CN111349105B

CN111349105B - Benzofuran derivative, preparation method and medical application thereof

Info

Publication number: CN111349105B
Application number: CN201911334136.5A
Authority: CN
Inventors: 杨方龙; 张羚; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2018-12-24
Filing date: 2019-12-23
Publication date: 2023-04-07
Anticipated expiration: 2039-12-23
Also published as: CN111349105A

Abstract

The invention relates to benzofuran derivatives, a preparation method and application thereof in medicines. In particular to a novel benzofuran derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative and application thereof as a therapeutic agent, in particular as a PAR-4 antagonist, wherein each substituent in the general formula (I) is as defined in the specification.

Description

Benzofuran derivative, preparation method and medical application thereof

Technical Field

The invention belongs to the field of medicines, and relates to a novel benzofuran derivative shown as a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and application of the derivative as a therapeutic agent, in particular as a PAR-4 antagonist.

Background

Protease Activated Receptors (PARs), a G protein-coupled receptor on the cell surface, belong to one of the members of the G protein-coupled receptor superfamily. Like other types of G protein-coupled receptors, protease-activated receptors also have a single-chain seven-transmembrane character. As one of the major receptors on the platelet surface, a total of four protease-activated receptors of this family have been discovered so far, named PAR-1, PAR-2, PAR-3 and PAR-4, respectively. Human platelets express PAR-1 and PAR-4, while murine platelets express PAR-3 and PAR-4 but not PAR-1.

The researchers discovered PAR-4 in 1998 and further cloned the PAR-4 gene and obtained its sequence from lymphoma cells to a total length of 4.9kb (e.g., 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 comprises 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, while fluorescence in situ hybridization experiments show that the human PAR-4 gene is located on chromosome 19p 12. Unlike the PAR-1 and PAR-3 binding sites, PAR-4 has no procoagulant hirudin-like binding site and has a lower affinity for thrombin than PAR-1 and PAR-3. Thus, higher concentrations of thrombin are required in order to activate PAR-4.

The activation principle of PAR-4 is: thrombin first binds to the extracellular N-terminus of PAR-4, cleaving the N-terminal arginine 47/glycine 48 to generate a new N-terminal tet-locking ligand, GYPGQV, which binds to the second extracellular domain and activates the receptor causing a series of signal transduction. In addition, the artificially synthesized polypeptide fragment GYPGQV (hPAR-4) or AYPGKF (mPAR-4) at the end of the targeting ligand can also directly activate PAR-4 (e.g., tatjana, F. Et al, J.biol.chem.275:19728-19734 (2000)).

The two thrombin receptors, PAR-1 and PAR-4, expressed by human platelets, are among the targets of antithrombotic drugs. In 5 months 2014, PAR-1 small molecule antagonist Vorapaxar, approved by the FDA for the prevention of thrombosis, is currently the only drug that treats thrombosis by antagonizing thrombin receptor activity (e.g., french, s. Et al, blood reviews.29:179-189 (2015)). However, antithrombotic agents targeting the PAR-1 receptor often lead to bleeding, and therefore Vorapaxar cannot be used in patients with cerebral hemorrhage. Research in recent years has found that the risk of bleeding is relatively low for antagonizing PAR-4 as compared to antagonizing PAR-1, and therefore small molecule antagonists of PAR-4 are considered to be potential, safer and more effective antithrombotic agents.

PAR-4 is expressed mainly in lung, pancreas, thyroid, testis, and small intestine, and is moderately expressed in the digestive tract. In addition to being associated with thrombosis, PAR-4 is involved in other important processes, such as regulation of vascular activity, mediation of cytokines, release of inflammatory mediators and regulation of the immune system. The main coupling pathway for signal transduction between PAR-4 and G protein subunits is activation of phospholipase C (PLC) by G protein Gq, leading to the production of inositol triphosphate (IP 3) and Diacylglycerol (DAG) leading to intracellular Ca ²⁺ Mobilization, and activation of Protein Kinase C (PKC). At the same time, PAR-4 can be activated by a variety of serine proteases and plays a role in regulating edema (via the kallikrein-kinin system) and in the recruitment of neutrophils in the inflammatory response.

It would therefore be desirable to develop antagonists to PAR-4 to prevent and/or treat thrombosis or a patient with a history of myocardial infarction or peripheral arterial disease for reducing thrombotic cardiovascular events. Published patent applications for antagonists of the PAR-4 receptor include WO2013163241, WO2013163244, WO2013163279, WO2016134450, WO2016138199, WO2017019828, WO2017066661, WO2017066683, and WO2017184520, among others.

Disclosure of Invention

The invention aims to provide a compound shown as a general formula (I) or a stereoisomer, a tautomer, a meso form, a racemate, an enantiomer, a diastereoisomer, a mixture form or a pharmaceutically acceptable salt form thereof:

wherein:

w is O or S;

L ¹ is a covalent bond or-CR ⁶ R ⁷ -；

Ring a is a 5-membered heteroaryl;

ring B is selected from aryl or heteroaryl;

y is selected from S or-CR ^a ＝CR ^b -；

R ^a And R ^b 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, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ^w is-alkylene-NR ⁸ R ⁹ Wherein said alkylene is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ¹ the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ² selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R ³ is alkyl or haloalkyl;

R ⁴ the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ⁵ 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, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ⁶ and R ⁷ 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, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ⁸ and R ⁹ 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, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

or, R ⁸ And R ⁹ Together with the nitrogen atom to which they are attached form a heterocyclic group, wherein said heterocyclic group optionally contains, in addition to 1 nitrogen atom, 0 to 2 heteroatoms, which may be the same or different, selected from N, O and S, and said heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, -C (O) R ¹⁰ Heterocyclyl, aryl and heteroaryl;

R ¹⁰ selected from alkyl, alkoxy, haloalkyl or cycloalkyl;

n is 0,1, 2 or 3;

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

p is 0,1 or 2.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is represented by formula (I) ^w Is- (CR) ¹¹ R ¹² ) _t -NR ⁸ R ⁹ ；R ¹¹ And R ¹² The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl; t is 1,2 or 3; r is ⁸ And R ⁹ As defined in formula (I).

In a preferred embodiment of the present invention, the compound of formula (I) or a stereoisomer, a tautomer, a meso, a racemic, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II) or a stereoisomer, a tautomer, a meso, a racemic, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

wherein:

ring A, ring B, Y, R ¹ ～R ⁹ N, s and p are as defined in formula (I).

In a preferred embodiment of the invention, the compound of formula (I) or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is a 5-membered heteroaryl group, optionally containing 1 to 3 heteroatoms, which may be the same or different, selected from N, O and S, preferably ring a is selected from thiazolyl, pyrazolyl and imidazolyl.

In a preferred embodiment of the invention, the compound of formula (I) or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl or a 5-to 6-membered heteroaryl group, optionally containing 1 to 3 identical or different heteroatoms selected from N, O and S, preferably ring B is phenyl.

In a preferred embodiment of the present invention, the compound of formula (I) or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ³ Is C _1-6 An alkyl group; preferably methyl.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is represented by formula (I) ⁶ And R ⁷ Is a hydrogen atom.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a stereoisomer, a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, a mixture thereof, or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a stereoisomer, a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁸ 、R ⁹ y, n and s are as defined in formula (III).

In a preferred embodiment of the present invention, the compound of formula (I) or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y is S; r ² Is a hydrogen atom.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is represented by formula (I) ¹ Are the same or different and are each independently selected from a hydrogen atom, an alkyl group or an alkoxy group; alkoxy groups are preferred.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a stereoisomer, a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, a mixture thereof, or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV) or a stereoisomer, a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, a mixture thereof, or a pharmaceutically acceptable salt thereof:

/>

wherein:

m is O or NR ¹⁴ ；

R ¹³ The same or different, and each is independently selected from the group consisting of alkyl, alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ¹⁴ selected from hydrogen atoms, alkyl groups or-C (O) R ¹⁰ ；

q is 0,1 or 2;

R ⁴ 、R ⁵ 、R ¹⁰ and s is as defined in formula (I).

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is represented by formula (I) ⁴ Is a hydrogen atom or an alkyl group.

In a preferred embodiment of the present invention, the compound of formula (I) or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ⁵ Is a hydrogen atom.

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

/>

/>

/>

/>

/>

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to a compound of formula (IIA) or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein: ring A, ring B, Y, R ¹ ～R ⁷ N, s and p are as defined in formula (II).

Another preferred embodiment of the present invention relates to a compound of formula (IIA) or a stereoisomer, a tautomer, a meso, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (IIIA) or a stereoisomer, a tautomer, a meso, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

/>

wherein:

R ¹ 、R ² 、R ⁴ 、R ⁵ y, n and s are as defined in formula (IIA).

Another preferred embodiment of the present invention relates to a compound of formula (IIA) or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is represented by formula (IVA) or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R ⁴ 、R ⁵ and s is as defined in formula (IIA).

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

/>

another aspect of the present invention relates to a process for preparing a compound of formula (IV) or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

reacting compound 1k with a compound of formula (IVB) to give a compound of formula (IV),

wherein:

x is a leaving group, preferably halogen and-OSO ₂ CH ₃ ；

R ⁴ 、R ⁵ 、R ¹³ M, s and q are as defined in formula (I).

Another aspect of the present invention relates to a method of preparing a compound of formula (II) or a stereoisomer, tautomer, meso, racemic, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

a compound of formula (IIA) and HNR ⁸ R ⁹ Reacting in the presence of a reducing agent to give a compound of the general formula (II),

wherein:

the reducing agent is preferably sodium triacetoxyborohydride;

ring A, ring B, Y, R ¹ ～R ⁹ N, s and p are as defined in formula (II).

Another aspect of the present invention relates to a process for preparing a compound of formula (III) or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

a compound of formula (IIIA) and HNR ⁸ R ⁹ Reacting in the presence of a reducing agent to give a compound of the general formula (III),

wherein:

the reducing agent is preferably sodium triacetoxyborohydride;

R ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁸ 、R ⁹ y, n and s are as defined in formula (III)And (5) defining.

a compound of the formula (IVA) and

reacting in the presence of a reducing agent to give a compound of the general formula (IV),

wherein:

the reducing agent is preferably sodium triacetoxyborohydride;

R ⁴ 、R ⁵ 、R ¹³ m, s and q are as defined in formula (IV).

Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable carriers, diluents and excipients.

Another aspect of the present invention relates to a compound of general formula (I) or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, for use as a medicament.

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

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

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

Another aspect of the present invention relates to the use of a compound of formula (I) or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, for the manufacture of a medicament for the treatment or prophylaxis of a thromboembolic disorder, wherein the thromboembolic disorder is preferably selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, cerebrovascular thromboembolic disorders, and thromboembolic disorders in the heart chambers or in the peripheral circulation.

Another aspect of the present invention relates to a method for treating or preventing diseases of platelet aggregation, which comprises administering to a patient a therapeutically effective dose of a compound represented by the general formula (I) or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

Another aspect of the present invention relates to a method for treating or preventing thromboembolic disorders, comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein said thromboembolic disorders are preferably selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, cerebrovascular thromboembolic disorders, and thromboembolic disorders in the heart chambers or peripheral circulation.

The dosage of the compound or composition used in the methods of treatment of the present invention 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 0.1 to 1000mg.

The pharmaceutical compositions of the invention may contain, in addition to the active compound, one or more adjuvants selected from the following: fillers (diluents), binders, wetting agents, disintegrants, excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents, and these tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or an oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. 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.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, 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 oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present 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 oil phase, the injection or microemulsion being injectable in the bloodstream of the patient by local bolus injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.

The pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

The compounds of the present invention may be administered in the form of suppositories 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 therefore will melt in the rectum to release the drug. Such materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health condition of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, and the like; in addition, the optimal treatment regimen, such as the mode of treatment, the daily amount of compound (I) of the formula or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Detailed description of the invention

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-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-methylhexyl, 3-methylhexyl, 4-methylhexyl, and the like 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched chain isomers thereof, and the like. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-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, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, independently optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, mercapto, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group having 2 residues derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, and is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkylene group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups 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-butylidene (-CH) ₂ CH ₂ CH ₂ CH ₂ -) and 1,5-butylene (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₂ -) and the like. The alkylene group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently optionally selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio,Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

The term "alkoxy" refers to the groups-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. Alkoxy may be optionally substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, independently optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, mercapto, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms or 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms (e.g., 3,4,5 or 6 carbon atoms), and most preferably 5 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyls depending on the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl groups. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

said cycloalkyl ring including a cycloalkyl ring as described above fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like; preferably phenyl and cyclopentyl, tetrahydronaphthyl. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, independently optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, mercapto, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) _m (wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably 4 to 6 ring atoms, of which 1-2 or 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, azetidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, with tetrahydropyranyl, piperidinyl, pyrrolidinyl, azetidinyl being preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to 5 to 20 membered polycyclic heterocyclic group having one atom in common between monocyclic rings (called spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) _m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered,A 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono spiroheterocyclyl group. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) _m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O) _m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

such heterocyclyl groups include those wherein the above-described heterocyclyl group is fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:

and the like.

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

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. Such aryl rings include those wherein the above-described aryl group is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, independently optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, mercapto, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g. 5, 6, 7, 8, 9 or 10 membered) containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferred are, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, 1H-1,2,3-triazolyl, 4H-1,2,4-triazolyl, 4H-1,2,3-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 5H-tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, pyridazinyl and the like, preferably thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl or imidazolyl. Such heteroaryl rings include those wherein the heteroaryl group described above is fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:

heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, independently optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, mercapto, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is 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" refers to fluorine, chlorine, bromine or iodine.

The term "amino" refers to the group-NH ₂ 。

The term "cyano" refers to — CN.

The term "nitro" means-NO ₂ 。

The term "oxo" means = O.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more 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 facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.

The present invention provides novel PAR-4 inhibitors having the general formula (I), in particular the R thereof ^w is-alkylene-NR ⁸ R ⁹ Compared with the compound in the prior art, the compound has the characteristic of good drug absorption, and the drug absorption is also obviously increased along with the increase of the dosage.

Synthesis of the Compounds of the invention

In order to achieve the purpose of the invention, the invention adopts the following technical scheme:

scheme one

The invention relates to a method for preparing a compound shown as a general formula (IV) or a stereoisomer, a tautomer, a meso form, a racemate, an enantiomer, a diastereoisomer or a mixture form thereof, or a pharmaceutically acceptable salt form thereof, which comprises the following steps:

reacting the compound 1k with a compound of the general formula (IVB) under alkaline conditions to obtain a compound of the general formula (IV),

wherein:

x is halogen;

R ⁴ 、R ⁵ 、R ¹³ m, s and q are as defined in formula (I).

The reagents that provide basic conditions include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, lithium bistrimethylsilylamide, potassium acetate, sodium t-butoxide, potassium t-butoxide, and sodium N-butoxide, and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, and lithium hydroxide, preferably cesium carbonate;

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, N-dimethylacetamide, water or N, N-dimethylformamide, and mixtures thereof.

Scheme two

The invention relates to a method for preparing a compound shown as a general formula (II) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises the following steps:

wherein:

the reducing agent includes but is not limited to sodium triacetoxyborohydride, sodium cyanoborohydride and sodium borohydride;

ring A, ring B, Y, R ¹ ～R ⁹ N, s and p are as defined in formula (II).

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

Scheme three

The invention relates to a method for preparing a compound shown as a general formula (III) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises the following steps:

wherein:

Scheme four

The invention relates to a method for preparing a compound shown as a general formula (IV) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises the following steps:

a compound of the general formula (IVA) and

wherein:

R ⁴ 、R ⁵ 、R ¹³ m, s and q are as defined in formula (IV).

Detailed Description

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard Tetramethylsilane (TMS).

MS was determined using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: thermo, model: finnigan LCQ advantage MAX).

High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC1200 DAD, agilent HPLC1200VWD and Waters HPLC e2695-2489 HPLC.

Chiral HPLC assay using Agilent 1260DAD HPLC.

High Performance liquid preparation Waters 2767, waters 2767-SQ Detector 2, shimadzu LC-20AP and Gilson-281 preparative chromatographs were used.

Chiral preparation was performed using Shimadzu LC-20AP preparative chromatograph.

The CombiFlash rapid preparation instrument uses CombiFlash Rf200 (TELEDYNE ISCO).

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

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

Average inhibition rate of kinase and IC ₅₀ The values were determined with a NovoStar microplate reader (BMG, germany).

Known starting materials for the present invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, acros Organics, aldrich Chemical Company, shaoyuan ChemBiotech (Accela ChemBio Inc), darril Chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

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

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction uses a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

The microwave reaction was carried out using a CEM Discover-S908860 microwave reactor.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: n-hexane/dichloromethane system, D: ethyl acetate/dichloromethane/n-hexane, E: ethyl acetate/dichloromethane/methanol, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

4- (4- (4- (((6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxy) methyl) -5-methylthiazol-2-yl) benzyl) morpholine 1

First step of

2-bromo-5-methylthiazole-4-carboxylic acid methyl ester 1b

2-bromo-5-methylthiazole-4-carboxylic acid 1a (700mg, 3.15mmol, shanghai Biao pharmaceutical science Co., ltd.) was dissolved in 15mL of methanol under argon atmosphere, concentrated sulfuric acid (10mg, 102.04mmol) was added to the reaction system, the mixture was heated to 65 ℃ in an oil bath, and the reaction was continued with stirring for 18 hours. The reaction was cooled and the reaction was concentrated under reduced pressure to give the crude title compound 1b (744 mg) which was directly used in the next reaction without purification.

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

Second step of

2- (4-formylphenyl) -5-methylthiazole-4-carboxylic acid methyl ester 1d

Crude compound 1b (750mg, 3.18mmol), 4-formylphenylboronic acid 1c (572mg, 3.81mmol, shaoyuan Shanghai technology, ltd.), tetrakis (triphenylphosphine) palladium (185mg, 0.116mmol) and sodium carbonate (675mg, 6.37mmol) were dissolved in 10mL1, 4-dioxane and 2mL of water and reacted at 120 ℃ for 0.5 hour by microwave under an argon atmosphere. To the reaction solution was added 20mL of water, and a solid was precipitated and filtered to dry to obtain the title compound 1d (0.6 g, yield: 72%).

MS m/z(ESI):262.1[M+1]

The third step

5-methyl-2- (4- (morpholinomethyl) phenyl) thiazole-4-carboxylic acid methyl ester 1f

Compound 1d (200.0 mg, 765.42umol) and morpholine 1e (67.0 mg, 0.77mmol) were dissolved in 10mL of dichloromethane under nitrogen, sodium triacetoxyborohydride (324.0 mg, 1.53mmol) was added, and the mixture was stirred at room temperature for 16 hours. To the reaction solution were added 20mL of water and a saturated sodium carbonate solution to a reaction solution pH of 8 to 10, followed by extraction with methylene chloride (30 mL. Times.3), combination of organic phases, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system B to give the title compound 1f (209.0 mg, yield: 82%).

MS m/z(ESI):333.4[M+1]

The fourth step

(5-methyl-2- (4- (morpholinomethyl) phenyl) thiazol-4-yl) methanol 1g

Compound 1f (209.0 mg, 0.63mmol) was dissolved in 10mL of tetrahydrofuran, and lithium aluminum hydride (95.0 mg, 2.50mmol) was added thereto at 0 ℃ and stirred for 1 hour. To the reaction solution was added 2M sodium hydroxide solution. The pad was filtered through celite and the filter cake was washed with ethyl acetate (100 mL). The filtrate was washed with water and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system B gave the title compound 1g (190.0 mg, yield: 99%).

MS m/z(ESI):305.2[M+1]

The fifth step

4- (4- (4- (chloromethyl) -5-methylthiazol-2-yl) benzyl) morpholine hydrochloride for 1h

After 1g (50.0 mg,0.16 mmol) of the compound was dissolved in 10mL of dichloromethane, thionyl chloride (391.0 mg, 3.29mmol) was slowly added under ice-bath conditions, and the reaction was stirred for 20 minutes. The reaction solution was concentrated under reduced pressure, 10mL of a mixed solvent of dichloromethane and n-hexane (V: V = 1) was added, slurried, and filtered to obtain the title compound 1h (53.0 mg, yield: 89%).

MS m/z(ESI):323.2[M+1]

The sixth step

6- (4-benzyloxy) -6-methoxybenzofuran-2-yl) -2-methylimidazo [2,1-b ] [1,3,4] thiadiazole 1j

1- (4- (benzyloxy) -6-methoxybenzofuran-2-yl) -2-bromoethan-1-one 1i (6.00g, 16.00mmol) (prepared by the method disclosed in patent application "WO 2013163244") and 5-methyl-1,3,4-thiadiazole-2-amine (3.68g, 31.96mmol, shaoyuan technologies (Shanghai) Co., ltd.) were added to 150mL of isopropanol and reacted in a tempered sealed bottle at 130 ℃ for 20 hours. After cooling, a solid precipitated and was filtered. Drying gave the title compound 1j (5.28 g, yield: 84%).

MS m/z(ESI):392.1[M+1]

Seventh step

6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-ol 1k

Compound 1j (5.28g, 13.49mmol) and 1,2,3,4,5-pentamethylbenzene (12.0g, 80.95mmol, shaoyuan technology (Shanghai) Co., ltd.) were dissolved in 150mL of dichloromethane, cooled to-78 ℃, and 40.4mL of 1M boron trichloride was added dropwise, followed by further reaction for 40 minutes. To the reaction mixture was slowly added 100mL of saturated ammonium chloride solution, 200mL of dichloromethane was added, stirring was carried out, methanol (50 mL) was added, extraction was carried out with dichloromethane (200 mL. Times.2), the organic phases were combined, and the organic phase was concentrated under reduced pressure. The resulting compound was slurried with methanol (10 mL) and filtered to give the title compound 1k (2.1 g, yield: 51%).

MS m/z(ESI):302.1[M+1]

The eighth step

Compound 1k (50.0 mg, 0.17mmol), compound 1h (53.0 mg,0.10 5 mmol) and cesium carbonate (162.0 mg, 0.50mmol) were dissolved in 3.0mL of N, N-dimethylformamide under an argon atmosphere, reacted at 60 ℃ for 0.5 hour, and after adding potassium iodide (27.0 mg, 0.16mmol), the reaction was continued for 2 hours. To the reaction solution was added 10mL of water, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 1 (63.0 mg, yield: 64%).

MS m/z(ESI):588.2[M+1]

¹ H NMR(400MHz,CDCl ₃ )δ8.00(s,1H),7.91(d,2H),7.48(brs,2H),7.12(d,1H),6.73(d,1H),6.59(d,1H),5.34(s,2H),3.87(s,3H),3.81-3.66(m,6H),2.75(s,3H),2.59(brs,7H)。

Example 2

Cyclopropyl (4- (4- (4- (((6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxy) methyl) -5-methylthiazol-2-yl) benzyl) piperazin-1-yl) methanone 2

First step of

(2-bromo-5-methylthiazol-4-yl) methanol 2b

2-bromo-5-methylthiazole-4-carboxylic acid ethyl ester 2a (1.25g, 4.99mmol, shaoyuan technologies (Shanghai) Co., ltd.) was dissolved in 10mL of tetrahydrofuran, the reaction solution was stirred to be clear, cooled to-78 ℃, diisobutylaluminum hydride (1.5M, 9.95mmol) was added dropwise, the reaction was continued for 1 hour, 1M hydrochloric acid (70 mL) was slowly added dropwise, 60mL of water was added thereto and stirred, ethyl acetate (60 mL. Times.2) was added thereto for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2B (390 mg, yield: 37.5%).

MS m/z(ESI):208.0[M+1]

Second step of

2-bromo-4- (chloromethyl) -5-methylthiazole 2c

Compound 2b (212mg, 1.01mmol) was dissolved in 5mL of dichloromethane, stirred, thionyl chloride (363mg, 3.05mmol) was added at 0 ℃ and the reaction was continued for 1 hour, and the reaction solution was concentrated under reduced pressure to give crude title compound 2c (230 mg) which was subjected to the next reaction without purification.

MS m/z(ESI):225.9[M+1]

The third step

6- (4- ((2-bromo-5-methylthiazol-4-yl) methoxy) -6-methoxybenzofuran-2-yl) -2-methylimidazo [2,1-b ] [1,3,4] thiadiazole 2d

Crude compound 2c (223mg, 0.98mmol) was dissolved in 10mL of N, N-dimethylformamide under an argon atmosphere, stirred, and compound 1k (297mg, 0.98mmol), cesium carbonate (1.60g, 4.91mmol) and potassium iodide (24551 mmol) were added at room temperature and reacted at 60 ℃ for 1 hour. The reaction liquid was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 2d (350 mg, yield: 72.2%). MS m/z (ESI) 491.0[ M +1]

The fourth step

4- (4- (((6-methoxy-2- (2-methylimidazole [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxy) methyl) -5-methylthiazol-2-yl) benzaldehyde 2e

Compound 2d (350mg, 0.71mmol) was dissolved in 10mL of 1, 4-dioxane under an argon atmosphere, 2mL of water was added, and stirring was carried out, and then Compound 1c (128mg, 0.85mmol), sodium carbonate (226mg, 2.13mmol) and tetrakis (triphenylphosphine) palladium (41mg, 0.04mmol) were added, and the reaction was carried out at 100 ℃ for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 2e (260 mg, yield: 70.6%).

MS m/z(ESI):517.1[M+1]

The fifth step

4- (Cyclopropylcarbonyl) piperazine-1-carboxylic acid tert-butyl ester 2g

Piperazine-1-carboxylic acid tert-butyl ester 2f (500mg, 2.69mmol, adamas) and potassium carbonate (743mg, 5.38mmol) were added to 20mL of dichloromethane, cooled to 0 deg.C, and cyclopropylcarbonyl chloride (309mg, 2.96mmol, shaoyuan technologies, ltd.) was added dropwise to the reaction system, allowed to naturally warm to room temperature, and the reaction was stirred for 3 hours. To the reaction system was added 10mL of dichloromethane, followed by washing with a citric acid solution (10 mL) (m/m = 10%), and the organic phase was washed with a saturated sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2g of the title compound (590 mg, yield: 86.4%).

MS m/z(ESI):255.2[M+1]

The sixth step

Cyclopropyl (piperazin-1-yl) methanone 2h

2g (590mg, 2.32mmol) of the compound was dissolved in 20mL of methylene chloride, and 5.8mL of a 4M hydrogen chloride solution in 1,4-dioxane was added to the above system, and the reaction was vigorously stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude title compound 2h (410 mg), which was directly used in the next reaction without purification.

MS m/z(ESI):155.2[M+1]

Step seven

Compound 2h (14mg, 0.09mmol) and compound 2e (30mg, 0.06mmol) were dissolved in 20mL of dichloromethane under a nitrogen atmosphere, sodium triacetoxyborohydride (37mg, 0.18mmol) was added to the above reaction system, and the reaction was continued with stirring for 18 hours. The reaction liquid was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 2 (15 mg, yield: 39.4%).

MS m/z(ESI):655.2[M+1]

¹ H NMR(400MHz,CDCl ₃ )δ7.79(s,1H),7.87(d,2H),7.39(d,2H),7.10(s,1H),6.70(s,1H),6.56(s,1H),5.31(s,2H),3.85(s,3H),3.68(s,4H),3.57(s,2H),2.71(s,3H),2.56(s,3H),2.48(s,4H),1.75-1.69(m,1H),1.01-0.96(m,2H),0.77-0.73(m,2H)。

Example 3

4- (4- (4- (((6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxy) methyl) thiazol-2-yl) benzyl) morpholine 3

First step of

2- (4- (Morpholinylmethyl) phenyl) thiazole-4-carboxylic acid ethyl ester 3b

Ethyl 2- (4-formylphenyl) thiazole-4-carboxylate 3a (200mg,0.77mmol, prepared by the method disclosed in patent application "U.S. Pat. No. 5, 6200978 (B1)") was dissolved in 20mL of dichloromethane under argon atmosphere, compound 1e (67mg,0.77mmol) was added, and sodium triacetoxyborohydride (324mg,1.53mmol) was added and stirred for 16 hours. The reaction solution was concentrated under reduced pressure to give crude compound 3b (254 mg, product was directly subjected to the next reaction without purification).

MS m/z(ESI):333.1[M+1]

Second step of

2- (4- (morpholinomethyl) phenyl) thiazol-4-yl) methanol 3c

Crude compound 3b (254mg, 0.77mmol) was dissolved in 10mL tetrahydrofuran, cooled to 0 deg.C, lithium aluminum hydride (35mg, 1.03mmol) was added and stirring continued for 0.5 h. 1mL of water was added to the reaction solution, dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure to give crude compound 3c (221 mg), which was directly subjected to the next reaction without purification.

MS m/z(ESI):291.1[M+1]

The third step

(2- (4- (morpholinomethyl) phenyl) thiazol-4-yl) methyl methanesulfonate 3d

Crude compound 3c (50mg, 0.17mmol) was dissolved in 20mL of dichloromethane, triethylamine (50mg, 0.49mmol) was added, cooled to 0 deg.C for reaction, methanesulfonyl chloride (30mg, 0.26mmol) was added, and stirred for 0.5 h. To the reaction solution was added 20mL of water, extracted with dichloromethane (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 3d (63 mg), which was used in the next reaction without purification. MS m/z (ESI) 369.1[ 2 ] M +1]

The fourth step

Compound 1k (33mg, 0.11mmol) was dissolved in 5mL of N, N-dimethylformamide, and compound 3d (63mg, 0.17mmol) and cesium carbonate (100mg, 0.31mmol) were added and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 3 (22 mg, yield: 35%).

MS m/z(ESI):574.2[M+1]

¹ H NMR(400MHz,CDCl ₃ )δ8.00(s,1H),7.95(d,2H),7.53-7.45(m,2H),7.38(s,1H),7.17(s,1H),6.72(s,1H),6.47(s,1H),5.40(s,2H),3.86(s,3H),3.81(brs,4H),3.67(s,2H),2.74(s,3H),2.57(brs,4H)。

Example 4

1- (4- (4- (4- (((6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxy) methyl) -5-methylthiazol-2-yl) phenyl) -N, N-dimethylmethylamine 4

Compound 2e (29mg, 0.06mmol) was dissolved in 10mL of dichloromethane under argon atmosphere, and dimethylamine (12mg, 0.27mmol, shaoshima technologies (Shanghai) Co., ltd.) and sodium triacetoxyborohydride (178mg, 0.84mmol) were added and reacted for 12 hours. To the reaction solution was added 10mL of ice water, extracted with dichloromethane (30 mL. Times.3), the organic phases were combined, washed with saturated sodium carbonate solution (15 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 4 (15 mg, yield: 49%).

MS m/z(ESI):546.2[M+1]

¹ H NMR(400MHz,CDCl ₃ )δ8.09-7.95(m,3H),7.68(d,2H),7.21(s,1H),6.70(s,1H),6.56(s,1H),5.32(s,2H),4.18(s,2H),3.85(s,3H),2.76(d,9H),2.59(s,3H)。

Example 5

1- (4- (4- (4- (((6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxy) methyl) -5-methylthiazol-2-yl) benzyl) piperazin-1-yl) propan-1-one 5

First step of

4-Propoylpiperazine-1-carboxylic acid tert-butyl ester 5a

Compound 2f (500mg, 2.68mmol) was dissolved in 15mL of dichloromethane, stirred, triethylamine (1.35g, 13.34mmol) and propionyl chloride (372.5mg, 4.02mmol) were added at 0 ℃ and the reaction was continued for 2 hours. To the reaction solution, 30mL of water was added, dichloromethane (60 mL. Times.2) was added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 5a (600 mg, yield: 92.2%).

MS m/z(ESI):243.2[M+1]

Second step of

1- (piperazin-1-yl) propan-1-one 5b

Compound 5a (600mg, 2.47mmol) was dissolved in 20mL of dichloromethane and stirred. A2M solution of hydrogen chloride in ethyl acetate (15.90 mmol) was added at 0 deg.C, stirred at room temperature for 3 hours, and the reaction was concentrated under reduced pressure to give the crude title compound 5b (400 mg) which was used in the next reaction without purification.

MS m/z(ESI):143.2[M+1]

The third step

Compound 2e (30mg, 0.06mmol) was dissolved in 10mL of dichloromethane under argon, and crude compound 5b (25mg, 0.17mmol) and sodium triacetoxyborohydride (36mg, 0.17mmol) were added and reacted for 12 hours. To the reaction solution was added 10mL of ice water, dichloromethane extraction (30 mL × 3) was performed, and the organic phases were combined, washed with saturated sodium carbonate solution (15 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to obtain the title compound 5 (15 mg, yield:

40.1％)。

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

¹ H NMR(400MHz,CDCl ₃ )δ7.97(s,1H),7.88(d,2H),7.43(s,2H),7.10(s,1H),6.70(s,1H),6.55(s,1H),5.31(s,2H),3.84(s,3H),3.46-3.63(m,6H),2.71(s,3H),2.56(s,3H),2.44(s,2H),2.32-2.34(m,2H),1.28-1.31(m,2H),1.12-1.16(m,3H)。

example 6

6- (6-methoxy-4- ((5-methyl-2- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) thiazol-4-yl) methoxy) benzofuran-2-yl) -2-methylimidazo [2,1-b ] [1,3,4] thiadiazole 6

First step of

5-methyl-2- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) thiazole-4-carboxylic acid methyl ester 6a

Compound 1d (200mg, 0.76mmol) was dissolved in 20mL of dichloromethane under argon atmosphere, methylpiperazine (91mg, 0.91mmol) and sodium triacetoxyborohydride (243mg, 1.15mmol) were added, and reaction was carried out for 12 hours. To the reaction solution was added 100mL of dichloromethane, saturated sodium carbonate solution was added to make the reaction solution pH 8 to 10, ethyl acetate was extracted (60 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to obtain the title compound 6a (160 mg, yield: 60.5%).

MS m/z(ESI):346.2[M+1]

Second step of

(5-methyl-2- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) thiazol-4-yl) methanol 6b

Compound 6a (160mg, 0.46mmol) was dissolved in 10mL of tetrahydrofuran, stirred at room temperature, cooled to 0 deg.C, and lithium aluminum hydride (30mg, 0.79mmol) was added in portions and the reaction was continued for 2 hours. To the reaction mixture was slowly dropped 0.06mL of a saturated ammonium chloride solution, stirred at room temperature for 10 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 6b (100 mg, yield: 68.0%).

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

The third step

4- (chloromethyl) -5-methyl-2- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) thiazole 6c

Compound 6b (50mg, 0.16mmol) was dissolved in 10mL of dichloromethane and stirred, and thionyl chloride (492mg, 4.14mmol) was added thereto at 0 ℃ to continue the reaction for 40 minutes. The reaction solution was concentrated under reduced pressure to give the title compound 6c (40 mg, yield: 75.6%).

MS m/z(ESI):335.9[M+1]

The fourth step

Compound 6c (40mg, 0.12mmol) was dissolved in 8mL of N, N-dimethylformamide under an argon atmosphere, stirred, and then compound 1k (35mg, 0.12mmol), cesium carbonate (189mg, 0.58mmol) and potassium iodide (20mg, 0.12mmol) were added to the solution to react at 60 ℃ for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 6 (35 mg, yield: 50.1%).

MS m/z(ESI):601.2[M+1]

¹ H NMR(400MHz,CDCl ₃ )δ7.97(s,1H),7.89(d,2H),7.43(d,2H),7.09(s,1H),6.70(s,1H),6.55(s,1H),5.30(s,2H),3.85(s,3H),3.77(s,2H),3.46-3.54(m,2H),3.06-3.20(m,6H),2.79(s,3H),2.72(s,3H),2.56(s,3H)。

Example 7

(R) - (4- (4- (4- (((6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxy) methyl) -5-methylthiazol-2-yl) benzyl) morpholin-3-yl) methanol 7

Compound 2e (28mg, 0.05mmol) was dissolved in 10mL of dichloromethane under argon, and (R) -3-hydroxymethylmorpholine (11mg, 0.09mmol, from Shanghai Bigdi, pharmaceutical science, co., ltd.) and sodium triacetoxyborohydride (50mg, 0.24mmol) were added and reacted for 12 hours. To the reaction solution was added 10mL of ice water, extracted with dichloromethane (30 mL. Times.3), the organic phases were combined, washed with saturated sodium carbonate solution (15 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 7 (10 mg, yield: 30%).

MS m/z(ESI):618.2[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ8.46(s,1H),7.84(d,2H),7.44(d,2H),6.98(s,1H),6.84(s,1H),6.68(s,1H),5.30(s,2H),4.62-4.61(m,1H),4.08(d,1H),3.82(s,3H),3.76(d,1H),3.68(d,1H),3.60(d,1H),3.46-3.27(m,4H),2.73(s,3H),2.56(s,3H),2.53-2.49(m,1H),2.43-2.40(m,1H),2.16(d,1H)。

Example 8

Cyclopropyl (4- (4- (4- (((6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxy) methyl) thiazol-2-yl) benzyl) piperazin-1-yl) methanone 8

First step of

2-bromo-4- (bromomethyl) thiazole 8b

(2-bromothiazol-4-yl) methanol 8a (970mg, 4.99mmol, shaoyuan technologies (Shanghai) Co., ltd.) was dissolved in 10mL of dichloromethane, triphenylphosphine (1.31g, 4.99mmol) was added, carbon tetrabromide (1.65g, 4.98mmol) was added thereto at a temperature of 0 ℃ and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 8B (270 mg, yield: 21%).

Second step of

6- (4- ((2-Bromothiazol-4-yl) methoxy) -6-methoxybenzofuran-2-yl) -2-methylimidazo [2,1-b ] [1,3,4] thiadiazole 8c

Compound 1k (301mg, 1.00mmol) and compound 8b (256mg, 1.00mmol), potassium iodide (331mg, 2.00mmol) and cesium carbonate (1.63g, 5.00mmol) were dissolved in 10mL of N, N-dimethylformamide under an argon atmosphere and reacted at 60 ℃ for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 8c (267 mg, yield: 56%).

MS m/z(ESI):477.0[M+1]

The third step

4- (4- (((6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxy) methyl) thiazol-2-yl) benzaldehyde 8d

Compound 8c (267mg, 0.56mmol) was dissolved in 10mL of 1, 4-dioxane and 1mL of water under an argon atmosphere, and compound 1c (167mg, 1.11mmol), tetrakis (triphenylphosphine) palladium (32mg, 0.03mmol) and sodium carbonate (177mg, 1.67mmol) were added to react at 100 ℃ for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 8d (233 mg, yield: 83%). MS m/z (ESI) 503.1[ 2 ] M +1]

The fourth step

4- (4- (4- (((6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxy) methyl) thiazol-2-yl) benzyl) piperazine-1-carboxylic acid tert-butyl ester 8e

Compound 8d (233mg, 0.46mmol) was dissolved in 10mL of dichloromethane under argon, and compound 2f (129mg, 0.69mmol) and sodium triacetoxyborohydride (294mg, 1.39mmol) were added and stirred for 16 hours. To the reaction solution was added 10mL of ice water, followed by extraction with dichloromethane (30 mL. Times.3), and the organic phases were combined, washed with saturated sodium carbonate solution (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 8e (267 mg, yield: 85%). MS m/z (ESI) 673.2[ 2 ], [ M +1]

The fifth step

6- (6-methoxy-4- ((2- (4- (piperazin-1-ylmethyl) phenyl) thiazol-4-yl) methoxy) benzofuran-2-yl) -2-methylimidazo [2,1-b ] [1,3,4] thiadiazole 8f

Compound 8e (267mg, 0.40mmol) was dissolved in 10mL of dichloromethane, and trifluoroacetic acid (452mg, 3.96mmol, 2mL) was added to stir the reaction for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound 8f (453 mg), which was directly subjected to the next reaction without purification.

MS m/z(ESI):573.2[M+1]

The sixth step

Cyclopropyl (4- (4- (4- (((6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxyamino) methyl) thiazol-2-yl) benzyl) piperazin-1-yl) methanone 8

Compound 8f (91mg, 0.08mmol) was dissolved in 10mL of dichloromethane, triethylamine (80mg, 0.80mmol) was added in an ice bath, and cyclopropylcarbonyl chloride (41mg, 0.39mmol) was added dropwise thereto, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 8 (32 mg, yield: 62%).

MS m/z(ESI):641.2[M+1]

¹ H NMR(400MHz,CDCl ₃ )δ7.99(s,3H),7.52(s,2H),7.39(s,1H),7.16(s,1H),6.72(s,1H),6.47(d,1H),5.39(s,2H),3.85(s,3H),3.68(s,4H),3.48(s,2H),2.73(s,5H),2.13(s,2H),1.70(s,1H),1.01(d,2H),0.79(s,2H)。

Example 9

1- (4- (4- (4- (((6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxy) methyl) thiazol-2-yl) benzyl) piperazin-1-yl) propan-1-one 9

Compound 8f (30.0 mg, 0.05mmol) was dissolved in 5mL of dichloromethane, triethylamine (53.0 mg, 0.52mmol) was added thereto under ice bath, and propionyl chloride (48.0 mg, 0.52mmol) was added dropwise, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 9 (23.0 mg, yield: 69%).

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

¹ H NMR(400MHz,CDCl ₃ )δ8.02(s,1H),8.00(d,2H),7.55(brs,2H),7.41(s,1H),7.19(s,1H),6.75(s,1H),6.49(s,1H),5.42(s,2H),3.96(s,3H),3.96-3.70(m,6H),2.76(s,3H),2.59(brs,4H),2.35(q,2H),0.91(t,3H)。

Example 10

6- (4- ((2- (4- ((4-ethylpiperazin-1-yl) methyl) phenyl) thiazol-4-yl) methoxy) -6-methoxybenzofuran-2-yl) -2-methylimidazo [2,1-b ] [1,3,4] thiadiazole 10

/>

First step of

2- (4-formylphenyl) thiazole-4-carboxylic acid ethyl ester 10b

Ethyl 2-bromothiazole-4-carboxylate 10a (1g, 4.24mmol, shaoyuan technologies (Shanghai) Co., ltd.), compound 1c (699mg, 4.66mmol), tetrakis (triphenylphosphine) palladium (294mg, 0.25mmol) and sodium carbonate (898mg, 8.47mmol) were dissolved in 10mL of 1, 4-dioxane and 2mL of water under an argon atmosphere and subjected to a microwave reaction at 120 ℃ for 0.5 hour. To the reaction solution, 50mL of water was added, extraction was performed with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 10B (590 mg, yield: 53%).

MS m/z(ESI):262.1[M+1]

¹ H NMR(400MHz,CDCl ₃ )δ10.08(s,1H),8.26(s,1H),8.21(d,2H),7.99(d,2H)，4.48(q,2H),1.45(t,3H)。

Second step of

2- (4- ((4-ethylpiperazin-1-yl) methyl) phenyl) thiazole-4-carboxylic acid ethyl ester 10c

Compound 10b (200mg, 0.77mmol) and compound 7a (87mg, 0.76mmol) were dissolved in 20mL of dichloromethane under argon, and sodium triacetoxyborohydride (324mg, 1.53mmol) was added thereto, followed by stirring for 16 hours. To the reaction solution was added 50mL of dichloromethane, a saturated sodium carbonate solution was added to a reaction solution to a pH of 8 to 10, extraction was performed with dichloromethane (30 mL × 3), drying was performed with anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system a to obtain crude title compound 10c (290 mg), which was directly subjected to the next reaction without purification.

MS m/z(ESI):360.2[M+1]

¹ H NMR(400MHz,CDCl ₃ )δ8.16(s,1H),7.97(d,2H),7.41(d,2H),4.46(q,2H),3.62(s,2H),2.42-3.10(m,10H),1.44(t,3H),1.29(t,3H)。

The third step

(2- (4- ((4-ethylpiperazin-1-yl) methyl) phenyl) thiazol-4-yl) methanol 10d

The crude compound 10c (290mg, 0.86mmol) was dissolved in 8mL of anhydrous tetrahydrofuran. Lithium aluminum hydride (33mg, 0.97mmol) was added thereto while cooling on ice, the reaction was stirred for 30 minutes, cooled to 0-5 ℃,2mL of a 2M sodium hydroxide solution and 20mL of water were added to the reaction solution, extracted with dichloromethane (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to obtain the title compound 10d (155 mg, yield: 60.5%).

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

The fourth step

4- (chloromethyl) -2- (4- ((4-ethylpiperazin-1-yl) methyl) phenyl) thiazole 10e

Compound 10d (55mg, 0.17mmol) was dissolved in 8mL of dichloromethane. While cooling on ice, thionyl chloride (412mg, 3.5mmol, 0.28mL) was added slowly. After 10 minutes of reaction, the reaction mixture was heated to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, slurried with a mixed reagent of 10mL of n-hexane and ethyl acetate (V: V = 15) and filtered to obtain 10e (50 mg, yield: 86%).

MS m/z(ESI):336.2[M+1]

The fifth step

6- (4- ((2- ((4-ethylpiperazin-1-yl) methyl) phenyl) thiazol-4-yl) methoxy) -6-methoxybenzofuran-2-yl) -2-methylimidazo [2,1-b ] [1,3,4] thiadiazole 10

Compound 1k (25mg, 0.083mmol) and compound 10e (34mg, 0.10mmol) were dissolved in 8mL of N, N-dimethylformamide under an argon atmosphere, and cesium carbonate (82mg, 0.25mmol) was added to stir the reaction for 1 hour. TLC plates showed unreacted starting material, oil bath heating, external temperature: the reaction was continued at 60 ℃ for 20 minutes. To the reaction solution, 30mL of water was added, extraction was performed with methylene chloride (30 mL. Times.3), and the organic phases were combined, washed with a saturated ammonium chloride solution (30 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography with eluent system A to give the title compound 10 (40 mg, yield: 80%).

MS m/z(ESI):600.9[M+1]

¹ H NMR(400MHz,CD ₃ OD)δ8.20(s,1H),7.97(d,2H),7.66(s,1H),7.49(d,2H),7.10(s,1H),6.75-6.78(m,1H),6.58(d,1H),5.35(s,2H),3.86(s,3H),3.63(s,2H)，2.40-3.05(m,13H),1.16(t,3H)。

Example 11

(S) - (4- (4- (4- (((6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxy) methyl) -5-methylthiazol-2-yl) benzyl) morpholin-3-yl) methanol 11

/>

Compound 2e (29mg, 0.06mmol) was dissolved in 10mL of dichloromethane under argon, and (S) -3-hydroxymethylmorpholine (19mg, 0.116mmol, haohnhong biomedical science and technology Co., ltd., shanghai) and sodium triacetoxyborohydride (178mg, 0.84mmol) were added and reacted for 12 hours. To the reaction solution was added 10mL of ice water, extracted with dichloromethane (30 mL. Times.3), the organic phases were combined, washed with saturated sodium carbonate solution (15 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 11 (21 mg, yield: 60%).

MS m/z(ESI):618.2[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ8.47(s,1H),7.84(d,2H),7.44(d,2H),6.98(s,1H),6.84(d,1H),6.69(s,1H),5.30(s,2H),4.60(t,1H),4.09(d,1H),3.82(s,3H),3.76(d,1H),3.68(d,1H),3.60(d,1H),3.46-3.27(m,4H),2.73(s,3H),,2.56(s,3H),2.53-2.49(m,1H),2.43-2.40(m,1H),2.15(t,1H)。

Example 12

1- (4- (4- (4- (((6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxy) methyl) thiazol-2-yl) benzyl) piperazin-1-yl) ethanone 12

Compound 8f (91mg, 0.08mmol) was dissolved in 10mL of dichloromethane, triethylamine (80mg, 0.80mmol) was added thereto under ice bath, acetyl chloride (31mg, 0.39mmol) was added dropwise, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 12 (31 mg, yield: 63%).

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

¹ H NMR(400MHz,CDCl ₃ )δ8.01(d,3H),7.71(s,2H),7.42(s,1H),7.16(s,1H),6.72(s,1H),6.46(s,1H),5.39(s,2H),4.19(s,2H),3.85(s,3H),3.55(d,4H),2.73(s,7H),2.11(d,3H)。

Example 13 (comparative example)

(4- (4- (((6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxy) methyl) -5-methylthiazol-2-yl) morpholine 13

Compound 13 was prepared using the synthesis of example 94 on page 294 of WO 2013163279.

MS m/z(ESI):514.1[M+1]

¹ H NMR(400MHz,CDCl ₃ )δ7.83(s,1H),7.05(s,1H),6.69(s,1H),6.51(s,1H),5.09(s,2H),4.20(s,3H),3.85(s,3H),3.82(t,4H),3.47(t,4H),2.37(s,3H)。

Example 14

(S) -4- (4- (4- (((6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxy) methyl) -5-methylthiazol-2-yl) benzyl) -3-methylmorpholine 14

/>

First step of

(S) -5-methyl-2- (4- ((3-methylmorpholine) methyl) phenyl) thiazole-4-carboxylic acid methyl ester 14b

Compound 1d (200mg, 0.77mmol) and (S) -3-methylmorpholine 14a (78mg, 0.77mmol) (Shanghai Tech Co., ltd.) were dissolved in 15mL of dichloromethane, and sodium triacetoxyborohydride (2454mg, 1.15mmol) (Shanghai Tech Co., ltd.) was added to the reaction system, followed by stirring for 18 hours. Methanol (20 mL) was added to the reaction system, and concentrated under reduced pressure to give the title compound 14b (140 mg, yield: 52.79%).

MS m/z(ESI):347.1[M+1]

Second step of

(S) - (5-methyl-2- (4- ((3-methylmorpholine) methyl) phenyl) thiazol-4-yl) methanol 14c

Compound 14b (140mg, 0.40mmol) was dissolved in 10mL of tetrahydrofuran, cooled to 0 deg.C, added with lithium aluminum hydride (32mg, 0.94mmol) (Shaoyuan scientific Shanghai, inc.), and reacted at 0 deg.C for 30 minutes. 0.75mL of saturated aqueous ammonium chloride was added, dried over anhydrous sodium sulfate, and filtered through celite. The filtrate was concentrated under reduced pressure to give the title compound 14c (110 mg, yield: 85.5%).

MS m/z(ESI):319.2[M+1]

The third step

(S) -4- (4- (4- (chloromethyl) -5-methylthiazol-2-yl) benzyl) -3-methylmorpholine 14d

Compound 14c (110mg, 0.35mmol) was dissolved in 15mL of dichloromethane, cooled to 0-5 ℃ and added thionyl chloride (820 mg, 6.89mmol), and the mixture was allowed to warm to room temperature to react for 120 minutes. The reaction solution was concentrated under reduced pressure, slurried with dichloromethane/n-hexane (V: V =1, 15, 20 mL) and filtered to give the title compound 14d (150 mg), which was directly subjected to the next reaction without purification.

MS m/z(ESI):337.1[M+1]

The fourth step

Crude compound 14d (93mg, 0.25mmol) and compound 1k (75mg, 0.25mmol) were dissolved in 3mL of N, N-dimethylformamide, and cesium carbonate (406mg, 1.24mmol) and potassium iodide (83mg, 0.50mmol) were added, and the reaction was heated to 60 ℃ in an oil bath under argon for 1 hour until no starting material remained. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography using developer system A to give the title compound 14 (50 mg, yield: 33.38%).

MS m/z(ESI):602.2[M+1]

¹ H NMR(400MHz,CDCl ₃ ):δ7.98(s,1H),7.86(s,2H),7.47(s,2H),7.11(s,1H),6.71(s,1H),6.57(s,1H),5.32(s,2H),4.10-4.14(m,1H),3.86(s,3H),3.73(s,2H),3.61(s,1H),3.33(s,1H),3.19(s,1H),2.73(s,3H),2.60(s,1H),2.57(s,3H),2.50(m,1H),2.21-2.24(m,1H),1.26-1.27(m,3H)。

Example 15

(R) -4- (4- (4- (((6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxy) methyl) -5-methylthiazol-2-yl) benzyl) -3-methylmorpholine 15

First step of

(R) -5-methyl-2- (4- ((3-methylmorpholine) methyl) phenyl) thiazole-4-carboxylic acid methyl ester 15b

Compound 1d (200mg, 0.77mmol) and (R) -3-methylmorpholine 15a (78mg, 0.77mmol) (Shanghai Bishi technology Co., ltd.) were dissolved in 15mL of dichloromethane, and sodium triacetoxyborohydride (324mg, 1.53mmol) (Shaoyuan technology Shanghai Co., ltd.) was added to the reaction system, followed by stirring for 18 hours. Methanol (20 mL) was added to the reaction system, and the reaction solution was concentrated under reduced pressure to give the title compound 15b (140 mg, yield: 52.79%).

MS m/z(ESI):347.1[M+1]

Second step of

(R) - (5-methyl-2- (4- ((3-methylmorpholine) methyl) phenyl) thiazol-4-yl) methanol 15c

Compound 15b (130mg, 0.38mmol) was dissolved in 10mL of tetrahydrofuran, cooled to 0 deg.C, added with lithium aluminum hydride (30mg, 0.88mmol) (Shao Yuan Tech Shanghai Co., ltd.), and reacted at 0 deg.C for 30 minutes. 0.75mL of saturated aqueous ammonium chloride was added, dried over anhydrous sodium sulfate, and filtered through celite. The filtrate was concentrated under reduced pressure to give the title compound 15c (110 mg, yield: 92.0%).

MS m/z(ESI):319.2[M+1]

The third step

(R) -4- (4- (4- (chloromethyl) -5-methylthiazol-2-yl) benzyl) -3-methylmorpholine 15d

Compound 15c (110mg, 0.35mmol) was dissolved in 15mL of dichloromethane, cooled to 0-5 ℃ and added thionyl chloride (820 mg, 6.89mmol), and the mixture was allowed to warm to room temperature to react for 120 minutes. The reaction solution was concentrated under reduced pressure, slurried with dichloromethane/n-hexane (V: V =1, 15, 20 mL) and filtered to give the title compound 15d (150 mg), which was directly subjected to the next reaction without purification.

MS m/z(ESI):337.1[M+1]

The fourth step

Compound 15d (93mg, 0.25mmol) and compound 1k (75mg, 0.25mmol) were dissolved in 3mL of N, N-dimethylformamide, and cesium carbonate (450mg, 1.38mmol) and potassium iodide (83mg, 0.50mmol) were added, and the mixture was heated to 60 ℃ in an oil bath under argon atmosphere for 1 hour until no starting material remained. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography using developer system A to give the title compound 15 (53 mg, yield: 35.38%).

MS m/z(ESI):602.2[M+1]

¹ H NMR(400MHz,CDCl ₃ ):δ7.98(s,1H),7.87(s,2H),7.47(s,2H),7.11(s,1H),6.71(s,1H),6.57(s,1H),5.32(s,2H),4.10-4.14(m,1H),3.86(s,3H),3.73(s,2H),3.61(s,1H),3.33(s,1H),3.19(s,1H),2.73(s,3H),2.60(s,1H),2.57(s,3H),2.50(m,1H),2.21-2.24(m,1H),1.26-1.27(m,3H)。

Example 16

(S) -4- (4- (4- (((6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxy) methyl) thiazol-2-yl) benzyl) -3-methylmorpholine 16

First step of

(S) Ethyl 2- (4- ((3-methylmorpholine) methyl) phenyl) thiazole-4-carboxylate 16a

Compound 10b (200mg, 0.77mmol) was dissolved in 10mL of dichloromethane under an argon atmosphere, compound 14a (93mg, 0.92mmol) was added, and stirred at room temperature for 0.5 hour, and sodium triacetoxyborohydride (324mg, 1.53mmol) was added in portions under ice bath and stirred at room temperature for 16 hours. The reaction solution was added with water (20 mL), extracted with dichloromethane (20 mL. Times.3), washed with an organic phase saturated aqueous sodium bicarbonate solution (10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system E to give the title compound 16a (205 mg, yield: 77.3%).

MS m/z(ESI):347.1[M+1]

Second step of

(S) - (2- (4- ((3-methylmorpholine) methyl) phenyl) thiazol-4-yl) methanol 16b

Compound 16a (200mg, 0.58mmol) was dissolved in 10mL of tetrahydrofuran, cooled to 0 deg.C, added with lithium aluminum hydride (30mg, 0.88mmol) (Shaoyuan Shanghai technology, inc.) and reacted at 0 deg.C for 30 minutes. 0.75mL of saturated aqueous ammonium chloride was added, dried over anhydrous sodium sulfate, and filtered through celite. Concentration under reduced pressure gave the title compound 16b (112 mg, yield: 63.7%).

MS m/z(ESI):305.1[M+1]

The third step

(S) -4- (4- (4- (chloromethyl) thiazol-2-yl) benzyl) methylmorpholine 16c

Compound 16b (112mg, 0.37mmol) was dissolved in 10mL of methylene chloride, cooled to 0-5 ℃, added thionyl chloride (875mg, 7.35mmol), and allowed to warm to room temperature for reaction for 2 hours. The reaction solution was concentrated under reduced pressure, slurried with dichloromethane/n-hexane (V: V =1, 15, 20 mL) and filtered to give the title compound 16c (78 mg), which was directly subjected to the next reaction without purification.

MS m/z(ESI):323.1[M+1]

The fourth step

Compound 16c (52mg, 0.14mmol) and compound 1k (40mg, 0.13mmol) were dissolved in 3mL of N, N-dimethylformamide, and cesium carbonate (130mg, 0.40mmol) and potassium iodide (3mg, 0.02mmol) were added, and the reaction was heated to 80 ℃ in an oil bath under argon for 4 hours until no starting material remained. Water (100 mL) was added, celite was filtered, the filtrate was extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 16 (20 mg, yield: 25.6%).

MS m/z(ESI):588.2[M+1]

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.43(s,1H),7.88(d,J＝8Hz,2H),7.84(s,1H),7.41(d,J＝8Hz,2H),7.05(s,1H),6.82(s,1H),6.63(s,1H),5.34(s,2H),3.98(d,J＝13.8Hz,1H),3.79(s,3H),3.62-3.59(m,2H),3.44-3.39(m,2H),3.18-3.10(m,2H),2.71(s,3H),2.42-2.33(m,1H),2.15-2.05(m,1H)，0.98(d,J＝6Hz,3H)。

Example 17

(R) -4- (4- (4- (((6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxy) methyl) thiazol-2-yl) benzyl) -3-methylmorpholine 17

First step of

(R) -2- (4- ((3-methylmorpholine) methyl) phenyl) thiazole-4-carboxylic acid ethyl ester 17a

Compound 10b (200mg, 0.77mmol) was dissolved in 10mL of dichloromethane under an argon atmosphere, compound 15a (93mg, 0.92mmol) was added, and stirred at room temperature for 0.5 hour, sodium triacetoxyborohydride (325mg, 1.53mmol) was added in portions in an ice bath, and stirred at room temperature for 16 hours. The reaction solution was added with water (20 mL), extracted with dichloromethane (20 mL. Times.3), the organic phase was washed with saturated aqueous sodium bicarbonate solution (10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography using silica gel column chromatography with eluent system E to give the title compound 17a (205 mg, yield: 77.3%).

MS m/z(ESI):347.1[M+1]

Second step of

(R) - (2- (4- ((3-methylmorpholine) methyl) phenyl) thiazol-4-yl) methanol 17b

Compound 17a (200mg, 0.58mmol) was dissolved in 10mL of tetrahydrofuran, cooled to 0 deg.C, added with lithium aluminum hydride (40mg, 1.18mmol ((Shaoyuan Shanghai science Co., ltd.), and reacted at 0 deg.C for 30 minutes, 0.75mL of saturated aqueous ammonium chloride was added, dried over anhydrous sodium sulfate, filtered through celite, and concentrated under reduced pressure to give the title compound 17a (112 mg, yield: 63.7%).

MS m/z(ESI):305.1[M+1]

The third step

(R) -4- (4- (4- (chloromethyl) thiazol-2-yl) benzyl) -3-methylmorpholine 17c

Compound 17b (112mg, 0.37mmol) was dissolved in 10mL of dichloromethane, cooled to 0-5 ℃ and added thionyl chloride (801mg, 6.73mmol), and allowed to warm to room temperature for reaction for 2 hours. Concentrated under reduced pressure, slurried with dichloromethane/n-hexane (V: V =1, 15, 20 mL) and filtered to give the title compound 17c (70 mg), which was directly subjected to the next reaction without purification.

MS m/z(ESI):323.1[M+1]

The fourth step

Compound 17c (48mg, 0.13mmol) and compound 1k (40mg, 0.13mmol) were dissolved in 3mL of N, N-dimethylformamide, and cesium carbonate (87mg, 0.27mmol) and potassium iodide (22mg, 0.13mmol) were added, and the reaction was heated to 80 ℃ in an oil bath under argon for 4 hours until no starting material remained. Water (100 mL) was added, celite was filtered, the filtrate was extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 17 (20 mg, yield: 25.6%).

MS m/z(ESI):588.2[M+1]

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.41(s,1H),7.86(d,J＝8Hz,2H),7.81(s,1H),7.39(d,J＝8Hz,2H),7.02(s,1H),6.79(s,1H),6.59(s,1H),5.31(s,2H),3.95(d,J＝12Hz,1H),3.76(s,3H),3.59-3.56(m,2H),3.36-3.41(m,2H),3.15-3.08(m,2H),2.68(s,3H),2.39-2.31(m,1H),2.10-2.03(m,1H),0.95(d,J＝8Hz,3H)。

Example 18

1- (4- (4- (((6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-yl) benzofuran-4-yl) oxy) methyl) thiazol-2-yl) phenyl) -N, N-dimethylmethylamine 18

First step of

2- (4- ((dimethylamino) methyl) phenyl) thiazole-4-carboxylic acid ethyl ester 18a

Compound 10b (700mg, 2.83mmol) and dimethylamine (2.77ml, 2mol/L,5.55mmol, adamax reagents, inc.) were dissolved in 50mL of dichloromethane under an argon atmosphere, and sodium triacetoxyborohydride (6.00g, 28.31mmol, shaoyuan technology, inc.) was added and the reaction was stirred for 16 hours. To the reaction solution was added 50mL of dichloromethane, a saturated sodium carbonate solution was added to a reaction solution pH of 8 to 10, extraction was performed with dichloromethane (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 18a (660 mg, yield: 80.3%).

MS m/z(ESI):291.2[M+1]

Second step of

2- (4- ((dimethylamino) methyl) phenyl) thiazol-4-yl) methanol 18b

Compound 18a (660 mg, 2.27mmol) was dissolved in 50mL of anhydrous tetrahydrofuran. Lithium aluminum hydride (100mg, 2.95mmol) was added thereto while cooling on ice, the reaction was stirred at 0 ℃ for 30 minutes, water was added, filtration was performed, washing was performed with methylene chloride (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 18b (525 mg, yield: 93.0%).

MS m/z(ESI):249.0[M+1]

The third step

1- (4- (4- (chloromethyl) thiazol-2-yl) phenyl) -N, N-dimethylmethylamine 18c

Compound 18b (525mg, 2.11mmol) was dissolved in 20mL of dichloromethane. Thionyl chloride (1.30g, 10.93mmol, 0.88mL) was added slowly while cooling on ice. After 10 minutes of reaction, the reaction mixture was heated to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, slurried with 10mL of a mixed reagent of n-hexane and ethyl acetate (V: V = 15) and filtered to give the title compound 18c (600 mg, yield: 93.6%).

MS m/z(ESI):267.1[M+1]

The fourth step

Compound 1k (50mg, 0.166mmol) and compound 18c (55mg, 0.181mmol) were dissolved in 5mL of N, N-dimethylformamide under an argon atmosphere, and cesium carbonate (180mg, 0.552mmol) and potassium iodide (3mg, 0.018mmol) were added, and the reaction was stirred at 60 ℃ for 16 hours. After cooling to room temperature, 100mL of water was added to the reaction mixture to precipitate a solid, which was filtered, the filter cake was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified by silica gel column chromatography using elution System E to obtain the title compound 18 (50 mg, yield: 56.7%).

MS m/z(ESI):532.0[M+1]

¹ H NMR(400MHz,CD ₃ OD)δ8.47(s,1H),7.92(d,2H),7.88(s,1H),7.42(d,2H),7.08(s,1H),6.85(s,1H),6.65(s,1H),5.37(s,2H),3.82(s,3H),3.44(s,2H)，2.74(s,3H),2.16(s,6H)。

Test example:

biological evaluation

Test example 1 determination of the inhibitory Activity of the Compounds of the invention against human PAR-4

The method is used for determining the inhibition effect of the compound on the activity of human PAR-4 protein expressed in HEK 293/human PAR-4 stable transformant cells.

1. Experimental materials and instruments

1.Fluo-4 NW Calcium Assay Kits(F36206，invitrogen)

2.MEM(Hyclone，SH30024.01B)

3.G418.Sulfate(Enzo，ALX-380-013-G005)

4. Cattle fetal serum (GIBCO, 10099)

5. Sodium pyruvate solution (sigma, S8636-100 ML)

MEM non-essential amino acid solution (100X) (sigma, M7145-100 ML)

Flexstation 3 multifunctional microplate reader (Molecular Devices)

Poly-D-Lysine 96-well microplate (356692, BD)

AF6 (synthesized by Gill Biochemical Co., ltd.)

10. Human PAR-4 (Jin Weizhi Biotechnology Co., ltd.)

11.

3000 transfection reagent (L3000-015, life Technology) & gt>

2. Experimental procedure

Mammalian expression vector containing hPAR4 gene, and its application

3000 transfection reagent is transferred into HEK293 cells; g418 antibiotic is added for screening every other day, and a monoclonal cell line is selected.

HEK 293/human PAR-4 stable transformants were plated one day in advance in 96-well plates at a density of 30000 cells/well. The following day, fluo-4 dye containing buffer was prepared using the reagents in Fluo-4 NW Calcium Assay Kits, the medium was removed, 100. Mu.l of Fluo-4 dye containing buffer was added to each well, and incubation was carried out at 37 ℃ for 30 minutes. After this time, the plate was allowed to equilibrate to room temperature for 10 minutes. Compound (10) ⁵ 、10 ⁴ 、10 ³ 、10 ² 1. Mu.l of each well, 10, 1, 0.1, 0nM, and incubation at room temperature for 10 min. The detection is carried out by a flexstation 3 plate reader, 50 mu l of 600 mu M AF6 polypeptide is automatically added by a machine, and the reading value is immediately 494/516nM. IC of the Compound ₅₀ The fluorescence values corresponding to different concentrations can be calculated by Graphpad Prism software.

The inhibitory Activity of the Compounds of the invention against human PAR-4 was determined by the above assay, and the IC measured ₅₀ The values are shown in Table 1.

TABLE 1 IC for inhibition of human PAR-4 activity by the compounds of the invention ₅₀

Example numbering	IC ₅₀ (nM)
		1	4
2	0.26
		3	0.26
4	0.14
		5	0.23
6	0.47
		7	0.11
8	0.37
		9	0.5
10	2.5
		11	0.1
12	1.6
		16	0.2
17	0.25

And (4) conclusion: the compound of the invention has obvious inhibiting effect on human PAR4 activity.

Test example 2 platelet aggregation assay induced by PAR 4-activating peptide (PAR 4-AP) with the Compound of the present invention

1. Experimental materials and instruments

1. Human platelet-rich plasma (PRP, platelet-rich plasma): human blood was collected using a blood collection tube without anticoagulant and immediately poured into a centrifuge tube containing 3.8% sodium citrate (1:9 volume, one part sodium citrate solution and nine blood anticoagulations). After the blood was centrifuged at 300g for 15 minutes (25 ℃), the upper layer of platelet-rich plasma was removed.

2. Human PAR 4-activating peptide (Ala- [ Phe (4-F) ] -Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH2, gill Biochemical customization)

3. Platelet aggregometer (Libosh instrument, LBY-NJ 4).

2. Experimental procedure

This experiment used human Platelet Rich Plasma (PRP) and tested 100 μ M induction of PAR 4-activating peptide (PAR 4-AP) by a platelet aggregometerInhibition of platelet aggregation by nM, 50nM, 30nM, 20nM, 10nM, 3nM, 1nM of test compound and EC was calculated ₅₀ 。

3. Data processing

The EC of the compounds for inhibiting the platelet aggregation reaction of PAR 4-activating peptide was calculated by curve fitting using GraphPad Prism and data analysis using this software ₅₀ 。

TABLE 2 EC of inhibition of PAR 4-activating peptide-induced platelet aggregation by the compounds of the invention ₅₀

Example numbering	EC ₅₀ (nM)
		1	4
2	14
		3	15
4	16
		5	17
6	15
		8	29
9	30
		10	31
11	37
		12	41
14	28
		15	35
18	28

And (4) conclusion: the compound has obvious inhibition effect on platelet aggregation reaction induced by PAR4 activating peptide.

Test example 3 solubility of the Compounds of the invention in FassIF and FessIF solutions

1. Experimental materials

Reagent: dimethyl sulfoxide (analytically pure), ethanol (analytically pure), acetonitrile (chromatographically pure), naH ₂ PO ₄ ·2H ₂ O (analytically pure), ammonium acetate (analytically pure), sodium taurocholate, lecithin, sodium hydroxide, sodium chloride (analytically pure)

The instrument comprises: liquid chromatograph

2. Experimental procedure

2.1 weighing a proper amount of test compound and using DMSO as a solvent to prepare a 10mM stock solution. In a 2mL sample bottle, 10 μ L of stock solution (concentration 10mM, dissolved in DMSO) and 990 μ L of organic mixed solvent (usually DMSO: acetonitrile: ethanol = 1.

2.2 dissolving 1mg of sample to be tested into 900 mul FassIF (or FessIF) solution, mixing strongly, and preparing two solutions in parallel; after shaking in a 37 ℃ water bath for 24 hours, the mixture was centrifuged at 4000rpm for 30min, and the supernatant was transferred to liquid chromatography as a sample solution.

3. Data processing

FassIF (or FessIF) solubility (μ M) = peak area of sample/peak area of reference × reference solution concentration (μ M) × dilution factor of sample solution.

The final FassIF and FessIF solubilities were averaged over the two measurements.

TABLE 3 solubility of the compounds of the invention

Example numbering	FassIF(μM)	FessIF(μM)
			1	9.1	131
3	22.2	379
			4	21.1	942
6	64.4	724
			10	13.2	1592
13 Comparative example	0.17	3
			14	22	601
15	25	307
			18	8	500

And (4) conclusion: the compounds of the present invention have good solubility in both FassIF and FessIF, with significantly improved solubility compared to the control.

Test example 4 rat pharmacokinetic testing of the Compound of the invention

1. Abstract

The drug concentrations in plasma of SD rats at various times after intravenous administration of the compound of example 3 were determined by LC/MS/MS method using SD rats as test animals. The pharmacokinetic behavior of the compounds of the invention in SD rats was studied and evaluated for their pharmacokinetic profile.

2. Test protocol

2.1 test drugs

Example 3 Compounds

2.2 test animals

SD rats 8, male and female halves, divided into 2 groups, purchased from shanghai jequirity laboratory animals ltd, animal production license number: SCXK (Shanghai) 2013-0006.

2.3 pharmaceutical formulation

Weigh an appropriate amount of sample, add 5% of DMSO +5% to the PEG400+90% physiological saline, sequentially.

2.4 administration of drugs

SD rats were fasted overnight and then gavaged at doses of 20mg/kg and 60mg/kg, respectively, at 10mL/kg, respectively, and at 2mg/mL and 6mg/mL, respectively.

3. Operation of

After fasting for one night, gavage is carried out, 0.2ml of blood is collected from the orbit before administration and 0.5,1.0,2.0,4.0,6.0,8.0,11.0 and 24.0 hours after administration, the blood is placed in a heparinized test tube, blood plasma is separated by centrifugation at 3500rpm for 10min, and the blood plasma is stored at-20 ℃. Food was consumed 2h after dosing.

Determination of the content of the test compound in the plasma of the drug SD rats at different concentrations after administration: 25 μ L of SD rat plasma at each time after administration was taken, 50 μ L of internal standard camptothecin solution (100 ng/mL) and 200 μ L of acetonitrile were added, vortex mixed for 5 minutes, centrifuged for 10 minutes (4000 rpm), and 2.0 μ L of supernatant was taken from the plasma samples for LC/MS/MS analysis.

4. Results of pharmacokinetic parameters in SD rat

The rat pharmacokinetic parameters for the compounds of the invention are as follows:

and (4) conclusion: the compound of the invention has good drug absorption in rats and pharmacokinetic advantage.

Test example 5 monkey pharmacokinetic testing of the Compound

1. Purpose of the experiment

The drug concentrations in plasma of cynomolgus monkeys at different times after gavage administration of the compound of example 3 were determined using the LC/MS method using cynomolgus monkeys as test animals. The pharmacokinetic behavior of the compound of the invention in cynomolgus monkeys was studied and the pharmacokinetic profile was evaluated.

2. Test animal

Male cynomolgus monkeys 6 (101, 102, 103, 201, 202 and 203) were divided into 2 groups on average.

3. Test drug

The compound of example 3.

4. Pharmaceutical formulation

A quantity of drug was weighed, and 5% by volume DMA, 90% by volume (10% HS-15), and 5% PEG400 were added to make up a colorless, clear, transparent liquid of 0.4mg/mL for ig 2mpk administration.

Weighing an amount of drug, adding 10% PEG400 and 90% by volume (10% TPGS +5% PVP K30) to make up a colorless clear transparent liquid of 10mg/mL for ig 100mpk administration.

5. Administration of drugs

After fasting overnight, the cynomolgus monkey is subjected to gastric lavage, the administration dose is respectively 2.0mg/kg and 100mg/kg, and the administration volume is respectively 5.0mL/kg and 10mL/kg.

6. Test protocol for pharmacokinetic testing of cynomolgus monkeys

6.1 test procedures

The compound of example 3 was administered to cynomolgus monkeys by intragastric administration, and 1.0ml of the blood was collected from the forelimb vein before and after administration at 0.5,1,2,4,6,8,12,24h, placed in a heparin anticoagulation tube, centrifuged at 3500rpm for 10min to separate plasma, and stored at-80 ℃; food was consumed 2h after dosing.

Determining the content of a compound to be tested in the plasma of the cynomolgus monkey after the administration of medicaments with different concentrations: 25 μ L of cynomolgus monkey plasma at each time after administration was taken, 50 μ L (100 ng/mL) of the internal standard camptothecin solution and 250 μ L of acetonitrile were added, vortex mixed for 5 minutes, centrifuged for 10 minutes (4000 rpm), and 1.0 μ L of supernatant was taken from the plasma sample for LC/MS/MS analysis.

6.2 results of pharmacokinetic parameters of cynomolgus monkey

The pharmacokinetic parameters of the compounds of the invention in cynomolgus monkeys are as follows:

and (4) conclusion: the compound of the invention has good drug absorption in the cynomolgus monkey body and pharmacokinetic advantage.

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

w is O or S;

L ¹ is-CR ⁶ R ⁷ -；

Ring a is a 5-membered heteroaryl;

ring B is 6 to 10 membered aryl or 5 to 10 membered heteroaryl;

y is S;

R ^w is-C _1-6 alkylene-NR ⁸ R ⁹ Wherein said C _1-6 Alkylene is optionally selected from halogen, C _1-6 Alkyl and C _1-6 Substituted with one or more substituents of haloalkyl;

R ¹ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano, amino and nitro;

R ² selected from hydrogen atoms, halogens, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano, amino and nitro;

R ³ is C _1-6 Alkyl or C _1-6 A haloalkyl group;

R ⁴ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano, amino and nitro;

R ⁵ are the same or different and are each independently selected from a hydrogen atom,Halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl, cyano, amino and nitro;

R ⁶ and R ⁷ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group;

R ⁸ and R ⁹ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl and C _1-6 A haloalkyl group;

or, R ⁸ And R ⁹ Together with the attached nitrogen atom form a 3-to 8-membered heterocyclyl group, wherein said 3-to 8-membered heterocyclyl group optionally contains, in addition to 1 nitrogen atom, 0 to 2 identical or different heteroatoms selected from N, O and S, and said 3-to 8-membered heterocyclyl group is optionally selected from C _1-6 Alkyl radical, C _1-6 Alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy, C _1-6 Hydroxyalkyl, 3-to 8-membered cycloalkyl and-C (O) R ¹⁰ Is substituted with one or more substituents of (1);

R ¹⁰ is selected from C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl or 3 to 8-membered cycloalkyl;

n is 0,1, 2 or 3;

s is 0,1, 2 or 3; and is provided with

p is 0,1 or 2.

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 wherein R is ^w Is- (CR) ¹¹ R ¹² ) _t -NR ⁸ R ⁹ ；R ¹¹ And R ¹² Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; t is 1,2 or 3; r ⁸ And R ⁹ As defined in claim 1.

3. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (II):

wherein:

ring A, ring B, Y, R ¹ To R ⁹ N, s and p are as defined in claim 1.

4. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein ring a is a 5-membered heteroaryl group, said 5-membered heteroaryl group optionally containing 1 to 3 heteroatoms, the same or different, selected from N, O and S.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 wherein ring a is selected from thiazolyl, pyrazolyl and imidazolyl.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring B is phenyl or 5-to 6-membered heteroaryl, said 5-to 6-membered heteroaryl optionally containing 1 to 3 heteroatoms, the same or different, selected from N, O and S.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring B is phenyl.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 wherein R is ³ Is C _1-6 An alkyl group.

9.A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ Is methyl.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 wherein R is ⁶ And R ⁷ Is a hydrogen atom.

11. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (III):

/>

wherein:

R ¹ 、R ² 、R ⁴ 、R ⁵ 、R ⁸ 、R ⁹ y, n and s are as defined in claim 1.

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 wherein Y is S; r ² Is a hydrogen atom.

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 wherein R is ¹ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl and C _1-6 An alkoxy group.

14. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 wherein R is ¹ Is C _1-6 An alkoxy group.

15. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (IV):

wherein:

m is O or NR ¹⁴ ；

R ¹³ Are the same or different and are each independently selectedFrom C _1-6 Alkyl radical, C _1-6 Alkoxy, oxo, halogen, amino, cyano, nitro, hydroxy and C _1-6 A hydroxyalkyl group;

R ¹⁴ selected from hydrogen atoms, C _1-6 Alkyl or-C (O) R ¹⁰ ；

q is 0,1 or 2;

R ⁴ 、R ⁵ 、R ¹⁰ and s is as defined in claim 1.

16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 wherein R is ⁴ Is a hydrogen atom or C _1-6 An alkyl group.

17. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 wherein R ⁵ Is a hydrogen atom.

18. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, selected from:

/>

/>

19. a compound selected from:

20. a compound of formula (IIA) or a pharmaceutically acceptable salt thereof:

wherein: ring A, ring B, Y, R ¹ To R ⁷ N, s and p are as defined in claim 3.

21. A compound of formula (IIA), or a pharmaceutically acceptable salt thereof, as claimed in claim 20, which is selected from:

22. a process for preparing a compound of formula (IV) or a pharmaceutically acceptable salt thereof according to claim 15, which comprises:

wherein:

x is a leaving group;

R ⁴ 、R ⁵ 、R ¹³ m, s and q are as defined in claim 15.

23. The method of claim 22, wherein the leaving group is halogen or-OSO ₂ CH ₃ 。

24. A process for the preparation of a compound of formula (II) according to claim 3, or a pharmaceutically acceptable salt thereof, which comprises:

a compound of the formula (IIA) and NHR ⁸ R ⁹ Reacting in the presence of a reducing agent to give a compound of the general formula (II),

wherein:

ring A, ring B, Y, R ¹ To R ⁹ N, s and p are as defined in claim 3.

25. The production method according to claim 24, wherein the reducing agent is sodium triacetoxyborohydride.

26. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

27. Use of a compound of general formula (I) according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 26 for the preparation of a medicament for antagonizing PAR-4.

28. Use of a compound of general formula (I) according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, for the manufacture of a medicament for the treatment or prevention of platelet aggregation.

29. Use of a compound of general formula (I) according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 26 for the preparation of a medicament for the treatment or prevention of a thromboembolic disorder.

30. The use according to claim 29, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, cerebrovascular thromboembolic disorders, and thromboembolic disorders in the heart chambers or in the peripheral circulation.