.69 (s, 1H), 7.63 (q, 2H), 7.54 (d, 1H), 7.38 (t, 1H), 7.12 (s, 1H), 7.06 (d, 1H), 7.00 (s, 2H), 5.31 (s, 2H), 4.20 (s, 3H), 3.87 (s, 3H), 2.39 (s, 3H) ).

Example 39

2-methoxy-6-(6-methoxy-4-((3-(pyridin-2-yl)phenoxy)methyl)benzofuran-2-yl)imidazo[2,1- b][1,3,4]thiadiazole 39

The title compound 39 (30 mg) was obtained from the title compound (yield).

MS m/z (ESI): 485.1 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.70 (d, 1H), 7.88 (s, 1H), 7.81-7.67 (m, 3H), 7.58 (d, 1H), 7.39 (t, 1H), 7.27 ( s, 1H), 7.11 (s, 1H), 7.08 (dd, 1H), 7.01 (d, 2H), 5.35 (s, 2H), 4.20 (s, 3H), 3.87 (s, 3H).

Example 40

2-methoxy-6-(6-methoxy-4-((5-(5-methoxypyrazin-2-yl)-2-methylphenoxy)methyl)benzofuran- 2-yl)imidazo[2,1-b][1,3,4]thiadiazole 40

Using the synthetic route of Example 5, the starting material compound was replaced with Compound 37a and Compound 3a to give the title compound 40 (30 mg).

MS m/z (ESI): 530.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.49 (s, 1H), 8.29 (s, 1H), 7.89 (s, 1H), 7.61 (s, 1H), 7.40 (d, 1H), 7.25 (d, 1H), 7.24 (d, 1H), 7.11 (s, 1H), 7.03 (s, 1H), 5.37 (s, 2H), 4.21 (s, 3H), 4.01 (s, 3H), 3.89 (s, 3H) ), 2.34 (s, 3H).

Example 41

2-methoxy-6-(6-methoxy-4-((4'-(methylsulfonyl)-[1,1'-biphenyl]-3-yl)oxy)methyl Benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole 41

The title compound 41 (18 mg) was obtained from the title compound (5).

MS m/z (ESI): 562.1 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.99 (d, 2H), 7.89 (s, 1H), 7.75 (d, 2H), 7.42-7.38 (m, 1H), 7.24 (s, 1H), 7.20 ( d, 1H), 7.12 (s, 1H), 7.07-7.03 (m, 1H), 6.99 (s, 1H), 6.98 (s, 1H), 5.33 (s, 2H), 4.22 (s, 3H), 3.88 (s, 3H), 3.09 (s, 3H).

Example 42

2-methoxy-6-(6-methoxy-4-((3-(2-methylthiazol-4-yl)phenoxy)methyl)benzofuran-2-yl)imidazo[ 2,1-b][1,3,4]thiadiazole 42

Using the synthetic route of Example 5, the first step starting material was replaced with compound 1b and 4-bromo-2-methylthiazole to give the title compound 42 (5 mg).

MS m/z (ESI): 505.1 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.88 (s, 1H), 7.58 (s, 1H), 7.48 (d, 1H), 7.41-7.30 (m, 2H), 7.12 (s, 1H), 6.99 ( t, 3H), 5.32 (s, 2H), 4.20 (s, 3H), 3.87 (s, 3H), 2.78 (s, 3H).

Example 43

6-(4-((2-(4-Chlorophenyl)pyridin-4-yl)oxy)methyl)-6-methoxybenzofuran-2-yl)-2-methoxyimidazole And [2,1-b][1,3,4]thiadiazole 43

Using the synthetic route of Example 5, the second starting material was replaced with compound 4c to give the title compound 43 (5 mg).

MS m/z (ESI): 519.1 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.56 (d, 1H), 7.89-7.96 (m, 4H), 7.45 (d, 2H), 7.33-7.36 (m, 1H), 7.06 (d, 2H), 6.94 (s, 1H), 5.42 (s, 2H), 3.16 (s, 3H), 3.07 (s, 3H).

Example 44

2-methoxy-6-(6-methoxy-4-((2-(4-methoxyphenyl)pyridin-4-yl)oxy)methyl)benzofuran-2-yl Imidazo[2,1-b][1,3,4]thiadiazole 44

The synthesis route in Example 5 was carried out, and the starting material was replaced with Compound 4a to give the title compound 44 (16 mg).

MS m/z (ESI): 515.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.51 (d, 1H), 7.94 (d, 2H), 7.89 (s, 1H), 7.29-7.32 (m, 1H), 7.08 (s, 1H), 7.04- 7.06(m,1H),6.99(d,2H),6.94-6.96(m,1H),6.88(s,1H),5.39(s,2H),4.21(s,3H),3.87(s,3H) , 3.86 (s, 3H).

Example 45

2-methoxy-6-(6-methoxy-4-(((2-(4-(methylsulfonyl)phenyl)pyridin-4-yl)oxy)methyl)benzofuran-2 -yl)imidazo[2,1-b][1,3,4]thiadiazole 45

Using the synthetic route of Example 5, the starting material of the first step was replaced with Compound 41a and Compound 10a to give the title compound 45 (3 mg).

MS m/z (ESI): 563.1 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.55 (d, 1H), 8.14 (d, 2H), 8.01 (d, 2H), 7.90 (s, 1H), 7.39 (d, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 6.95-6.93 (m, 2H), 5.39 (s, 2H), 4.22 (s, 3H), 3.88 (s, 3H), 3.08 (s, 3H).

Example 46

6-(4-((2-(4-fluorophenyl)pyridin-4-yl)oxy)methyl)-6-methoxybenzofuran-2-yl)-2-methoxyimidazole And [2,1-b][1,3,4]thiadiazole 46

Using the synthetic route of Example 5, the starting material of the first step was replaced with the compound (4-fluorophenyl)boronic acid and the compound 4a to give the title compound 46 (6 mg).

MS m/z (ESI): 503.1 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.49 (d, 1H), 7.94-7.90 (m, 3H), 7.29 (d, 1H), 7.15-7.09 (m, 3H), 7.05 (s, 1H), 6.96 (s, 1H), 6.87 (dd, 1H), 5.37 (s, 2H), 4.22 (s, 3H), 3.88 (s, 3H).

Example 47

2-methoxy-6-(6-methoxy-4-(((2-(5-methoxypyridin-2-yl)-5-methylthiazol-4-yl)oxy)methyl) Benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole 47

The synthesis route in Example 12 was carried out, and the starting material was replaced with the compound 5-methoxypyridinecarbonitrile to give the title compound 47 (5 mg).

MS m/z (ESI): 535.7 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.24 (s, 1H), 8.06 (d, 1H), 7.87 (s, 1H), 7.28-7.30 (m, 1H), 7.17-7.19 (m, 1H), 7.00 (s, 2H), 5.59 (s, 2H), 4.21 (s, 3H), 3.90 (s, 3H), 3.86 (s, 3H), 2.28 (s, 3H).

Example 48

6-(4-(((2-(4-chlorophenyl)-5-methylthiazol-4-yl)oxy)methyl)-6-methoxybenzofuran-2-yl)-2 -Methoxy-imidazo[2,1-b][1,3,4]thiadiazole 48

The starting material of the first step was replaced with 4-chlorobenzothioamide and ethyl 2-bromopropionate using the synthetic route from Example 12 to give the title compound 48 (10 mg).

MS m/z (ESI): 538.7 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.88 (s, 1H), 7.81 (d, 2H), 7.37 (d, 2H), 7.20 (s, 1H), 7.01 (d, 2H), 5.60 (s, 2H), 4.22 (s, 3H), 3.87 (s, 3H), 2.28 (s, 3H).

Example 49

2-methoxy-6-(6-methoxy-4-(((5-methyl-2-phenylthiazol-4-yl)oxy)methyl)benzofuran-2-yl)imidazole And [2,1-b][1,3,4]thiadiazole 49

The title compound 49 (6 mg) was obtained by substituting the material of the first step to ethyl 2-bromopropionate and benzothioamide.

MS m/z (ESI): 505.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83-7.94 (m, 3H), 7.33-7.46 (m, 3H), 7.19 (s, 1H), 6.98-7.07 (m, 2H), 5.62 (s, 2H) ), 4.22 (s, 3H), 3.87 (s, 3H), 2.28 (s, 3H).

Example 50

3'-((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl )methoxy)-N,N-dimethyl-[1,1'-biphenyl]-4-carboxamide 50

The title compound 50 (45 mg) was obtained from the title compound.

MS m/z (ESI): 555.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.89 (s, 1H), 7.61 (d, 2H), 7.48 (d, 2H), 7.37 (t, 1H), 7.27 (s, 1H), 7.25 (d, 1H), 7.22-7.18 (m, 1H), 7.05-7.00 (m, 3H), 5.33 (s, 2H), 4.24 (s, 3H), 3.88 (s, 3H), 3.08 (d, 6H).

Example 51

3'-((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl )methoxy)-N-methyl-[1,1'-biphenyl]-4-carboxamide 51

Using the synthetic route of Example 15, the first step of the material was replaced with methylamine hydrochloride to give the title compound 51 (17 mg).

MS m/z (ESI): 541.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.88 (s, 1H), 7.81 (d, 2H), 7.63 (d, 2H), 7.37 (t, 1H), 7.21 (d, 1H), 7.11 (s, 1H), 7.03 (dt, 2H), 6.98 (d, 1H), 6.15 (s, 1H), 5.32 (s, 2H), 4.21 (s, 3H), 3.87 (s, 3H), 3.04 (d, 3H) ).

Example 52

3'-((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl )methoxy)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-[1,1'-biphenyl]-4-carboxamide 52

The title compound 52 (10 mg) was obtained from the title compound (m.p.

MS m/z (ESI): 625.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.87 (s, 1H), 7.61 (d, 2H), 7.43 (d, 2H), 7.36 (t, 1H), 7.25 (s, 1H), 7.20 (d, 1H), 7.14 (s, 1H), 7.03 (d, 2H), 6.98 (d, 1H), 5.32 (s, 2H), 4.20 (s, 3H), 4.03 (d, 2H), 3.87 (s, 3H) ), 3.74-3.20 (m, 2H), 3.20-2.75 (m, 3H), 2.60-2.20 (m, 1H), 2.15 - 1.50 (m, 4H).

Example 53

(S)-(3-hydroxypyrrolidin-1-yl)(3'-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4 Thiazol-6-yl)benzofuran-4-yl)methoxy)-[1,1'-biphenyl]-4-yl)methanone 53

The title compound 53 (20 mg) was obtained after the title compound was obtained from the compound (S)-pyrrolidin-3-ol.

MS m/z (ESI): 597.2 [M+1]

_{1H NMR (400MHz, CDCl 3)} δ7.90 (s, 1H), 7.61 (d, 4H), 7.38 (t, 1H), 7.26 (s, 1H), 7.24-7.15 (m, 2H), 7.07-6.98 (m, 3H), 5.33 (d, 2H), 4.55 (d, 1H), 4.23 (s, 3H), 3.89 (s, 5H), 3.74-3.63 (m, 1H), 3.61-3.47 (m, 1H) ), 2.12 (d, 2H).

Example 54

N-cyclopropyl-3'-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzene And furan-4-yl)methoxy)-[1,1'-biphenyl]-4-carboxamide 54

Using the synthetic route of Example 15, the starting material of the first step was replaced with the starting material of propylamine to give the title compound 54 (37 mg).

MS m/z (ESI): 567.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.88 (s, 1H), 7.79 (d, 2H), 7.62 (d, 2H), 7.36 (t, 1H), 7.25 (t, 1H), 7.20 (d, 2H), 7.05-6.97 (m, 3H), 6.29 (s, 1H), 5.32 (s, 2H), 4.22 (s, 3H), 3.87 (s, 3H), 2.93 (tt, 3.5 Hz, 1H), 0.90-0.87 (m, 2H), 0.66-0.61 (m, 2H).

Example 55

(3'-((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4- Methoxy)-[1,1'-biphenyl]-4-yl)(morphinolinyl)methanone 55

Using the synthetic route of Example 15, the first step starting material was replaced with compound 23b to give the title compound 55 (5 mg).

MS m/z (ESI): 597.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.89 (s, 1H), 7.63 (d, 2H), 7.48 (d, 2H), 7.36-7.42 (m, 1H), 7.14-7.26 (m, 3H), 6.99-7.06 (m, 3H), 5.33 (s, 2H), 4.22 (s, 3H), 3.88 (s, 3H), 3.64-3.80 (m, 4H), 1.56-1.85 (m, 4H).

Example 56

(S)-(3-(hydroxymethyl)morphinyl)(4-(4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1, 3,4]thiadiazole-6-yl)benzofuran-4-yl)methoxy)pyridin-2-yl)phenyl)methanone 56

Using the synthetic route of Example 16, the third step starting material was replaced with compound 21a and compound 1k, and the fifth step starting material was replaced with compound 15a to give the title compound 56 (26 mg).

MS m/z (ESI): 628.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.61 (d, 1H), 8.02 (s, 2H), 7.90 (s, 1H), 7.57 (d, 2H), 7.42 (s, 1H), 7.14-7.03 ( m, 3H), 6.95 (s, 1H), 5.49 (s, 2H), 4.69 (s, 1H), 4.22 (s, 3H), 4.15-3.49 (m, 9H), 3.88 (s, 3H).

Example 57

4-(3-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4 -yl)methoxy)phenyl)morpholine 57

Using the synthetic route of Example 1, the starting material of the tenth step was replaced with 3-morphinolinylphenol (prepared by the method of the patent application "WO2010067078 (A2)") to give the title compound 57 (3 mg).

MS m/z (ESI): 493.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.89 (s, 1H), 7.21-7.17 (m, 1H), 7.10 (s, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 6.57- 6.54 (m, 3H), 5.24 (s, 2H), 4.22 (s, 3H), 3.87 (s, 3H), 3.86-3.83 (m, 4H), 3.16 - 3.14 (m, 4H).

Example 58

(R)-4-(3-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzene) And furan-4-yl)methoxy)phenyl)-2-methylmorpholine 58

Using the synthetic route in Example 5, the starting material was replaced with compound 5a and compound (R)-2-methylmorpholine to give the title compound 58 (8 mg).

MS m/z (ESI): 507.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.88 (s, 1H), 7.20-7.16 (m, 1H), 7.09 (s, 1H), 7.01 (s, 1H), 6.97 (s, 1H), 6.56- 6.53 (m, 3H), 5.24 (s, 2H), 4.21 (s, 3H), 3.98 (dd, 1H), 3.87 (s, 3H), 3.78-3.74 (m, 2H), 3.46-3.38 (m, 2H), 2.84-2.81 (m, 1H), 2.47 (t, 1H), 1.31-1.22 (m, 3H).

Example 59

(S)-4-(3-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzene) And furan-4-yl)methoxy)phenyl)-2-methylmorpholine 59

Using the synthetic route of Example 5, the second step of the starting material was replaced by (S)-3-(2-methylmorphinolinyl)phenol (prepared by the method disclosed in the patent application "WO2010067078 (A2)"), The title compound 59 (10 mg) was obtained.

MS m/z (ESI): 507.2 [M+1]

Example 60

2-methoxy-6-(6-methoxy-4-((3-(piperidin-1-yl)phenoxy)methyl)benzofuran-2-yl)imidazo[2,1 -b][1,3,4]thiadiazole 60

Using the synthetic route of Example 5, the starting material of the first step was replaced with the starting material piperidine to give the title compound 60 (5 mg).

MS m/z (ESI): 491.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.88 (s, 1H), 7.17-7.13 (m, 1H), 7.09 (s, 1H), 7.01 (s, 1H), 6.97 (s, 1H), 6.60- 6.57 (m, 2H), 6.49 (d, 1H), 5.23 (s, 2H), 4.21 (s, 3H), 3.87 (s, 3H), 3.16-3.14 (m, 4H), 1.71-1.57 (m, 6H).

Example 61

Cyclopropyl (4-(3-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzene) And furan-4-yl)methoxy)phenyl)piperazin-1-yl)methanone 61

Using the synthetic route in Example 30, the first step starting material was replaced with cyclopropylcarbonyl chloride to give the title compound 61 (5 mg).

MS m/z (ESI): 560.3 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.88 (s, 1H), 7.24-7.30 (m, 2H), 7.10 (s, 1H), 7.01 (s, 2H), 6.95 (s, 1H), 6.70 ( d, 1H), 5.25 (s, 2H), 4.21 (s, 3H), 3.90-4.05 (m, 4H), 3.87 (s, 3H), 3.20-3.35 (m, 4H), 1.55-1.80 (m, 1H), 1.00-1.05 (m, 2H), 0.86-0.88 (m, 2H).

Example 62

4-(3-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4 -yl)methoxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 62

Using the synthetic route of Example 5, the second starting material was replaced with compound 32a to give the title compound 62 (55 mg).

MS m/z (ESI): 588.8 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (s, 1H), 7.23 - 7.27 (m, 1H), 7.19 (s, 1H), 7.01 - 7.04 (m, 2H), 6.97 - 7.01 (m, 3H) ), 6.90-6.94 (m, 1H), 5.27 (s, 2H), 4.24 (s, 3H), 4.05-4.08 (m, 2H), 3.87 (s, 3H), 3.61-3.64 (m, 2H), 2.49-2.52 (m, 2H), 1.49 (s, 9H).

Example 63

2-methoxy-6-(6-methoxy-4-((3-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenoxy) )methyl)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole 63

Using the synthetic route of Example 32, the second step of the material was replaced with methanesulfonyl chloride to give the title compound 63 (19 mg).

MS m/z (ESI): 567.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 (s, 1H), 7.23 - 7.28 (m, 1H), 7.14 (s, 1H), 6.93-7.05 (m, 5H), 6.06 (s, 1H), 5.27 (s, 2H), 4.22 (s, 3H), 3.95-3.98 (m, 2H), 3.87 (s, 3H), 3.48-3.55 (m, 2H), 2.85 (s, 3H), 2.61-2.68 ( m, 2H).

Example 64

6-(6-Methoxy-4-((3-(5-methoxypyridin-2-yl)phenoxy)methyl)benzofuran-2-yl)-2-methylimidazo[ 2,1-b][1,3,4]thiadiazole 64

Using the synthetic route of Example 4, the starting material of the first step was replaced with compound 35a and compound 1b to give the title compound 64 (20 mg).

MS m/z (ESI): 499.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.40 (d, 1H), 8.03 (s, 1H), 7.63-7.71 (m, 2H), 7.50-7.58 (m, 1H), 7.34-7.42 (m, 1H ), 7.27-7.32 (m, 1H), 7.18 (s, 1H), 6.97-7.09 (m, 3H), 5.36 (s, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 2.73 ( s, 3H).

Example 65

6-(6-Methoxy-4-((3-(5-methoxypyrazin-2-yl)phenoxy)methyl)benzofuran-2-yl)-2-methylimidazolium [2,1-b][1,3,4]thiadiazole 65

Using the synthetic route of Example 4, the second step of the starting material was replaced by the compound 3b to give the title compound 65 (20 mg).

MS m/z (ESI): 500.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.50 (s, 1H), 8.29 (s, 1H), 8.02 (s, 1H), 7.63 (s, 1H), 7.50 (d, 1H), 7.38 (t, 1H), 7.17 (s, 1H), 7.03 (dd, 3H), 5.34 (s, 2H), 4.01 (s, 3H), 3.87 (s, 3H), 2.73 (s, 3H).

Example 66

(4-cyclopropylpiperazin-1-yl)(3'-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thia) Zh-6-yl)benzofuran-4-yl)methoxy)-[1,1'-biphenyl]-4-yl)methanone 66

The title compound 66 (32 mg) was obtained from the title compound.

MS m/z (ESI): 620.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.04 (s, 1H), 7.59-7.65 (m, 2H), 7.45-7.51 (m, 2H), 7.34-7.41 (m, 1H), 7.24-7.27 (m , 1H), 7.19-7.23 (m, 1H), 7.18 (s, 1H), 7.01-7.07 (m, 2H), 6.98-7.01 (m, 1H), 5.33 (s, 2H), 3.89 (m, 3H) ), 3.65-3.87 (m, 2H), 3.39-3.55 (m, 2H), 2.51-2.81 (m, 7H), 1.64-1.72 (m, 1H), 0.37-0.56 (m, 4H).

Example 67

(3'-((6-Methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl) )methoxy)-[1,1'-biphenyl]-4-yl)(4-methylpiperazin-1-yl)methanone 67

Using the synthetic route of Example 13, the title compound was replaced with the starting material 1-methylpiperazine to give the title compound 67 (40 mg).

MS m/z (ESI): 594.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) ¹ H NMR (400 MHz, CDCl ₃ ) δ 8. s (s, 1H), 7.62 (d, 2H), 7.47 (d, 2H), 7.37 (t, 1H), 7.23 ( t,1H), 7.18(d,2H), 7.06-7.02(m,2H), 6.98(d,1H), 5.32(s,2H),3.88(s,7H),2.85(d,7H),2.57 (s, 3H).

Example 68

(S)-(4-ethyl-2-methylpiperazin-1-yl)(3'-((6-methoxy-2-(2-methylimidazo[2,1-b][ 1,3,4]thiadiazole-6-yl)benzofuran-4-yl)methoxy)-[1,1'-biphenyl]-4-yl)methanone 68

Using the synthetic route of Example 29, the first step starting material was replaced with the compound iodoethane, the third step starting material was replaced by the compound 13c, and the fifth step starting material was replaced with the compound 4e to give the title compound 68 (28 mg).

MS m/z (ESI): 622.3 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (s, 1H), 7.61 (d, 2H), 7.44 (d, 2H), 7.37 (t, 1H), 7.23 (t, 1H), 7.21-7. m, 2H), 7.07-6.97 (m, 3H), 5.32 (s, 2H), 3.87 (s, 3H), 3.50-2.25 (m, 9H), 2.73 (s, 3H), 1.12-1.35 (m, 6H).

Example 69

(S)-(3'-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran) 4-yl)methoxy)-[1,1'-biphenyl]-4-yl)(2-methyl-4-propylpiperazin-1-yl)methanone 69

Using the synthetic route of Example 16, the third step starting material was replaced by compound 14b, and the fifth step starting material was replaced by compound 29c to give the title compound 69 (15 mg).

MS m/z (ESI): 636.3 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (s, 1H), 7.61 (d, 2H), 7.44 (d, 2H), 7.32-7.40 (m, 1H), 7.21 - 7.25 (m, 1H), 7.18(d,1H),7.16(s,1H),7.01-7.03(m,2H), 6.85-6.99(m,1H),5.32(s,2H),3.87(s,3H),2.73(s, 3H), 2.14-2.25 (m, 1H), 1.95-2.04 (m, 2H), 1.58-1.71 (m, 4H), 1.28-1.34 (m, 2H), 1.25 (s, 3H), 0.92-0.96 ( m, 3H), 0.86-0.89 (m, 2H).

Example 70

(4-(cyclopropylmethyl)piperazin-1-yl)(3'-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3, 4]thiadiazole-6-yl)benzofuran-4-yl)methoxy)-[1,1'-biphenyl]-4-yl)methanone 70

The title compound 70 (25 mg) was obtained from the title compound.

MS m/z (ESI): 634.3 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.04 (s, 1H), 7.64 (d, 2H), 7.49 (d, 2H), 7.41-7.37 (m, 1H), 7.24-7.17 (m, 3H), 7.07-6.99 (m, 3H), 5.34 (s, 2H), 4.00-3.60 (m, 7H), 2.99-2.57 (m, 7H), 1.40-1.30 (m, 2H), 0.89-0.82 (m, 3H) ), 0.44 (m, 2H).

Example 71

(6-(3-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4 -yl)methoxy)phenyl)pyridin-3-yl)(4-propylpiperazin-1-yl)methanone 71

The title compound 71 (35 mg) was obtained from the compound from the title compound.

MS m/z (ESI): 623.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.68-8.79 (m, 1H), 8.04 (s, 1H), 7.77-7.87 (m, 2H), 7.71-7.76 (m, 1H), 7.58-7.65 (m) , 1H), 7.36-7.47 (m, 1H), 7.18 (s, 1H), 7.09-7.15 (m, 1H), 6.97-7.08 (m, 2H), 5.37 (s, 2H), 3.64-4.09 (m , 7H), 2.21-2.94 (m, 9H), 1.24-1.28 (m, 2H), 0.99 (t, 3H).

Example 72

(3'-((6-Methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl) Methoxy)-4'-methyl-[1,1'-biphenyl]-4-yl)(4-propylpiperazin-1-yl)methanone 72

Using the synthetic route of Example 16, the material of the fifth step was replaced by the compound 13d to give the title compound 72 (12 mg).

MS m/z (ESI): 636.3 [M+1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (s, 1H), 7.59 (d, 2H), 7.47-7.45 (d, 2H), 7.25 (d, 1H), 7.16-7.13 (m, 3H) ), 7.03 (s, 2H), 5.35 (s, 2H), 3.91-3.60 (m, 7H), 2.75-2.49 (m, 7H), 2.35 (s, 3H), 1.70-1.60 (m, 2H), 1.35-1.25 (m, 2H), 0.96 (t, 3H).

Example 73

(S)-(2,4-dimethylpiperazin-1-yl)(3'-((6-methoxy-2-(2-methylimidazo[2,1-b][1, 3,4]thiadiazole-6-yl)benzofuran-4-yl)methoxy)-[1,1'-biphenyl]-4-yl)methanone 73

Using the synthetic route of Example 16, the third step of the starting material was replaced by the compound 14b, and the fifth step of the starting material was replaced by (S)-1,3-dimethylpiperazine (using the patent application "EP1621537 (A1)" The title compound 73 (14 mg) was obtained.

MS m/z (ESI): 608.3 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ8.09 (s, 1H), 7.59 (d, 2H), 7.42 (d, 2H), 7.33-7.28 (m, 1H), 7.21 (s, 1H), 7.16-7.14 (m, 2H), 7.01-6.98 (m, 2H), 6.95 (s, 1H), 5.31 (s, 2H), 3.85 (s, 3H), 3.67-3.65 (m, 1H), 3.51- 3.48 (m, 1H), 3.24 - 3.12 (m, 1H), 3.11-3.09 (m, 1H), 2.80-2.72 (m, 1H), 2.68 (s, 3H), 2.64 (s, 3H), 2.50- 2.20 (m, 2H), 1.44-1.42 (m, 3H).

Example 74

(4-ethylpiperazin-1-yl)(3'-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazole) -6-yl)benzofuran-4-yl)methoxy)-[1,1'-biphenyl]-4-yl)methanone 74

The title compound 74 (25 mg) was obtained from the title compound.

MS m/z (ESI): 608.3 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ8.51 (s, 1H), 6.79-6.80 (m, 2H), 7.42-7.48 (m, 2H), 7.35-7.42 (m, 2H), 7.25-7.31 (m, 1H), 7.24 (s, 1H), 7.15-7.21 (m, 1H), 7.06-7.12 (m, 1H), 7.02-7.06 (m, 1H), 5.44 (s, 2H), 3.83 (s , 3H), 3.83-3.73 (m, 4H), 2.74 (s, 3H), 2.24-2.44 (m, 6H), 1.01 (t, 3H).

Example 75

(S)-(4-ethyl-3-methylpiperazin-1-yl)(3'-((6-methoxy-2-(2-methylimidazo[2,1-b][ 1,3,4]thiadiazole-6-yl)benzofuran-4-yl)methoxy)-[1,1'-biphenyl]-4-yl)methanone 75

Using the synthetic route of Example 16, the third step was replaced by (S)-4-(3'-hydroxy-[1,1'-biphenyl]-4-carbonyl)-2-methylpiperazine- tert-Butyl 1-carboxylate (prepared by the method disclosed in the patent application "WO2009154769"), the fourth step was replaced with ethyl iodide to give the title compound 75 (25 mg).

MS m/z (ESI): 622.3 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (s, 1H), 7.61 (d, 2H), 7.47 (d, 2H), 7.37 (t, 1H), 7.24 (d, 1H), 7.19 (d, 2H), 7.03 (dt, 2H), 6.98 (d, 1H), 5.33 (s, 2H), 3.88 (s, 3H), 3.15-2.10 (m, 9H), 2.73 (s, 3H), 1.25 (s) , 6H).

Example 76

(R)-(4-ethyl-2-methylpiperazin-1-yl)(3'-((6-methoxy-2-(2-methylimidazo[2,1-b][ 1,3,4]thiadiazole-6-yl)benzofuran-4-yl)methoxy)-[1,1'-biphenyl]-4-yl)methanone 76

Using the synthetic route in Example 29, the first step starting material was replaced with (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 76a and ethyl iodide, and the third step starting material was replaced with compound 13c. The title compound 76 (5 mg) was obtained. MS m/z (ESI): 622.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (s, 1H), 7.61 (d, 2H), 7.44 (d, 2H), 7.32-7.40 (m, 1H), 7.21 - 7.25 (m, 1H), 7.18(d,1H),7.16(s,1H),7.01-7.0 3(m,2H), 6.85-6.99(m,1H),5.33(s,2H),3.88(s,3H),2.73(s , 3H), 1.95-1.98 (m, 7H), 1.30-1.34 (m, 3H), 1.26 (s, 3H), 1.25-1.29 (m, 2H).

Example 77

(R)-(4-ethyl-3-methylpiperazin-1-yl)(3'-((6-methoxy-2-(2-methylimidazo[2,1-b][ 1,3,4]thiadiazole-6-yl)benzofuran-4-yl)methoxy)-[1,1'-biphenyl]-4-yl)methanone 77

Using the synthetic route in Example 16, the third step was replaced by (R)-4-(3'-hydroxy-[1,1'-biphenyl]-4-carbonyl)-2-methylpiperazine. Tert-butyl-1-carboxylate (prepared by the method disclosed in the patent application "WO20009154769"), the fourth step of the starting material was replaced with ethyl iodide to give the title compound 77 (10 mg).

MS m/z (ESI): 621.5 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (s, 1H), 7.64 (d, 2H), 7.48 (t, 2H), 7.38 (t, 1H), 7.23 (d, 1H), 7.18 (d, 2H), 7.07-6.96 (m, 3H), 5.33 (s, 2H), 3.88 (s, 3H), 3.55-3.31 (m, 5H), 3.25-3.10 (m, 2H), 2.89-2.76 (m, 2H), 2.74 (s, 3H), 1.75-1.50 (m, 6H).

Example 78

(4'-Fluoro-3'-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzo) Furan-4-yl)methoxy)-[1,1'-biphenyl]-4-yl)(4-propylpiperazin-1-yl)methanone 78

Using the synthetic route of Example 14, the first starting material was replaced by the compound 13a and the compound 17b, and the third step was replaced by the compound 13d to give the title compound 78 (28 mg).

MS m/z (ESI): 640.3 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ8.48 (s, 1H), 7.70 (d, 2H), 7.62 (d, 1H), 7.41 (d, 2H), 7.25-7.35 (m, 3H), 7.18(s,1H), 7.03(s,1H),5.53(s,2H), 3.80(s,3H), 3.50-3.61(m,4H), 2.72(s,3H),2.14-2.31(m, 6H), 1.36-1.45 (m, 2H), 0.81-0.85 (m, 3H).

Example 79

(4-(4-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4 -yl)methoxy)pyridin-2-yl)phenyl)(4-propylpiperazin-1-yl)methanone 79

Using the synthetic route of Example 16, the starting material of the second step was replaced by the compound 13a and the compound 10a, and the material of the fifth step was replaced with the compound 13d to give the title compound 79 (20 mg).

MS m/z (ESI): 623.3 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.54 (s, 1H), 8.06 (s, 1H), 8.01 (d, 2H), 7.51 (d, 2H), 7.37 (d, 1H), 7.07 (s, 1H), 6.98 (d, 1H), 6.94 (d, 1H), 6.93 (d, 1H), 5.40 (s, 2H), 3.90 (s, 3H), 3.54-3.71 (m, 4H), 2.76 (s) , 3H), 2.50-2.71 (m, 6H), 0.96-0.99 (m, 2H), 0.88-0.91 (m, 3H).

Example 80

(4-ethylpiperazin-1-yl)(4-(4-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiophene) Diazol-6-yl)benzofuran-4-yl)methoxy)-5-methylthiazol-2-yl)phenyl)methanone 80

Using the synthetic route of Example 22, the starting material of the fifth step was replaced by the compound 14d to give the title compound 80 (20 mg).

MS m/z (ESI): 629.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.02 (s, 1H), 7.93 (d, 2H), 7.46 (d, 2H), 7.22 (s, 1H), 7.03-6.98 (m, 2H), 5.61 ( s, 2H), 3.87 (s, 3H), 3.65-3.45 (m, 4H), 3.09 (d, 2H), 2.98-2.51 (m, 4H), 2.74 (s, 3H), 2.30 (s, 3H) , 1.51 (d, 3H).

Example 81

1-(6-(3-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran) 4-yl)methoxy)phenyl)pyridin-3-yl)-N,N-dimethylmethylamine 81

Using the synthetic route of Example 23, the first starting material was replaced with the compound dimethylamine to give the title compound 81 (40 mg).

MS m/z (ESI): 526.2 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ8.61 (s, 1H), 8.04 (s, 1H), 7.98 (s, 1H), 7.77-7.74 (m, 2H), 7.60 (d, 1H), 7.42-7.38(m,1H),7.18(s,1H),7.09(d,1H),7.04(s,1H),7.01(s,1H),5.36(s,2H),3.88(s,3H) , 3.73 (s, 2H), 2.74 (s, 3H), 2.46 (s, 6H).

Example 82

6-(6-Methoxy-4-((4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-3-yl)oxy) Methyl)benzofuran-2-yl)-2-methylimidazo[2,1-b][1,3,4]thiadiazole 82

Using the synthetic route of Example 25, the third step was replaced by 1-methylpiperazine to give the title compound 82 (20 mg).

MS m/z (ESI): 580.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.02 (s, 1H), 7.54 (d, 2H), 7.36 (d, 3H), 7.23 (s, 1H), 7.17 (d, 2H), 7.06-6.96 ( m, 3H), 5.31 (s, 2H), 3.87 (s, 3H), 3.65 (s, 2H), 3.13 - 2.61 (m, 14H).

Example 83

6-(4-((3-(4-butylpiperazin-1-yl)phenoxy)methyl)-6-methoxybenzofuran-2-yl)-2-methylimidazo[ 2,1-b][1,3,4]thiadiazole 83

Using the synthetic route of Example 29, the starting material of the first step was replaced with the compound 23a and 1-iodobutane, and the material of the third step was replaced with the compound 5a to give the title compound (35 mg).

MS m/z (ESI): 532.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.05 (s, 1H), 7.23-7.15 (m, 2H), 7.04 (d, 1H), 6.98 (d, 1H), 6.62-6.53 (m, 3H), 5.26(s,2H), 3.89(s,3H), 3.35(d,4H), 2.76(s,6H),2.56(s,3H), 1.48-1.30(m,4H),0.97(t,3H) .

Example 84

(6-(6-Methoxy-4-((3-(4-propylpiperazin-1-yl)phenoxy)methyl)benzofuran-2-yl)-2-methylimidazolium [2,1-b][1,3,4]thiadiazole 84

Using the synthetic route in Example 27, the starting material was replaced with compound 5a to give the title compound 84 (13 mg).

MS m/z (ESI): 518.3 [M+1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.51 (s, 1H), 7.14 - 7.25 (m, 2H), 7.03-7.13 (m, 1H), 6.93-7.03 (m, 1H), 6.37-6. (m, 3H), 5.30 (s, 2H), 3.82 (s, 3H), 2.97-3.18 (m, 4H), 2.74 (s, 3H), 2.42-2.46 (m, 4H), 2.17-2.30 (m , 2H), 1.38-1.53 (m, 2H), 0.85 (t, 3H).

Example 85

6-(4-((3-(4-ethylpiperazin-1-yl)phenoxy)methyl)-6-methoxybenzofuran-2-yl)-2-methylimidazo[ 2,1-b][1,3,4]thiadiazole 85

Using the synthetic route of Example 27, the starting material of the first step was replaced with Compound 5a and Compound 14d to give the title compound 85 (27 mg).

MS m/z (ESI): 504.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.03 (s, 1H), 7.18 (t, 1H), 7.14 (d, 1H), 7.03-7.00 (m, 1H), 6.95 (d, 1H), 6.63- 6.48(m,3H), 5.24(s,2H), 3.87(s,3H), 3.47(s,4H),3.23-2.51(m,6H),2.73(s,3H),1.27(d,3H) .

Example 86

6-(4-((2-Fluoro-5-(4-propylpiperazin-1-yl)phenoxy)methyl)-6-methoxybenzofuran-2-yl)-2-yl Imidazo[2,1-b][1,3,4]thiadiazole 86

Using the synthetic route of Example 27, the first step starting material was replaced with compound 16b to give the title compound 86 (8 mg).

MS m/z (ESI): 536.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.03 (s, 1H), 7.18 (s, 1H), 7.02-6.96 (m, 3H), 6.64 (dd, 1H), 6.45-6.43 (m, 1H), 5.32 (s, 2H), 3.87 (s, 3H), 3.14 - 3.11 (m, 4H), 2.74 (s, 3H), 2.69-2.66 (m, 4H), 2.43 (t, 2H), 1.59-1.54 ( m, 2H), 0.92 (t, 3H).

Example 87

6-(6-Methoxy-4-((3-(4-methylpiperazin-1-yl)phenoxy)methyl)benzofuran-2-yl)-2-methylimidazo[ 2,1-b][1,3,4]thiadiazole 87

Using the synthetic route of Example 27, the starting material of the first step was replaced with the compound 5a and the compound 1-methylpiperazine to give the title compound 87 (28 mg).

MS m/z (ESI): 490.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.02 (s, 1H), 7.18 (t, 1H), 7.13 (d, 1H), 7.01 (dd, 1H), 6.95 (d, 1H), 6.63-6.52 ( m, 3H), 5.23 (s, 2H), 3.87 (s, 3H), 3.45 (s, 4H), 2.93 (s, 4H), 2.73 (s, 3H), 2.60 (s, 3H).

Example 88

(R)-6-(6-methoxy-(4-((3-(2-methyl-4-propylpiperazin-1-yl)phenoxy)methyl)benzofuran-2- 2-methylimidazo[2,1-b][1,3,4]thiadiazole 88

Using the synthetic route of Example 29, the first step starting material was replaced by compound 76a to give the title compound 88 (15 mg).

MS m/z (ESI): 532.3 [M+1]

^{1 H NMR (400MHz, MeOD)} δ8.25 (s, 1H), 7.20-7.18 (m, 1H), 7.15 (d, 1H), 7.07 (dd, 1H), 6.97 (d, 1H), 6.66 (t , 1H), 6.61 (ddd, 2H), 5.30 (s, 2H), 3.86 (s, 3H), 3.71 (d, 1H), 3.19-3.03 (m, 3H), 2.76 (s, 3H), 2.75- 2.69 (m, 1H), 2.53 (d, 2H), 2.43 - 2.25 (m, 2H), 1.55 (q, 2H), 1.01 - 0.89 (m, 6H).

Example 89

6-(4-((2-Chloro-5-(4-propylpiperazin-1-yl)phenoxy)methyl)-6-methoxybenzofuran-2-yl)-2-yl Imidazo[2,1-b][1,3,4]thiadiazole 89

The title material was replaced with the compound 5-bromo-2-chlorophenol using the synthetic route from Example 27 to give the title compound 89 (15 mg).

MS m/z (ESI): 552.2 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ8.49 (s, 1H), 7.30-7.19 (m, 3H), 7.06 (s, 1H), 6.88 (s, 1H), 6.53 (d, 1H), 5.44 (s, 2H), 3.83 (s, 3H), 3.30-2.85 (m, 7H), 2.75 (s, 4H), 2.47-2.25 (m, 2H), 1.65-1.45 (m, 2H), 0.88 ( t, 3H).

Example 90

6-(6-Methoxy-4-((2-methyl-5-(1-propylpiperidin-4-yl)phenoxy)methyl)benzofuran-2-yl)-2- Methylimidazo[2,1-b][1,3,4]thiadiazole 90

Using the synthetic route of Example 31, the first starting material was replaced with compound 16b to give the title compound 90 (20 mg).

MS m/z (ESI): 531.3 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.07 (s, 1H), 7.17 (s, 1H), 7.12 (d, 1H), 7.04 (d, 2H), 6.86 (s, 1H), 6.81 (d, 1H), 5.29 (s, 2H), 3.90 (s, 3H), 3.40-3.51 (m, 2H), 2.76 (s, 3H), 2.52-2.54 (m, 4H), 2.50-2.51 (m, 1H) , 2.28 (s, 3H), 1.87-2.05 (m, 4H), 1.63-1.66 (m, 2H), 1.00-1.04 (m, 3H).

Example 91

6-(6-Methoxy-4-((3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)phenoxy)methyl)benzofuran-2- 2-methylimidazo[2,1-b][1,3,4]thiadiazole 91

Using the synthetic route in Example 31, the starting material in the fourth step was replaced by the compound 31c, and the starting material in the sixth step was replaced with the compound 14f to give the title compound 91 (16 mg).

MS m/z (ESI): 515.3 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.02 (s, 1H), 7.21-4.24 (m, 1H), 7.14 (s, 1H), 6.95-7.04 (m, 4H), 6.89-6.93 (m, 1H ), 6.03 (s, 1H), 5.26 (s, 2H), 3.86 (s, 3H), 3.30-3.41 (m, 2H), 2.85-2.95 (m, 2H), 2.73 (s, 3H), 2.61 2.75 (m, 4H), 1.61-1.75 (m, 2H), 0.95-0.99 (m, 3H).

Example 92

2-(6-Methoxy-4-((3-(5-methoxypyrazin-2-yl)phenoxy)methyl)benzofuran-2-yl)-6-methylimidazolium [1,2-b]pyridazine 92

first step

6-Methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yltrifluoromethanesulfonate 92b

6-Methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-ol 92a (600 mg, 2.03 mmol, using the patent application "WO2013163241A1" Prepared by the method disclosed) dissolved in 60 mL of tetrahydrofuran, cooled to -20 ° C, added potassium t-butoxide (274 mg, 2.44 mmol), warmed to 0 ° C, stirred for 30 minutes, cooled to -20 ° C, added N- Phenyl bis(trifluoromethanesulfonyl)imide (871 mg, 2.44 mmol), which was taken to room temperature, stirred for 16 hr. Compound 92b (830 mg), Yield: 96%.

Second step

6-Methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-carboxylic acid methyl ester 92c

Compound 92b (830 mg, 1.93 mmol) was dissolved in 50 mL of N,N-dimethylformamide, and palladium acetate (44 mg, 0.20 mmol) and 1,1'-bisdiphenylphosphinoferrocene (269 mg, 0.48 mmol), triethylamine (393 mg, 3.88 mmol), methanol (3.95 g, 123.28 mmol), and reacted at 60 ° C for 16 hours under a carbon monoxide atmosphere. The organic layer was combined with EtOAc (EtOAc)EtOAc. The eluent system A was purified to give crystals crystals crystals crystals crystals crystals

third step

(6-Methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)methanol 92d

The compound 92c (200 mg, 0.59 mmol) was dissolved in 30 mL of tetrahydrofuran, and a solution of diisobutylaluminum hydride in n-hexane (2.96 mL, 2.96 mmol) was added, and the mixture was stirred for 1.5 hours, and a saturated ammonium chloride solution was slowly added dropwise and stirred. After 10 minutes, the mixture was filtered. EtOAcjjjjjjjjj

the fourth step

(6-Methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)methyl methanesulfonate 92e

Compound 92d (70 mg, 0.23 mmol) was dissolved in dichloromethane (5 mL). EtOAc (EtOAc, m. The mixture was extracted with methylene chloride (5 mL, EtOAc).

the fifth step

The crude compound 92e (80 mg, 0.21 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and then compound 3b (20 mg, 0.10 mmol), cesium carbonate (67 mg, 0.20 mmol), stirred for 16 hours, decompressed Concentration, water (10 mL), EtOAc (EtOAc (EtOAc) Rate: 78%.

MS m/z (ESI): 494.2 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ): δ8.51 (d, 1H), 8.29 (d, 1H), 8.22 (s, 1H), 7.83 (d, 1H), 7.64 (t, 1H), 7.51 (d , 1H), 7.39 (t, 2H), 7.05-7.08 (m, 2H), 7.02 (d, 1H), 6.95 (d, 1H), 5.36 (s, 2H), 4.01 (s, 3H), 3.89 ( s, 3H), 2.59 (s, 3H).

Example 93

2-(6-Methoxy-4-((2-methyl-5-(4-propylpiperazin-1-yl)phenoxy)methyl)benzofuran-2-yl)-6- Methylimidazo[1,2-b]pyridazine 93

first step

2-(4-(Chloromethyl)-6-methoxybenzofuran-2-yl)-6-methylimidazo[1,2-b]pyridazine 93a

Compound 92d (115 mg, 0.37 mmol) was dissolved in 50 mL of dichloromethane, cooled to 0 ° C - 5 ° C, and then chlorosulfoxide (2650 mg, 22.27 mmol) was added to the above reaction system and heated to 27 ° C. The title compound 93a (110 mg) was obtained.

MS m/z (ESI): 328.1 [M+1]

Second step

Compound 27a (22 mg, 0.09 mol) and compound 93a (30 mg, 0.09 mmol) were dissolved in 3 mL of N,N'-dimethylformamide, and hydrazine carbonate (90 mg, 0.28 mmol) was added, and the reaction was stirred for 18 hours. The mixture was quenched with water (1 mL).

MS m/z (ESI): 526.0 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.22 (s, 1H), 7.83 (d, 1H), 7.33 (s, 1H), 7.07-7.04 (m, 3H), 6.95 (d, 1H), 6.60 ( s, 1H), 6.48 (d, 1H), 5.28 (s, 2H), 3.89 (s, 3H), 3.17 (t, 4H), 2.60-2.59 (m, 7H), 2.37 (t, 2H), 2.22 (s, 3H), 1.57-1.54 (m, 2H), 0.93 (t, 3H).

Example 94

(4-ethylpiperazin-1-yl)(6-(3-((6-methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzene) And furan-4-yl)methoxy)phenyl)pyridin-3-yl)methanone 94

The compound 14e (29 mg, 0.09 mmol) and the compound 93a (37 mg, 0.09 mmol) were dissolved in 3 mL of N,N'-dimethylformamide, and cesium carbonate (121 mg, 0.37 mmol) was added, and the reaction was stirred for 18 hours. The title compound 94 (17 mg) was obtained from EtOAc (EtOAc m. Yield: 30.2%.

MS m/z (ESI): 603.3 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.75 (s, 1H), 8.23 (s, 1H), 7.75 (d, 3H), 7.63 (s, 1H), 7.61 (d, 1H), 7.39-7.42 ( m,1H), 7.37(s,1H), 7.09(d,1H),7.02(s,1H),6.97(s,1H),6.96(d,1H),5.38(s,2H),4.05-4.12 (m, 2H), 3.89 (s, 3H), 3.65-3.70 (m, 2H), 2.95-3.06 (m, 2H), 2.74-2.78 (m, 2H), 2.60 (s, 3H), 1.55-1.57 (m, 2H), 1.26 (s, 3H).

Example 95

(3'-((6-Methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-yl)methoxy)-[1 ,1'-biphenyl]-4-yl)(4-methylpiperazin-1-yl)methanone 95

Using the synthetic route of Example 13, the fourth step starting material was replaced with the compound 1-methylpiperazine, and the fifth starting material was replaced with the compound 93a to give the title compound 95 (40 mg).

MS m/z (ESI): 588.3 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.22 (s, 1H), 7.82 (d, 1H), 7.63 (d, 2H), 7.48 (d, 2H), 7.41-7.34 (m, 2H), 7.24 ( s, 1H), 7.20 (d, 1H), 7.116.98 (m, 3H), 6.95 (d, 1H), 5.34 (s, 2H), 3.89 (s, 7H), 2.59 (s, 10H).

Example 96

(4-ethylpiperazin-1-yl)(3'-((6-methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran) 4-yl)methoxy)-[1,1'-biphenyl]-4-yl)methanone 96

Using the synthetic route of Example 13, the fourth step starting material was replaced by the compound 14d, and the fifth step starting material was replaced with the compound 92d to give the title compound 96 (32 mg).

MS m/z (ESI): 602.3 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (s, 1H), 7.82 (d, 1H), 7.64 - 7.59 (m, 2H), 7.49-7.45 (m, 2H), 7.40-7.34 (m, 2H) ), 7.24 (d, 1H), 7.20 (d, 1H), 7.08 (d, 1H), 7.06-6.99 (m, 2H), 6.95 (d, 1H), 5.34 (s, 2H), 3.89 (s, 3H), 3.88-3.50 (m, 4H), 2.59 (s, 3H), 2.58-2.32 (m, 6H), 1.15 (s, 3H).

Example 97

4-((6-(3-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzo) Furan-4-yl)methoxy)-4-methylphenyl)pyridin-3-yl)methyl)morpholine 97

Using the synthetic route of Example 23, the second starting material was replaced with compound 37a to give the title compound 97 (40 mg).

MS m/z (ESI): 582.2 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ8.54 (d, 1H), 8.51 (s, 1H), 7.93 (d, 1H), 7.82 (s, 1H), 7.76 (d, 1H), 7.58 ( d,1H), 7.25-7.29 (m, 2H), 7.18 (d, 1H), 7.07 (d, 1H), 5.47 (s, 2H), 3.83 (s, 3H), 3.55-3.59 (m, 4H) , 3.51 (s, 2H), 2.74 (s, 3H), 2.34 - 2.39 (m, 4H), 2.26 (s, 3H).

Example 98

(4-ethylpiperazin-1-yl)(6-(3-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiophene) Diazol-6-yl)benzofuran-4-yl)methoxy)-4-methylphenyl)pyridin-3-yl)methanone 98

Using the synthetic route of Example 14, the first starting material was replaced with compound 37a and 6-bromonicotinic acid to give the title compound 98 (66 mg).

MS m/z (ESI): 623.3 [M+1]

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.73 (s, 1H), 8.03 (d, 1H), 7.87-7.79 (m, 1H), 7.79-7.70 (m, 2H), 7.50 (d, 1H), 7.27 (s, 1H), 7.17 (s, 1H), 7.03 (d, 2H), 5.39 (s, 2H), 3.88 (d, 7H), 2.71 (t, 9H), 2.35 (d, 3H), 1.24 (s, 3H).

Example 99

6-(6-Methoxy-4-((3-(5-methylpyridin-2-yl)phenoxy)methyl)benzofuran-2-yl)-2-methylimidazo[2 , 1-b][1,3,4]thiadiazole 99

Using the synthetic route of Example 5, the first starting material was replaced with compound 38a and compound 1b, and the second step was replaced by compound 14f to give the title compound 99 (76 mg).

MS m/z (ESI): 483.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.60 (s, 1H), 8.03 (s, 1H), 7.74 (d, 3H), 7.60 (s, 1H), 7.41 (s, 1H), 7.19 (s, 1H), 7.10 (d, 1H), 7.03 (s, 2H), 5.40 (s, 2H), 3.88 (s, 3H), 2.73 (s, 3H), 2.43 (s, 3H).

Example 100

4-((3'-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran- 4-yl)methoxy)-4'-methyl-[1,1'-biphenyl]-4-yl)methyl)morpholine 100

Using the synthetic route of Example 24, the second step of the material was replaced by compound 37a to give the title compound 100 (76 mg).

MS m/z (ESI): 581.2 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ8.51 (s, 1H), 7.60 (d, 2H), 7.39-7.32 (m, 3H), 7.29 (s, 1H), 7.23 (d, 1H), 7.18(d,1H),7.14(d,1H),7.07(d,1H),5.48(s,2H),3.83(s,3H),3.57(t,4H),3.47(s,2H),2.75 (s, 3H), 2.36-2.33 (m, 4H), 2.25 (s, 3H).

Example 101

(4-(3-hydroxypropyl)piperazin-1-yl)(3'-((6-methoxy-2-(2-methylimidazo[2,1-b][1,3, 4]thiadiazole-6-yl)benzofuran-4-yl)methoxy)-[1,1'-biphenyl]-4-yl)methanone 101

Using the synthetic route in Example 16, the third step starting material was replaced with compound 13b, and the fifth step starting material was replaced with the compound 3-(piperazin-1-yl)propyl-1-ol (using patent application US2012171116 (A1) The title compound 101 (35 mg) was obtained.

MS m/z (ESI): 638.3 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (s, 1H), 7.63 (d, 2H), 7.48 (d, 2H), 7.37 (t, 1H), 7.23 (s, 1H), 7.18 (d) , 2H), 7.04 (d, 2H), 6.99 (d, 1H), 5.32 (s, 2H), 4.15-3.81 (m, 9H), 3.25-3.05 (m, 6H), 2.73 (s, 3H), 2.15-1.91 (m, 1H), 1.71-1.51 (m, 2H).

Test case:

Biological evaluation

Test Example 1. Determination of the inhibitory activity of the compound of the present invention against human PAR-4

This method was used to determine the inhibitory effect of the compounds of the present invention on human PAR-4 protein activity expressed in HEK293/human PAR-4 stably transformed cells.

First, experimental materials and instruments

1.Fluo-4 NW Calcium Assay Kit (F36206, invitrogen)

2.MEM (Hyclone, SH30024.01B)

3.G418. Sulfate (Enzo, ALX-380-013-G005)

4. Bovine fetal serum (GIBCO, 10099)

5. Sodium pyruvate solution (sigma, S8636-100ML)

6.MEM non-essential amino acid solution (100×) (sigma, M7145-100ML)

7.Flexstation 3 multi-function microplate reader (Molecular Devices)

8. Poly-D-lysine 96-well microplate (356692, BD)

9.AF6 (synthesis of Gil Biochemical Co., Ltd.)

10. Human PAR-4 (Jinweizhi Biotechnology Co., Ltd.)

11.

3000 transfection reagent (L3000-015, Life Technology)

Second, the experimental steps

Mammalian expression vector containing hPAR4 gene,

3000 transfection reagents were transferred to HEK293 cells; G418 antibiotics were screened every other day to select monoclonal cell lines.

HEK293/human PAR-4 stable cell lines were seeded in 96-well plates at a density of 30,000 cells/well one day in advance. On the next day, the Fluo-4NW Calcium Assay Kits were used to prepare the Fluo-4 dye-containing loading buffer. The medium was removed and 100 μl of Fluo-4 dye-containing loading buffer was added to each well at 37 °C. Incubate for 30 minutes. After the time, the plate was allowed to equilibrate to room temperature for 10 minutes. The compound was formulated to a concentration of 10 ⁵ , 10 ⁴ , 10 ³ , 10 ² , 10, ¹ , 0.1, 0 nM, 1 μl was added per well, and incubated for 10 minutes at room temperature. The test was performed with a flexstation 3 microplate reader, and the machine was automatically added with 600 μM of the AF6 polypeptide 50 ul, and the value was immediately read at 494/516 nM. IC ₅₀ values of the compounds of fluorescence corresponding to different concentrations can be calculated by Graphpad Prism software to obtain.

The human PAR-4 inhibitory activity of the compound of the present invention was measured by the above test, and the measured IC ₅₀ values are shown in Table 1.

Table 1 IC _{50 of the} inhibition of human PAR-4 activity by the compounds of the present invention

实施例编号Example number	IC ₅₀(nM) IC ₅₀ (nM)
22	0.880.88
33	1.181.18
44	0.170.17
55	0.170.17
66	0.140.14
77	0.230.23
88	0.170.17
99	0.310.31
1010	0.350.35
1111	0.380.38
1212	0.560.56
1313	0.220.22
1414	0.70.7
1515	0.20.2
1616	0.170.17
1717	0.30.3
1818	0.730.73
2020	6.256.25
21twenty one	0.180.18
22twenty two	0.190.19
23twenty three	0.220.22
24twenty four	0.720.72
2525	2.062.06
2626	0.790.79
2727	0.260.26
2828	0.210.21

2929	0.440.44
3030	0.220.22
3131	4.194.19
3232	0.170.17
3333	0.20.2
3434	0.490.49
3535	0.80.8
3636	0.550.55
3737	0.720.72
3838	0.150.15
3939	0.210.21
4040	0.280.28
4141	0.180.18
4242	1.91.9
4343	0.10.1
4444	0.150.15
4545	0.070.07
4646	0.390.39
4747	1.121.12
4848	0.370.37
4949	0.660.66
5050	0.250.25
5151	1.741.74
5252	0.510.51
5353	0.640.64
5454	0.830.83
5555	0.150.15
5656	0.390.39
5757	0.130.13
5858	0.20.2
5959	0.210.21
6060	0.120.12
6161	0.220.22
6262	0.120.12
6363	0.410.41
6464	0.210.21
6565	0.210.21
6666	0.610.61
6767	0.970.97

7070	0.480.48
7171	0.610.61
7272	0.270.27
7373	0.610.61
7474	0.510.51
7575	0.660.66
7878	0.710.71
7979	0.440.44
8080	0.160.16
8383	1.131.13
8484	0.490.49
8686	1.731.73
8888	1.711.71
8989	1.431.43
9090	1.481.48
9191	3.123.12
9292	0.50.5
9393	1.621.62
9494	4.664.66
9595	2.112.11
9696	0.840.84
101101	2.152.15

Conclusion: The compounds of the present invention have a significant inhibitory effect on human PAR4 activity.

Test Example 2 Platelet aggregation assay induced by the compound of the present invention against PAR4-activated peptide (PAR4-AP)

First, experimental materials and instruments

1. Human platelet-rich plasma (PRP): Blood is collected from a blood collection tube containing no anticoagulant and immediately poured into a centrifuge tube containing 3.8% sodium citrate (1:9 volume, one part) Sodium citrate solution and nine parts of blood anticoagulation). The blood was centrifuged at 300 g for 15 minutes (25 ° C), and the upper platelet-rich plasma was taken out.

2. Human PAR4-Activating Peptide (Ala-[Phe(4-F)]-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH2, Gil Biochemical Customization)

3. Platelet aggregator (Plymouth instrument, LBY-NJ4).

Second, the experimental steps

In this experiment, human platelet-rich plasma (PRP) was used to test 100 nM, 50 nM, 30 nM, 20 nM, 10 nM, 3 nM, 1 nM test compounds induced by 25 μM PAR4-activating peptide (PAR4-AP) by platelet agglutinator. Inhibition of platelet aggregation, and calculation of MEC.

Third, data processing

Curve fitting was performed by GraphPad Prism, and the software data was used to analyze the MEC value of the inhibition of the platelet aggregation reaction of the PAR4-activator by the compound.

Table 2 MEC values of the inhibitory effect of the compounds of the present invention on PAR4-activated peptide-induced platelet aggregation.

实施例编号Example number	MEC(nM)MEC(nM)
22	1010
33	33
44	1010
55	1010
66	1010
77	33
88	1010
99	3030
1010	3030
1111	1010
1212	1010
1313	3333
1414	1515
1515	1010
1616	1515
1717	3535
1818	3030
1919	4040
2020	9090
21twenty one	4040
22twenty two	3535
23twenty three	3030
24twenty four	4040
2525	4545
2626	6060
2727	55
2828	1010
2929	1818
3030	1212
3131	4040
3232	1515
3333	3030
3434	1010
3535	1010
3636	1010
3737	1010

3838	1010
3939	3030
4040	1010
4141	1010
4242	3030
4343	1010
4444	1010
4545	1010
4646	1010
4747	1010
4848	3030
4949	3030
5050	55
5151	55
5252	1515
5353	3030
5454	1010
5555	33
5656	5050
5757	3030
5858	3030
5959	3030
6060	3030
6161	1515
6262	3030
6363	3030
6464	1010
6565	33
6666	1010
6767	1212
6868	3030
6969	2525
7070	4040
7171	3535
7272	3535
7373	4545
7474	1515
7575	3333
7676	5050

7777	2020
7878	4040
7979	4545
8080	3535
8181	3535
8383	1515
8484	2020
8585	3535
8686	3535
8888	4545
8989	4545
9090	4040
9191	4040
9292	1010
9393	4040
9494	6060
9595	6060
9696	4040
101101	6060

Conclusion: The compounds of the present invention have a significant inhibitory effect on platelet aggregation induced by PAR4 activating peptide.

Test Example 3 Solubility of the compound of the present invention in FassIF solution

Experimental material

Reagents: dimethyl sulfoxide (analytical grade), ethanol (analytical grade), acetonitrile (chromatographically pure), NaH ₂ PO ₄ · 2H ₂ O (analytical grade), ammonium acetate (analytical grade), sodium taurocholate, egg Phospholipids, sodium hydroxide, sodium chloride (analytical grade)

Instrument: Liquid Chromatograph

2, the experimental steps

2.1 Weigh the appropriate amount of test compound. Using DMSO as a solvent, prepare a 10 mM stock solution. Accurately measure 10 μL stock solution (concentration 10 mM, dissolved in DMSO) and 990 μL organic mixed solvent (usually DMSO: acetonitrile: ethanol = 1:1:1) in a 2 mL sample vial and mix to obtain a clear 100 μM sample solution. As a reference solution.

2.2 Preparation of FassIF solution

Solution (A): Add 4.441g NaH ₂ PO ₄ ·2H ₂ O, 0.348g NaOH particles and 6.186g NaCl in 900mL ultrapure water, mix well, add 1M NaOH to adjust the pH of the solution to 6.5±0.05, and dilute with water. Up to 1000mL. Refrigerated at 4 ° C for use.

FassIF solution: Dissolve 0.161 g of sodium taurocholate (NaTC) and 59 mg of lecithin in 20 mL of solution (A), stir vigorously overnight to form a clear micelle solution, add solution (A) to a volume of 100 mL, and chill at 4 °C. (not more than 2 weeks).

2.3 Dissolve 1 mg of the sample to be tested to 900 μL of FassIF solution, mix vigorously, and prepare two solutions in parallel; shake for 24 hours in a 37 ° C water bath, centrifuge at 4000 rpm for 30 min, and transfer the supernatant as a sample solution to transfer to liquid chromatography.

3, data processing

FassIF solubility (μM) = peak area of the sample / peak area of the reference * reference solution concentration (μM) * dilution factor of the sample solution.

Take two measurements worth the average as the final FassIF solubility.

Table 3. FassIF solubility of the compounds of the invention.

实施例编号Example number	FassIF(μM)FassIF (μM)
1313	7979
1414	5959
1616	1414
22twenty two	1919
2727	176176
2929	3838
6767	4747
6868	6161
6969	5555
7070	4747
7272	5353
7474	23twenty three
7575	6565
7979	1414
8080	4242
8181	3232
8282	5959
8484	23twenty three
9090	136136
9595	1717
9696	1414
9797	4646
9898	1414
100100	1616
101101	4343

Conclusion: The compounds of the invention have good solubility in FassIF.

Test Example 4, Rat Pharmacokinetic Test of the Compound of the Invention

1. Summary

SD rats were used as test animals, and SD rats were intravenously administered with the compound of Example 2, the compound of Example 6, the compound of Example 12, the compound of Example 13, and the compound of Example 14 by LC/MS/MS. The concentration of the drug in plasma at different times after the compound of Example 15, the compound of Example 34, the compound of Example 35 and the compound of Example 44. The pharmacokinetic behavior of the compounds of the present invention in SD rats was investigated and their pharmacokinetic characteristics were evaluated.

2, the test plan

2.1 Test drugs

The compound of Example 2, the compound of Example 6, the compound of Example 12, the compound of Example 13, the compound of Example 14, the compound of Example 15, the compound of Example 34, the compound of Example 35 and the compound of Example 44.

2.2 Test animals

Thirty-six SD rats, male and female, were divided into 9 groups and purchased from Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2013-0006.

2.3 Drug preparation

Weigh the appropriate amount of sample, add 10% DMSO + 5% PEG400 + 85% (10% HS-15), and add sequentially.

2.4 Administration

The SD rats were intragastrically administered overnight after the fasting, and the dose was 2 mg/kg (mpk), the administration volume was 10 mL/kg, and the administration concentration was 2 mg/mL.

3, operation

After fasting overnight, the rats were intragastrically administered before and after administration 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 h. 0.2 ml of blood was collected from the eyelids, placed in heparinized tubes, centrifuged at 3500 rpm for 10 min to separate plasma. , stored at -20 ° C. Eat 2 hours after administration.

To determine the content of test compound in plasma after administration of different concentrations of drug SD rats: take 25 μL of SD rat plasma at each time after administration, add 30 μL (100 ng/mL) of internal standard camptothecin solution, 200 μL of acetonitrile, vortex The mixture was spun for 5 minutes, centrifuged for 10 minutes (4000 rpm), and the plasma sample was subjected to supernatant analysis of 4.0 μL for LC/MS/MS analysis.

4. Results of pharmacokinetic parameters of SD rats

The rat pharmacokinetic parameters of the compounds of the invention are as follows:

Conclusion: The compound of the present invention has good pharmacological absorption in rats and has pharmacokinetic advantages.

Claims

A compound of the formula (I):

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

X is an O atom or an S atom;

W is an O atom or an S atom;

Ring A is selected from the group consisting of cycloalkyl, aryl and heteroaryl;

Ring B is a heteroaryl group;

R 1 is the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, and a hetero group. a cycloalkyl, aryl and heteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halo, alkyl, alkoxy, haloalkyl Substituting one or more substituents of a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R 2 is selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl base;

R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, and a hetero group. a cyclic group, an aryl group and a heteroaryl group;

R 4 and R 5 are the same or different and are each independently a hydrogen atom or an alkyl group;

R 6 is selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl a group wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyanide Base, amino, nitro, -CONR 9 R 10 , -CH 2 NR 9 R 10 , -NR 9 R 10 , -S(O) 2 R 11 , -COR 11 , -COOR 12 , -OR 12 , naphthenic Substituted by one or more substituents in the group, heterocyclic group, aryl group and heteroaryl group;

Or R 6 is
Wherein J is a covalent bond or an alkylene group, wherein the alkylene group is optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cyclo Substituted by one or more substituents of an alkyl group, a heterocyclic group, an aryl group and a heteroaryl group, the ring C is selected from the group consisting of an aryl group, a heteroaryl group, a cycloalkyl group and a heterocyclic group, and R 8 is the same or different, and Each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, -CONR 9 R 10 , -CH 2 NR 9 R 10 , -NR 9 R 10 , -S(O) 2 R 11 , -COR 11 , -COOR 12 , -OR 12 , cycloalkyl, heterocyclic, aryl and heteroaryl;

R 7 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, and a hetero group. a cycloalkyl, aryl and heteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halo, alkyl, alkoxy, haloalkyl Substituting one or more substituents of a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R 9 and R 10 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

Or R 9 and R 10 together with the attached nitrogen atom form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different selected from N atom, O in addition to 1 nitrogen atom. a hetero atom of an atom and an S atom, and the heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, -COR 11 Substituting one or more substituents of a cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl and heteroaryl group;

R 11 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R 12 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

n is 0, 1, 2 or 3;

s is 0, 1, 2, 3 or 4;

p is 0, 1, 2 or 3;

t is 0, 1, 2 or 3.
The compound of the formula (I) according to claim 1, wherein the R 6 is
J is a covalent bond, and ring C is selected from the group consisting of an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclic group, and R 8 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, or an alkyl halide. , haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, -CONR 9 R 10 , -CH 2 NR 9 R 10 , -S(O) 2 R 11 , -COR 11 and -COOR 12 , and R 9 to R 12 are as defined in claim 1.
The compound of the formula (I) according to claim 1 or 2, wherein the ring B is a heteroaryl group of 5 to 10 members, preferably selected from the group consisting of
Or a pyrimidinyl group, wherein: G is an N atom, CR 3 or CH; Y is selected from the group consisting of an S atom, an O atom, CH=CH, CH=N and N=CH; and R 3 is as defined in claim 1.
The compound of the formula (I) according to any one of claims 1 to 3, which is a compound represented by the formula (II):

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

G is N atom, CR 3 or CH;

Y is selected from the group consisting of an S atom, an O atom, CH=CH, CH=N, and N=CH;

Ring C is selected from the group consisting of an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclic group;

R 8 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, -CONR 9 R 10 , -CH 2 NR 9 R 10 , -S(O) 2 R 11 , -COR 11 and -COOR 12 ;

W, ring A, R 1 to R 5 , R 7 , R 9 to R 12 , X, n, s, p and t are as defined in claim 1.
The compound of the formula (I) according to claim 3 or 4, wherein the Y is an S atom or CH=CH.
The compound of the formula (I) according to any one of claims 1 to 5, which is a compound represented by the formula (III), the formula (IV) or the formula (V):

Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

Ring C is selected from the group consisting of an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclic group;

R 8 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, -CONR 9 R 10 , -CH 2 NR 9 R 10 , -S(O) 2 R 11 , -COR 11 and -COOR 12 ;

Ring A, R 1 to R 5 , R 7 , R 9 to R 12 , X, n, s, p and t are as defined in claim 1.
The compound of the formula (I) according to any one of claims 1 to 6, wherein the W is O.
The compound of the formula (I) according to any one of claims 1 to 7, wherein the ring A is selected from a phenyl group, a C 3-6 cycloalkyl group or a 5- to 6-membered heteroaryl group. The heteroaryl group optionally contains 1 to 3 hetero atoms which are the same or different from the N atom, the O atom and the S atom; the ring A is preferably selected from the group consisting of a phenyl group, a pyridyl group, a thiazolyl group, a pyrimidinyl group, and a pyrazole. Base and imidazolyl.
The compound of the formula (I) according to any one of claims 1 to 8, which is represented by the formula (III'), the formula (IV') or the formula (V')

Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

Ring C is selected from the group consisting of an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclic group;

R 8 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, -CONR 9 R 10 , -CH 2 NR 9 R 10 , -S(O) 2 R 11 , -COR 11 and -COOR 12 ;

R 1 to R 5 , R 7 , R 9 to R 12 , X, n, s, p and t are as defined in the formula (I).
The compound of the formula (I) according to claim 4, wherein the compound represented by the formula (II) is a compound represented by the formula (II bb):

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

G is N atom, CR 3 or CH;

Y is selected from the group consisting of an S atom, an O atom, CH=CH, CH=N, and N=CH;

Ring C is selected from the group consisting of heterocyclic groups, aryl groups and heteroaryl groups;

R 9 and R 10 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

Or R 9 and R 10 together with the attached nitrogen atom form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different selected from N atom, O in addition to 1 nitrogen atom. a hetero atom of an atom and an S atom, and the heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, -COR 11 Substituting one or more substituents of a cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl and heteroaryl group;

W, ring A, R 1 to R 5 , R 7 , R 11 , X, n, s and p are as defined in the formula (I).
The compound of the formula (I) according to any one of claims 1 to 10, wherein the ring C is selected from the group consisting of a phenyl group, a 5- to 6-membered heteroaryl group, and a C 3-8 cycloalkyl group. And a 3- to 8-membered heterocyclic group, each of the heteroaryl and heterocyclic groups optionally containing 1 to 3 hetero atoms which are the same or different and are selected from the group consisting of an N atom, an O atom and an S atom; the ring C is preferably selected from the group consisting of Phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, piperidinyl, piperazinyl, 1,2,3,6-tetrahydropyridyl, 1,2,3,4-tetra Hydropyridyl and morpholine.
The compound of the formula (I) according to any one of claims 1 to 11, wherein R 1 is selected from a hydrogen atom, an alkyl group and an alkoxy group, preferably an alkoxy group; n is 0 or 1.
The compound of the formula (I) according to any one of claims 1 to 12, wherein R 2 is a hydrogen atom or an alkyl group; R 3 is the same or different and each is independently selected from a hydrogen atom. , alkyl and alkoxy.
The compound of the formula (I) according to any one of claims 1 to 13, wherein the X is O.
The compound of the formula (I) according to any one of claims 1 to 14, wherein R 4 and R 5 are the same or different and each independently is a hydrogen atom.
The compound of the formula (I) according to any one of claims 1 to 15, wherein the R 7 is selected from the group consisting of a hydrogen atom, a halogen and an alkyl group.
The compound of the formula (I) according to any one of claims 1 to 16, which is selected from the group consisting of:
A compound of the formula (IA):

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

M is selected from the group consisting of halogen, -OH and -OS(O) 2 R 13 ;

X is an O atom or an S atom;

Ring B is a heteroaryl group;

R 1 is the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, and a hetero group. a cycloalkyl, aryl and heteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halo, alkyl, alkoxy, haloalkyl Substituting one or more substituents of a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R 2 is selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl base;

R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, and a hetero group. a cyclic group, an aryl group and a heteroaryl group;

R 4 and R 5 are the same or different and are each independently a hydrogen atom or an alkyl group;

R 13 is selected from the group consisting of alkyl, amino, NR 14 R 15 and cycloalkyl;

R 14 and R 15 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

Or R 14 and R 15 together with the attached nitrogen atom form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different selected from N atom, O in addition to 1 nitrogen atom. a hetero atom of an atom and an S atom, and said heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl Substituting one or more substituents in a heterocyclic group, an aryl group, and a heteroaryl group;

n is 0, 1, 2 or 3;

s is 0, 1, 2, 3 or 4.
A compound of the formula (IA) according to claim 18 which is of the formula (IIA):

Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

G is N atom, CR 3 or CH;

Y is an S atom, an O atom or CH=CH;

M, X, R 1 to R 5 , n and s are as defined in claim 18.
A compound of the formula (IA) according to claim 18 or 19, which is selected from the group consisting of:
A method of preparing a compound of the formula (I) according to claim 1, the method comprising:

A compound of the formula (IA) is reacted with a compound of the formula (IB) to give a compound of the formula (I),

among them:

M is selected from the group consisting of halogen, -OH and -OS(O) 2 R 13 ;

R 13 is selected from the group consisting of alkyl, amino, -NR 14 R 15 and cycloalkyl;

R 14 and R 15 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

Or R 14 and R 15 together with the attached nitrogen atom form a heterocyclic group, wherein the heterocyclic group optionally contains 1 to 2 identical or different selected from N atom, O in addition to 1 nitrogen atom. a hetero atom of an atom and an S atom, and said heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl Substituting one or more substituents in a heterocyclic group, an aryl group, and a heteroaryl group;

Ring A, Ring B, W, X, R 1 to R 7 , n, s and p are as defined in claim 1.
A pharmaceutical composition comprising the compound of the formula (I) according to any one of claims 1 to 17, or a tautomer thereof, a mesogen, a racemic form thereof a form, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
The compound of the formula (I) according to any one of claims 1 to 17, or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Use of a construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, in the manufacture of a medicament for antagonizing PAR-4.
The compound of the formula (I) according to any one of claims 1 to 17, or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Use of a construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, for the manufacture of a medicament for the treatment or prevention of platelet aggregation.
The compound of the formula (I) according to any one of claims 1 to 17, or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Use of a construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, for the preparation of a medicament for the treatment or prevention of a thromboembolic disorder, preferably said thromboembolism The disease is selected from the group consisting of arterial cardiovascular thromboembolic disease, venous cardiovascular thromboembolic disease, cerebrovascular thromboembolic disease, and thromboembolic disease in the heart or peripheral circulation.