CN113135930B - Furopyridone imidazole compounds and preparation methods and uses thereof - Google Patents

Abstract

The invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to furopyridoneimidazole compounds and their preparation methods and uses. Its structure is shown in the following general formula (I). These compounds or their stereoisomers, racemates, geometric isomers, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts and pharmaceutical compositions thereof, can be used to treat or /And prevent related diseases mediated by Factor XIa (FXIa for short).

Description

Furanopyridone imidazole compound and preparation method and use thereof

Technical Field

The present invention belongs to the field of pharmaceutical chemistry. Specifically, the present invention relates to novel compounds or their stereoisomers, racemates, geometric isomers, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts, and pharmaceutical compositions containing them, which are coagulation factor XIa (Factor XIa, referred to as FXIa) inhibitors with a completely new structure.

Background Art

Thromboembolic disease is a disease caused by abnormal blood clots formed in blood vessels during the survival of humans and animals. There are three reasons for thrombosis: vascular damage, blood changes and blood stasis; it is a group of complications caused by many different diseases and different reasons. Due to the differences in various underlying diseases and the different sites of thromboembolism, thrombosis may clinically manifest as myocardial infarction, stroke, deep vein thrombosis (DVT), pulmonary embolism, atrial fibrillation and cerebral infarction, etc., especially myocardial infarction, cerebral infarction and pulmonary infarction with embolism and infarction as the main causes, which ranks first among various causes of death, claiming nearly 12 million lives each year worldwide, close to a quarter of the world's total death toll.

The blood coagulation process in the human body consists of the intrinsic pathway, the extrinsic pathway, and the common pathway. It is a coagulation cascade reaction in which a series of coagulation factors are activated one after another and then amplified, eventually forming fibrin. The intrinsic pathway (also known as the contact activation pathway) and the extrinsic pathway (also known as the tissue factor pathway) initiate the generation of coagulation factor Xa (Factor Xa, referred to as FXa), and then generate thrombin IIa (Factor IIa, referred to as FIIa) through the common pathway, and finally form fibrin. Procoagulant (hemostasis) and anticoagulant (antithrombotic) oppose each other in the human blood system and maintain a relative balance. When the function of the anticoagulant fibrinolytic system in the body is reduced and the coagulation and anticoagulant functions in the blood lose balance, coagulation occurs, causing thrombosis or embolism.

With the elucidation of the mechanism of thrombosis, the antithrombotic drugs that have been studied and developed mainly include anticoagulants (such as warfarin and heparin, etc.), antiplatelet aggregation drugs (such as aspirin and clopidogrel, etc.) and thrombolytic drugs (such as urokinase and reteplase, etc.). The domestic anticoagulant drug market is growing rapidly, among which traditional varieties such as heparin drugs still occupy the main share, but the market size is gradually stabilizing. And the new therapeutic drug direct thrombin (FIIa) inhibitor (such as dabigatran, etc.) and activated coagulation factor Xa (FXa) inhibitor (such as rivaroxaban and apixaban, etc.) show strong market vitality and are strong competitors of heparin drugs. The use of activated coagulation factor (FXa) inhibitors is growing rapidly because their efficacy and safety have good performance in preventing and treating thromboembolic diseases such as stroke, pulmonary embolism and venous thromboembolism (VTE). However, this is accompanied by an increase in hospitalization and mortality related to bleeding, which is a major complication of anticoagulant therapy. In 2016, approximately 117,000 hospitalized patients died from FXa inhibitor-related bleeding in the United States alone, equivalent to nearly 2,000 bleeding-related deaths per month. Therefore, it is of great significance to develop anticoagulant drugs with less bleeding tendency.

Coagulation factor XI (FXI) is a plasma serine protease necessary for maintaining the intrinsic pathway. After activation, it generates activated coagulation factor XIa (FXIa), which plays a key role in the amplification of the coagulation cascade. In the coagulation cascade, thrombin can feedback activate FXI, and activated FXI in turn promotes the massive production of thrombin, thereby amplifying the coagulation cascade. Therefore, drugs targeting the FXI target can block the intrinsic pathway and inhibit the amplification of the coagulation cascade, thereby having an anti-thrombotic effect. In recent years, clinical data on the association between human coagulation factor XI (FXI) deficiency or elevated FXI levels and the occurrence of thrombotic diseases, as well as antithrombotic experimental studies on animals with FXI deficiency, knockout or inhibition have shown that compared with direct FXa inhibitors, inhibition of FXI may have a lower risk of bleeding and is a new target for antithrombotic prevention and treatment.

Human FXI deficiency, also known as hemophilia C, has a mild bleeding phenotype, rarely spontaneous bleeding, and rarely joint bleeding and intramuscular bleeding. This shows that the risk of bleeding is lower when FXI is inhibited. Second, the incidence of ischemic stroke and deep vein thrombosis is significantly reduced in patients with FXI deficiency, indicating that FXI inhibition is beneficial to reduce the risk of ischemic stroke and deep vein thrombosis. Third, in a study on thrombotic tendency with 474 patients and controls, the risk of DVT in people with high FXI levels was 2.2 times that of other people, indicating that high levels of FXI are a risk factor for DVT, and FXI levels are positively correlated with the occurrence of DVT. Other studies have shown that elevated FXI levels can significantly increase the risk of stroke and venous thrombosis. If FXI can be inhibited, thrombotic diseases may be reduced.

FXI gene knockout mice can survive healthily, and their fertility and hemostasis function are the same as those of wild-type mice. They also show prolonged activated partial thromboplastin time (aPTT) and normal prothrombin time (PT) like FXI-deficient patients. FXI gene knockout mice can inhibit arterial and venous thrombosis. Compared with several clinically used antithrombotic drugs, the antithrombotic effect is equivalent to or even more effective than high-dose heparin, and more effective than other drugs such as aspirin, clopidogrel or argatroban. Moreover, these antithrombotic drugs may cause a small amount of bleeding, while the tail bleeding time of FXI gene knockout mice is no different from that of wild-type mice. This suggests that FXI may be an antithrombotic target with less bleeding side effects. The reported FXI inhibitors mainly include monoclonal antibodies, antisense oligonucleotides, chemical small molecules, peptides or proteins, and peptide mimetics. At present, Novartis's FXIa monoclonal antibody MAA-868 and Bayer's monoclonal antibody BAY1213790 have entered clinical phase II research. Ionis's FXIa antisense oligonucleotide ISIS416858/BAY2306001/IONIX-FXIRx, developed in cooperation with Bayer, is currently in clinical phase II research. BMS-986177, a small molecule oral FXIa inhibitor developed in cooperation with Johnson & Johnson, has completed multiple phase I clinical studies and entered phase II clinical trials; ONO-7684, a small molecule oral FXIa inhibitor developed by Ono Pharmaceuticals of Japan, has entered clinical phase I research. BMS's intravenous small molecule FXIa inhibitor BMS-962122 has completed clinical phase I trials. Monoclonal antibodies and antisense oligonucleotides need to be injected, and have the disadvantages of being expensive, slow to take effect, and potentially difficult to control. Chemical small molecules have advantages such as relatively good oral bioavailability and better patient compliance. Therefore, the development of new FXIa small molecule inhibitors that are safe, effective, specific, and highly active may make up for the shortcomings of current clinical anticoagulant and antithrombotic drugs that are prone to bleeding complications and meet unmet clinical needs.

Plasma kallikrein (PK) is a serine protease similar to trypsin that exists in plasma. It is similar to the gene of coagulation factor XIa, and the amino acid sequence similarity is as high as 58%. In the blood, most plasma kallikrein exists in the form of a complex with high molecular weight kininogen (HMWK). Plasma kallikrein participates in blood coagulation, fibrinolysis and kinin generation, and plays a role in coagulation and many inflammatory diseases. Activated factor XIIa (FXIIa) cleaves prekallikrein to form kallikrein (PK), which promotes HWMK cleavage to form bradykinin, thereby promoting coagulation. Plasma kallikrein inhibitors may be used to treat diseases such as hereditary angioedema (HAE) and advanced diabetic macular edema. The plasma kininase inhibitor large molecule protein drug Ecallantide (Kalbitor) has been approved by the FDA for the treatment of HAE. However, no small molecule plasma kininase inhibitor has been approved for marketing. The development of safe and effective new Kallikrein small molecule inhibitor drugs may also meet unmet clinical needs.

Summary of the invention

The inventors of the present invention have rationally designed and synthesized a series of small molecule compounds of novel structures represented by the following general formula (I) through repeated experimental studies, which have high inhibitory activity against coagulation factor XIa (FXIa). These compounds or their stereoisomers, racemates, geometric isomers, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof and pharmaceutical compositions can be used to treat and/or prevent diseases mediated by FXIa.

The compound of the present invention has high FXIa inhibitory activity and provides a new treatment option for the treatment of diseases such as thromboembolism.

The present invention provides a compound represented by formula (I), an optical isomer thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof,

in,

R ₁ is selected from CN, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-C (= O) -, 5-6 membered heteroaryl and 5-6 membered heterocycloalkenyl, wherein the C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-C (= O) -, 5-6 membered heteroaryl or 5-6 membered heterocycloalkenyl is optionally substituted by 1, 2 or 3 R;

_R2 is selected from F, Cl, Br, I, OH, _NH2 and Me;

_R3 is selected from H, halogen, OH, _NH2 , CN, _C1-6 alkyl, phenyl- _C1-6 alkyl-, 5- to 6-membered heteroaryl- _C1-6 alkyl-, 3- to 6-membered heterocycloalkyl- _C1-6 alkyl-, and _C3-6 cycloalkyl- _C1-6 alkyl-, wherein the _C1-6 alkyl, phenyl- _C1-6 alkyl-, 5- to 6-membered heteroaryl- _C1-6 alkyl-, 3- to 6-membered heterocycloalkyl- _C1-6 alkyl-, or _C3-6 cycloalkyl- _C1-6 alkyl- is optionally substituted with 1, 2 or 3 R;

R ₄ are independently selected from H, F, Cl, Br, OH, NH ₂ and CN;

R ₅ is independently selected from H, F, Cl, Br, I, OH, NH ₂ and Me;

Ring A is selected from phenyl, naphthyl, 5-10 membered heteroaryl, benzo 5-6 membered heterocycloalkyl, benzo C _5-6 cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl and C _5-6 cycloalkyl;

Ring B is selected from 5-6 membered heteroaryl groups;

R is independently selected from H, F, Cl, Br, I, NH ₂ , CN, C _1-6 alkyl and C _1-6 heteroalkyl, wherein the C _1-6 alkyl or C _1-6 heteroalkyl is optionally substituted by 1, 2 or 3 R';

R' is independently selected from H, F, Cl, Br, I, _NH2 and CN;

n is selected from 0, 1, 2 or 3;

m is selected from 0, 1, 2 or 3;

represent and

The 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl, 5- to 6-membered heterocycloalkenyl, 3- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl, 5- to 6-membered heteroaryl and 5- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl and _C5-6 cycloalkyl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) _2- and N.

In some embodiments of the present invention, R is independently selected from H, F, Cl, Br, I, _NH2 , CN, _C1-3 alkyl, _C1-3 alkoxy and _C1-3 alkylamino, wherein the _C1-3 alkyl, _C1-3 alkoxy or _C1-3 alkylamino is optionally substituted with 1, 2 or 3 R', and the remaining variables are as defined in the present invention.

In some embodiments of the present invention, R is independently selected from H, F, Cl, Br, I, NH ₂ , CN, Me, The remaining variables are as defined in the present invention.

In some embodiments of the present invention, R ₁ is selected from CN, C _1-3 alkyl, C _1-3 alkoxy, 1H-1,2,3-triazolyl, 1H-tetrazolyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 4,5-dihydroisoxazolyl and The C _1-3 alkyl, C _1-3 alkoxy, 4,5-dihydroisoxazolyl or is optionally substituted with 1, 2 or 3 R, the 1H-1,2,3-triazolyl, isoxazolyl or oxazolyl is optionally substituted with 1 or 2 R, the 1H-tetrazolyl, 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl is optionally substituted with 1 R, and the remaining variables are as defined herein.

In some embodiments of the present invention, R ₁ is selected from CN, OCHF ₂ , The remaining variables are as defined in the present invention.

In some embodiments of the present invention, R ₃ is selected from H, Me, CF ₃ , The remaining variables are as defined in the present invention.

In some embodiments of the present invention, ring A is selected from phenyl, pyridyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, indolyl, dihydroindolin-2-one, 3,4-dihydroquinolin-2(1H)-one, 1,2,3,4-tetrahydro-1,8-naphthyridinyl and 2H-benzo[b][1,4]oxazin-3(4H)-one, and the remaining variables are as defined herein.

In some embodiments of the present invention, the structural unit Selected from The remaining variables are as defined in the present invention.

In some embodiments of the present invention, Ring B is selected from imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, and the remaining variables are as defined herein.

In some embodiments of the present invention, the structural unit Selected from The remaining variables are as defined in the present invention.

In another aspect of the present invention, the present invention also provides a compound of the following formula, an optical isomer thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, which is selected from

In another aspect of the present invention, the present invention also provides a pharmaceutical composition, which comprises the above-mentioned compound, its optical isomer, its pharmaceutically acceptable salt or its prodrug.

In some embodiments of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, diluents or excipients.

In yet another aspect of the present invention, the present invention also provides the use of the aforementioned compound, its optical isomer, its pharmaceutically acceptable salt or its prodrug or the aforementioned pharmaceutical composition in the preparation of FXIa inhibitors.

In another aspect of the present invention, the present invention also proposes the use of the aforementioned compound, its optical isomer, its pharmaceutically acceptable salt or its prodrug or the aforementioned pharmaceutical composition in the preparation of drugs for preventing and/or treating diseases mediated by FXIa factor.

In some embodiments of the present invention, the above-mentioned FXIa factor-mediated disease is selected from cardiovascular and cerebrovascular diseases.

In some embodiments of the present invention, the above-mentioned cardiovascular and cerebrovascular diseases are selected from thromboembolic diseases.

In some embodiments of the present invention, the above-mentioned thromboembolic disease is selected from hereditary angioedema, advanced diabetic macular edema, myocardial infarction, angina pectoris, re-occlusion and restenosis after angioplasty or aortocoronary bypass, disseminated intravascular coagulation, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis.

definition

The following terms and symbols used in this application have the meanings described below unless otherwise indicated in the context in which they are used.

A hyphen ("-") that is not between two letters or symbols indicates the point of attachment of a substituent. For example, _C1-6 alkylcarbonyl- refers to a _C1-6 alkyl group that is attached to the rest of the molecule via a carbonyl group. However, when the point of attachment of a substituent is obvious to one skilled in the art, for example, a halogen substituent, the "-" may be omitted.

When the group valence bond is marked with a dotted line When, for example, In the examples, the dashed line represents the point of attachment of the group to the rest of the molecule.

When the listed linking group does not indicate its linking direction, its linking direction is arbitrary, for example, The connecting group L is at this time You can connect benzene rings and cyclohexane in the same direction as reading from left to right to form You can also connect benzene rings and cyclohexane in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and/or variations thereof are permissible only if such combinations result in stable compounds.

The term "alkyl" as used herein refers to a straight or branched saturated monovalent hydrocarbon group having 1-8 carbon atoms, such as 1-6 carbon atoms, such as 1-4 carbon atoms, such as 1, 2 or 3 carbon atoms. For example, "C _1-8 alkyl" means an alkyl group having 1-8 carbon atoms. Similarly, "C _1-6 alkyl" means an alkyl group having 1-6 carbon atoms; "C _1-4 alkyl" means an alkyl group having 1-4 carbon atoms; "C _1-3 alkyl" means an alkyl group having 1-3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl ("Me"), ethyl ("Et"), propyl groups such as n-propyl ("n-Pr") or isopropyl ("i-Pr"), butyl groups such as n-butyl ("n-Bu"), isobutyl ("i-Bu"), sec-butyl ("s-Bu") or tert-butyl ("t-Bu"), pentyl, hexyl, and the like. This definition applies regardless of whether the term "alkyl" is used alone or as part of another group such as haloalkyl, alkoxy, and the like.

As used herein, the term "alkoxy" refers to the group -O-alkyl, wherein alkyl is as defined above. For example, "C _1-8 alkoxy" means -OC _1-8 alkyl, i.e., an alkoxy having 1-8 carbon atoms. Similarly, "C _1-6 alkoxy" means -OC _1-6 alkyl, i.e., an alkoxy having 1-6 carbon atoms; "C _1-4 alkoxy" means -OC _1-4 alkyl, i.e., an alkoxy having 1-4 carbon atoms; "C _1-3 alkoxy" means -OC _1-3 alkyl, i.e., an alkoxy having 1-3 carbon atoms. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy such as n-propoxy or isopropoxy, butoxy such as n-butoxy, isobutoxy, tert-butoxy, pentoxy and hexoxy, etc. This definition applies whether the term "alkoxy" is used alone or as part of another group.

The term "cycloalkyl" as used herein refers to a saturated monovalent monocyclic or bicyclic hydrocarbon group having 3-12 ring carbon atoms, such as 3-8 ring carbon atoms, such as 3-6 ring carbon atoms, such as 3-4 ring carbon atoms. For example, "C _3-12 cycloalkyl" means a cycloalkyl group having 3-12 ring carbon atoms. Similarly, "C _3-8 cycloalkyl" means a cycloalkyl group having 3-8 ring carbon atoms; "C _3-6 cycloalkyl" means a cycloalkyl group having 3-6 ring carbon atoms; "C _3-4 cycloalkyl" means a cycloalkyl group having 3-4 ring carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

As used herein, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, paracyclic and bridged rings. In addition, with respect to the "3-6 membered heterocycloalkyl", heteroatoms may occupy the position where the heterocycloalkyl is connected to the rest of the molecule. The 3-6 membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc. Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

As used herein, the term "4-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 4 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, paracyclic and bridged rings. In addition, with respect to the "4-6 membered heterocycloalkyl", heteroatoms may occupy the position where the heterocycloalkyl is connected to the rest of the molecule. The 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc. Examples of 4-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

As used herein, the term "5-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 5 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, paracyclic and bridged rings. In addition, with respect to the "5-6 membered heterocycloalkyl", heteroatoms may occupy the position where the heterocycloalkyl is connected to the rest of the molecule. The 5-6 membered heterocycloalkyl includes 5-membered and 6-membered heterocycloalkyl. Examples of 5-6 membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

The term "3-5 membered heterocycloalkyl" as used herein, by itself or in combination with other terms, represents a saturated monocyclic group consisting of 3 to 5 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). In addition, with respect to the "3-5 membered heterocycloalkyl", the heteroatom may occupy the position of connection of the heterocycloalkyl with the rest of the molecule. The 3-5 membered heterocycloalkyl includes 4-5, 4, and 5 membered heterocycloalkyls, etc. Examples of 3-5 membered heterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl, thiinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.) or tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), etc.

Unless otherwise specified, the term "5-6 membered heterocycloalkenyl" by itself or in combination with other terms refers to a partially unsaturated cyclic group consisting of 5 to 6 ring atoms containing at least one carbon-carbon double bond, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, paracyclic and bridged rings, and any ring of this system is non-aromatic. In addition, with respect to the "5-6 membered heterocycloalkenyl", heteroatoms can occupy the connection position of the heterocycloalkenyl group to the rest of the molecule. The 5-6 membered heterocycloalkenyl group includes 5-membered and 6-membered heterocycloalkenyl groups, etc. Examples of 5-6 membered heterocycloalkenyl groups include, but are not limited to

Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" of the present invention can be used interchangeably. The term "5-10 membered heteroaryl" refers to a cyclic group consisting of 5 to 10 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic system, wherein each ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). The 5-10 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a carbon atom. The 5-10 membered heteroaryl includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl, etc. Examples of the 5-10 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4- thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.), or quinolyl (including 3-quinolyl and 6-quinolyl, etc.).

Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably. The term "5-6 membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). The 5-6 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl) and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

The term "benzo 5-6 membered heterocycloalkyl" as used herein refers to a bicyclic ring formed by a phenyl group and a 5-6 membered heterocycloalkyl group, examples of which include but are not limited to wait.

The term "benzo C _5-6 cycloalkyl" as used herein refers to a bicyclic ring formed by a phenyl group and a 5- to 6-membered heterocycloalkyl group, examples of which include but are not limited to wait.

The term "5- to 6-membered heteroaryl and 5- to 6-membered heterocycloalkyl" as used herein refers to a bicyclic ring formed by a phenyl group and a 5- to 6-membered heterocycloalkyl group, examples of which include but are not limited to wait.

The term "5-6 membered heteroaryl C _5-6 cycloalkyl" as used herein refers to a bicyclic ring formed by a phenyl group and a 5-6 membered heterocycloalkyl group, examples of which include but are not limited to wait.

Unless otherwise specified, Cn _-n+m or _Cn - _Cn+m includes any specific case of n to n+m carbon atoms, for example, _C1-12 includes _C1 , _C2 , C3, _C4 , _C5 , _C6 , _C7 , _C8 , _C9 , _C10 , _C11 , and _C12 , and also includes any range from n to n+m, for example, _C1-12 includes _C1-3 , C1-6, _C1-9 , _{C3-6 , C3-9} , _C3-12 , _C6-9 , _C6-12 , _and C13. _9-12, etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.

As used herein, the term "optionally" means that the subsequently described event may or may not occur, and that the description includes instances where the event occurs as well as instances where the event does not occur. For example, "optionally substituted alkyl" refers to unsubstituted alkyl and substituted alkyl, wherein alkyl is as defined herein. It will be understood by those skilled in the art that for any group containing one or more substituents, the group does not include any sterically impractical, chemically incorrect, synthetically infeasible and/or inherently unstable substitution patterns.

As used herein, the term "substituted" or "substituted by" means that one or more hydrogen atoms on a given atom or group are replaced, for example, by one or more substituents selected from a given substituent group, provided that the normal valence of the given atom is not exceeded. When the substituent is oxo (i.e., =O), then two hydrogen atoms on a single atom are replaced by oxygen. Combinations of substituents and/or variables are permitted only if they result in chemically correct and stable compounds. A chemically correct and stable compound means that the compound is sufficiently stable to be isolated from a reaction mixture and the chemical structure of the compound can be determined, and then formulated into a formulation that at least has practical utility. For example, in the absence of explicit listing of substituents, the term "substituted" or "substituted" as used herein means that one or more hydrogen atoms on a given atom or group are independently replaced by one or more, e.g., 1, 2, 3 or 4, substituents independently selected from the group consisting of deuterium (D), halogen, -OH, mercapto, cyano, _-CD3 , alkyl (preferably _C1-6 alkyl), alkoxy (preferably _C1-6 alkoxy), haloalkyl (preferably halogenated _C1-6 alkyl), haloalkoxy (preferably halogenated _{C1-6 alkoxy} ), -C(O) _NRaRb and -N( _Ra )C(O) _Rb and -C(O) _OC1-4alkyl (wherein _Ra and _Rb are each independently selected from hydrogen, _C1-4 alkyl, _haloC1-4 alkyl), carboxyl (-COOH), cycloalkyl (preferably 3-8 membered cycloalkyl), heterocyclyl (preferably 3-8 membered heterocyclyl), aryl, heteroaryl, aryl-C1-6alkyl, -C _1-6 alkyl-, heteroaryl-C _1-6 alkyl-, -OC _1-6 alkylphenyl, -C _1-6 alkyl-OH (preferably -C _1-4 alkyl-OH), -C _1-6 alkyl-SH, -C _1-6 alkyl-OC _1-2 , -C _1-6 alkyl-NH ₂ (preferably -C _1-3 alkyl-NH ₂ ), -N(C _1-6 alkyl) ₂ (preferably -N(C _1-3 alkyl) ₂ ), -NH(C _1-6 alkyl) (preferably -NH(C _1-3 alkyl)), -N(C _1-6 alkyl)(C _1-6 alkylphenyl), -NH(C _1-6 alkylphenyl), nitro, -C(O)OC _1-6 alkyl (preferably -C(O)OC _1-3 alkyl), -NHC(O)(C _1-6 alkyl), -NHC(O)(phenyl), -N(C _1-6 alkyl)C(O)(C _{-C 1-6} alkyl), -N(C _1-6 alkyl)C(O)(phenyl), -C( _{O )} C _1-6 alkyl, -C(O)heteroaryl (preferably -C(O)-5-7 membered heteroaryl), -C(O)C _1-6 alkylphenyl, -C(O)C _1-6 haloalkyl, -OC(O)C _1-6 alkyl (preferably -OC(O)C _1-3 alkyl), alkylsulfonyl (e.g. -S(O) ₂ -C _1-6 alkyl), alkylsulfinyl (-S(O)-C _1-6 alkyl), -S(O) ₂ -phenyl, -S(O) ₂ -C _1-6 haloalkyl, -S(O) ₂ NH ₂ , -S(O) ₂ NH(C _1-6 alkyl), -S ₍ O) ₂ NH(phenyl), -NHS(O) ₂ (C _1-6 alkyl), -NHS(O) ₂ (phenyl) and -NHS(O) ₂ (C _1-6 haloalkyl), wherein the alkyl, cycloalkyl, phenyl, aryl, heterocyclyl and heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of halogen, -OH, -NH ₂ , cycloalkyl, 3-8 membered heterocyclyl, C _1-4 alkyl, C _1-4 haloalkyl-, -OC _{1-4 alkyl, -C 1-4} alkyl-OH, -C _1-4 alkyl-OC _1-4 alkyl, -OC _1-4 haloalkyl, cyano, nitro, -C(O)-OH, -C(O)OC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -CONH( _{C 1-6 alkyl} ), -CONH ₂ , -NHC(O)(C _1-6 alkyl), -NH(C _1-6 alkyl)C(O)(C _1-6 alkyl), -SO ₂ (C _1-6 alkyl), -SO _{2 When one} atom _{or group is} substituted with _{a plurality of} substituents _, the substituents _may be the _same or _{different .}

As used herein, the term "pharmaceutically acceptable" means non-toxic, biologically tolerable, and suitable for administration to an individual.

The term "pharmaceutically acceptable salt" as used herein refers to non-toxic, biologically tolerable acid addition salts or base addition salts of the compound of formula (I) suitable for administration to a subject, including but not limited to: acid addition salts of the compound of formula (I) with inorganic acids, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, etc.; and acid addition salts of the compound of formula (I) with organic acids, such as formates, acetates, malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethanesulfonates, benzoates, salicylates, stearates, and salts with alkanedicarboxylic acids of the formula HOOC-(CH ₂ ) _n -COOH (wherein n is 0-4), etc. "Pharmaceutically acceptable salts" also include base addition salts of the compound of formula (I) with an acidic group and pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium and ammonium.

In addition, if the compounds described herein are obtained in the form of acid addition salts, their free base forms can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is in the form of a free base, its acid addition salt, especially a pharmaceutically acceptable acid addition salt, can be obtained by dissolving the free base in a suitable solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art can determine various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable acid addition salts without undue experimentation.

The compounds of the present invention may exist in the form of solvates. The term "solvate" means a solvent addition form containing a stoichiometric or non-stoichiometric amount of a solvent. If the solvent is water, the solvate formed is a hydrate, and when the solvent is ethanol, the solvate formed is an ethanolate. Hydrates are formed by one or more molecules of water with one molecule of the substance, wherein the water retains its molecular state of H ₂ O, and such a combination can form one or more hydrates, such as hemihydrates, monohydrates and dihydrates.

The term "prodrug" as used herein refers to an active or inactive compound that is chemically modified into a compound of the present invention by physiological effects in vivo such as hydrolysis, metabolism, etc. after administration to an individual. The suitability and technology involved in the preparation and use of prodrugs are well known to those skilled in the art. Exemplary prodrugs include, for example, esters of free carboxylic acids and S-acyl derivatives of thiols and O-acyl derivatives of alcohols or phenols. Suitable prodrugs are generally pharmaceutically acceptable ester derivatives that can be converted into parent carboxylic acids by solvolysis under physiological conditions, such as lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as ω-(amino, mono- or di-lower alkylamino, carboxyl, lower alkoxycarbonyl)-lower alkyl esters, α-(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as pivaloyloxymethyl esters, etc., which are conventionally used in the art.

It will be appreciated by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers and therefore may exist as two or more stereoisomers. Therefore, the compounds of the present invention may exist as single stereoisomers (e.g. enantiomers, diastereomers) and mixtures thereof in any proportion, such as racemates, and, where appropriate, as tautomers and geometric isomers.

The term "stereoisomer" as used herein refers to compounds that have identical chemical constitution but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers, and the like.

As used herein, the term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

The term "diastereomer" as used herein refers to stereoisomers having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers can be separated by high resolution analytical methods such as electrophoresis and chromatography such as HPLC.

Stereochemical definitions and conventions may be followed in S. P. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l or (+) and (-) are used to indicate the sign of rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that are optically inactive.

The racemic mixture can be used in its own form or resolved into individual isomers. Stereochemically pure compounds or mixtures enriched in one or more isomers can be obtained by resolution. Methods for separating isomers are well known (see Allinger N.L. and Eliel E.L., "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), including physical methods, such as chromatography using chiral adsorbents. Individual isomers in chiral form can be prepared from chiral precursors. Alternatively, the individual isomers can be chemically separated from the mixture by forming diastereomeric salts with chiral acids (e.g., individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing the salts, then freeing one or both of the resolved bases, and optionally repeating this process to obtain one or both isomers that are substantially free of the other isomer, i.e., the desired stereoisomers having an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight. Alternatively, as is well known to those skilled in the art, the racemates can be covalently linked to chiral compounds (auxiliaries) to obtain diastereomers.

As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations, e.g. and are tautomers, representing the same compound. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

As used herein, the term "treatment" refers to the administration of one or more drug substances, particularly compounds of formula (I) and/or pharmaceutically acceptable salts thereof, to an individual suffering from a disease or symptoms of the disease, in order to cure, alleviate, mitigate, alter, cure, improve, ameliorate or affect the disease or symptoms of the disease. As used herein, the term "prevention" refers to the administration of one or more drug substances, particularly compounds of formula (I) and/or pharmaceutically acceptable salts thereof, to an individual with a physique susceptible to the disease, in order to prevent the individual from suffering from the disease. When referring to a chemical reaction, the terms "treating", "contacting" and "reacting" refer to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and/or desired product. It should be understood that the reaction that produces the indicated and/or desired product may not necessarily result directly from the combination of the two reagents initially added, that is, there may be one or more intermediates generated in the mixture, which ultimately lead to the formation of the indicated and/or desired product.

The term "effective amount" as used herein refers to an amount that is generally sufficient to produce a beneficial effect on an individual. The effective amount of the compound of the present invention can be determined by conventional methods (e.g., modeling, dose escalation studies or clinical trials) in combination with conventional influencing factors (e.g., mode of administration, pharmacokinetics of the compound, severity and course of the disease, individual medical history, individual health status, individual response to the drug, etc.).

Technical and scientific terms used herein without specific definition have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

DETAILED DESCRIPTION

The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only intended to illustrate the present invention and are not intended to limit the scope of the present invention. In the following examples, the experimental methods without specifying specific conditions are usually based on the normal conditions of this type of reaction, or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts. Unless otherwise stated, the ratio of liquid is volume ratio.

Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

In the following examples, ¹ H-NMR spectra were recorded using a Bluker AVANCE III HD 400 MHz NMR instrument; ¹³ C-NMR spectra were recorded using a Bluker AVANCE III HD 400 MHz NMR instrument, and chemical shifts are expressed in δ (ppm); mass spectra were recorded using a Shimadzu LCMS-2020 (ESI type) or Agilent 6215 (ESI) mass spectrometer; reverse phase preparative HPLC separations were performed using a Gilson GX281 UV-guided fully automated purification system ( Prep C18OBDTM 19*250mm 10μm column)/or Waters QDa-guided fully automated purification system ( Prep C18OBD 29*250mm 10μm column). Chiral analysis HPLC was performed using a Waters UPCC supercritical fluid analysis system ( OD-H4.6*250mm 5μm column or AS-3 0.3cm*100mm 3μm column); chiral separation SFC was performed using Waters-SFC80 supercritical fluid purification system ( OD 2.5*25cm, 10μm column or AS 2.5*25cm, 10μm column).

Among them, the Chinese names of reagents represented by chemical formulas or English abbreviations are as follows:

AcOH or HOAc represents acetic acid; AcONH ₄ , NH ₄ OAc or CH ₃ COONH ₄ represents ammonium acetate; Aq represents aqueous solution; br represents broad peak; ℃ represents degrees Celsius; CDCl ₃ represents deuterated chloroform; conc. represents concentration; DAST represents diethylaminosulfur trifluoride; DCM or CH ₂ Cl ₂ represents dichloromethane; DIPEA or DIEA represents N,N-diisopropylethylamine; DMAP represents 4-dimethylaminopyridine or N,N-dimethyl-4-aminopyridine; DMF represents dimethylformamide; DMSO represents dimethyl sulfoxide; EA or EtOAc represents ethyl acetate; ELSD represents evaporative light scattering detector; ESI represents electrospray ionization; g represents gram; h represents hour; H ₂ O represents water; HCl represents hydrogen chloride or hydrochloric acid; HPLC represents high performance liquid chromatography; K ₂ CO ₃ represents potassium carbonate; KOAc represents potassium acetate; LCMS represents liquid chromatography-mass spectrometry; m represents multiplet; M represents molar concentration; m/z represents mass-to-charge ratio; MeCN, ACN or CH ₃ CN represents acetonitrile; MW or W represents microwave; MeOH represents methanol; min represents minute; mg represents milligram; mL represents milliliter; mmol represents millimole; mol represents mole; MOMCl represents chloromethyl methyl ether; N ₂ represents nitrogen; N ₂ H ₄ represents hydrazine; NH ₂ NH ₂ ·H ₂ O represents hydrazine hydrate; NaHCO ₃ represents sodium bicarbonate; NaN ₃ represents sodium azide; NaNO ₂ represents sodium nitrite; Na ₂ SO ₄ represents sodium sulfate; NBS represents N-bromosuccinimide; NMP represents N-methyl-2-pyrrolidone; Pd(dppf)Cl ₂ or PdCl ₂ (dppf) represents 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride; Pd(PPh ₃ ) ₄ represents tetrakis(triphenylphosphine)palladium(0); PE represents petroleum ether; PhNTf ₂ represents N-phenyl(trifluoromethanesulfonyl imide); POCl ₃ represents phosphorus oxychloride; Py represents pyridine; rt or RT represents room temperature; s represents singlet; Selectfluor represents 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate); t represents triplet; TLC represents thin layer chromatography; TFA or CF ₃ COOH represents trifluoroacetic acid; THF represents tetrahydrofuran; Toluene or tol. represents toluene.

Synthesis of Examples

Example 1: Synthesis of Compound A1

Step 1: Synthesis of intermediate 1

2-Bromo-4-chloro-nitrobenzene (4729 mg, 20.00 mmol), biboronic acid pinacol ester (6095 mg, 24.00 mmol), KOAc (3926 mg, 40.00 mmol) were added to 1,4-dioxane (40 mL). Pd(dppf)Cl ₂ (1463 mg, 2.00 mmol) was added to the above mixture. The reaction system was protected by nitrogen and heated to 100°C for overnight reaction. The reaction solution was dried and purified by column chromatography (biotage, 80 g, silica gel column, UV254, DCM/PE=0-50%) to obtain intermediate 1. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.21 (d, J = 8.8 Hz, 1H), 7.78 ( dd, J = 8.8, 2.4 Hz, 1H), 7.71 ( d, J = 2.3 Hz, 1H), 1.35 ( s, 12H).

Step 2. Synthesis of Intermediate 2

At room temperature, 6-fluoro-5-iodopyridin-2-amine (22.2 g, 93.28 mmol), di-tert-butyl dicarbonate (22.4 g, 102.61 mmol), DMAP (1.14 g, 9.328 mmol) and acetonitrile (444 mL) were added to a 1 L round bottom bottle and reacted for 4 hours. TLC detection showed that the starting material disappeared. The reaction solution was filtered to remove the solid, and the filtrate was concentrated and purified by normal phase column (PE/EA=0-5%) to obtain intermediate 2. LC-MS: m/z 282.9 (M-56+H) ⁺ .

Step 3. Synthesis of Intermediate 3

At room temperature, intermediate 2 (15.2 g, 44.95 mmol), tributyl (1-ethoxyvinyl) stannane (18.9 g, 52.33 mmol), Pd (PPh ₃ ) ₄ (1.22 g, 1.056 mmol) and DMF (75 mL) were added to a 250 mL round-bottom flask. Under argon protection, the temperature was raised to 120°C and the reaction was carried out for 16 h. LC-MS detection showed that the reaction was complete. EA (300 mL) and 1 M potassium fluoride aqueous solution (600 mL) were added to the reaction solution, stirred for 30 min, and solid precipitated, which was filtered. The filtrate was extracted with EA (2*200 mL), separated, the organic phases were combined, and dried over anhydrous Na ₂ SO _4. Purification with a normal phase column (PE/EA=0-5%) gave intermediate 3. LC-MS: m/z 227.2 (M-56+H) ⁺ .

Step 4. Synthesis of intermediate 4

Add intermediate 3 (5.0 g, 17.7 mmol), THF (60 mL) and water (20 mL) to a 250 mL round-bottom flask, stir, and cool to 0°C in an ice bath. Add NBS (3.14 g, 17.7 mmol) in batches at 0°C. After the addition, keep the reaction at 0°C for 30 min. LC-MS detection shows that the reaction is complete. The reaction solution is extracted with EA (3*100 mL) and the organic phases are combined. The organic phase is washed with saturated NaHCO ₃ aqueous solution (2*200 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated to obtain a crude product. The crude product is purified by normal phase column (PE/EA=0-20%) to obtain intermediate 4. LCMS: m/z 276.9 (M-56+H) ⁺ .

Step 5. Preparation of intermediate 6

Dissolve methyl 3-aminofuran-2-carboxylate (850 mg, 6.02 mmol) in 10 mL of methanol, add p-anisaldehyde (984 mg, 7.20 mmol), add acetic acid (361 mg, 6.02 mmol) under ice bath conditions, add sodium cyanoborohydride (760 mg, 12.04 mmol) in batches, monitor by TLC after 30 minutes, and continue to add acetic acid and sodium cyanoborohydride until p-anisaldehyde reacts completely. Add H ₂ O (50 ml) to the reaction solution, extract with EA (50 ml*3), combine the organic phases, dry and concentrate to obtain a crude product, and purify it with a normal column to obtain intermediate 6. LC-MS: m/z 262.2 (M+H) ⁺ ; ¹ H NMR (400MHz, Chloroform-d) δ7.25 (s, 2H), 7.23 (s, 1H), 6.88 (s, 1H), 6.86 (s, 1H), 6.14 (d, J = 2.0Hz, 1H), 4.33 (s, 2H), 3.87 (s, 3H ),3.80(s,3H).

Step 6. Preparation of intermediate 7

Dissolve intermediate 6 (857 mg, 3.28 mmol) in 5 mL of dichloromethane, add triethylamine (498 mg, 4.92 mmol) and methyl malonyl chloride (717 mg, 5.251 mmol) under ice bath, monitor the reaction of raw materials after 30 minutes by TLC. Add H ₂ O (100 ml) to the reaction solution, extract with EA (100 ml*3), combine the organic phases, dry and concentrate to obtain a crude product, and purify it with a normal column to obtain intermediate 7. LC-MS: m/z 362.2 (M+H) ⁺ ; ¹ H NMR (400MHz, Chloroform-d) δ7.47 (d, J = 1.9 Hz, 1H), 7.12 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 2.1 Hz, 2H), 6.18 (d, J = 1.9 Hz, 1H), 5.02 (s, 1 H), 4.58 (s, 1H), 3.78 (d, J = 7.2Hz, 6H), 3.68 (s, 3H), 3.32 (s, 2H).

Step 7. Preparation of intermediate 8

Intermediate 7 (7.2 g, 19.94 mmol) was dissolved in 50 mL of methanol, sodium methoxide (2.15 g, 39.89 mmol) was added, and the mixture was refluxed at 85°C for 1 hour. The raw material was converted into a ring-closed product by LCMS monitoring. After cooling to room temperature, 25 mL of H ₂ O and sodium hydroxide (4 g, 99.7 mmol) were added in an ice bath, and the mixture was heated to 120°C and refluxed overnight. After cooling, the methanol was dried by spin-drying, and 1 M dilute hydrochloric acid was slowly added dropwise in an ice bath to neutralize the mixture to weak acidity. Solids precipitated during the addition process, and the mixture was filtered, and the filter cake was washed with water and spin-dried to obtain Intermediate 8. LC-MS: m/z 272.2 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.50 (s, 1H), 8.07–7.92 (m, 1H), 7.26 (d, J = 8.7Hz, 2H), 6.94 (d, J = 2.1Hz, 1H), 6.86 (d, J = 8.7Hz, 2H), 5.62 (s, 1H), 5.09 (s, 2H), 3.71(s,3H).

Step 8. Preparation of intermediate 9

The intermediate 8 (1.1 g, 4.06 mmol) was dissolved in 5 mL of DMF, triethylamine (820 mg, 8.122 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (1.88 g, 5.28 mmol) were added under ice bath, and the mixture was reacted at room temperature for 5 hours. After TLC monitoring, the reaction of the raw materials was completed, _H2O (100 ml) was added to the reaction solution, and the mixture was extracted with EA (100 ml*3). The organic phases were combined, dried and concentrated to obtain a crude product 9.

Step 9. Preparation of intermediate 10

Intermediate 9 was dissolved in 30 mL of dioxane and 2.5 mL of water, and intermediate 1 (1.5 g, 52.8 mmol), potassium carbonate (1.1 g, 8.12 mmol) and Pd(dppf)Cl ₂ (208 mg, 0.28 mmol) were added, nitrogen was replaced, and the reaction was carried out at 110°C overnight. After cooling, H ₂ O (100 ml) was added to the reaction solution, and extracted with EA (100 ml*3). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by a normal column to obtain intermediate 10. LC-MS: m/z 411.1 (M+H) ⁺ .

Step 10. Preparation of intermediate 11

Intermediate 10 (1.5 g, 3.65 mmol) was dissolved in 10 mL of trifluoroacetic acid, sealed, reacted at 100° C. overnight, concentrated to obtain a crude product, and purified by a forward column to obtain intermediate 11. LC-MS: m/z 291.1 (M+H) ⁺ .

Step 11. Preparation of intermediate 12

In a 50 mL round-bottom flask, add intermediate 11 (1000 mg, 3.45 mmol), tert-butyl 2-bromoacetate (1010 mg, 5.18 mmol), potassium carbonate (1430 mg, 10.35 mmol) and DMF (15 mL), heat to 50 ° C, and stir to react for 16 hours. LC-MS shows that the product is generated and the reaction is complete. The reaction solution is added with water (50 mL), extracted with EA (3*50 mL), and the organic phase is washed with saturated brine (100 mL), dried and concentrated. The crude product is purified by normal phase column (PE/EA=0-50%) to obtain intermediate 12. LC-MS: m/z 405.1 (M+H) ⁺ .

Step 12. Preparation of intermediate 13

In a 50 mL round-bottom flask, intermediate 12 (910 mg, 2.25 mmol) and TFA/DCM (2/8 mL) were added and reacted at room temperature for 2 hours. LCMS showed that the product was generated and the reaction was complete. The reaction solution was spin-dried to obtain intermediate 13. LC-MS: m/z 349.1 (M+H) ⁺ .

Step 13. Synthesis of intermediate 14

In a 100 mL round-bottom flask, intermediate 13 (800 mg crude product, 2.25 mmol) and ethanol (20 mL) were added, Raney Ni (catalytic amount) was added to the above reaction solution, and then hydrazine hydrate (563 mg, 11.25 mmol) was added. After the addition, the reaction was allowed to proceed at room temperature for 3 hours. LCMS showed that a product was generated, and the reaction was terminated. The reaction solution was filtered and dried. The crude product was purified by reverse phase column (biotage, C-18, 40 g, UV214, MeCN/0.5% TFA aqueous solution = 0-95%) to obtain intermediate 14. LC-MS: m/z 319.0 (M+H) ⁺ .

Step 14. Synthesis of Intermediate 15

In a 25 mL round-bottom flask, intermediate 14 (520 mg, 1.63 mmol), trimethyl orthoformate (domestic) (693 mg, 6.54 mmol) and acetic acid (3 mL) were added and stirred at room temperature for 30 minutes. Then NaN ₃ (425 mg, 6.54 mmol) was added, the temperature was raised to 40°C, and the reaction was continued for 16 hours. LCMS showed that the reaction was complete. The reaction was purified by reverse phase column (biotage, C-18, 40 g, UV214, MeCN/0.5% TFA aqueous solution = 0-95%) to obtain intermediate 15. LC-MS: m/z 372.1 (M+H) ⁺ .

Step 15. Synthesis of intermediate 16

A solution of intermediate 15 (180 mg, 0.48 mmol), intermediate 4 (194 mg, 0.58 mmol) and DIPEA (186 mg, 1.44 mmol) in NMP (2 mL) was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction solution and extracted with EA (10 mL) three times. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was washed with toluene.

/HOAc (10:1, 2mL) solution was dissolved, and NH ₄ OAc (373mg, 4.80mmol) was added. The mixture was heated to 100°C and stirred for 16 hours. The reaction solution was cooled to room temperature and dried. The residue was purified by silica gel column chromatography (EA/PE=0-100%) to obtain intermediate 16. LC-MS: m/z 604.1 (M+H) ⁺ .

Step 16. Synthesis of Compound A1

A solution of intermediate 16 (25 mg, 0.041 mmol) in DCM/TFA (4:1, 1 mL) was stirred at room temperature for 2 hours. The reaction solution was spin-dried and the residue was purified by prep-HPLC to obtain product A1. LC-MS: m/z 504.1 (M+H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.10 (s, 1H), 9.75 (s, 1H), 7.96-7.90 (m, 4H), 7.81 (s, 1H), 7.08 (d, J=2.4 Hz, 1H), 6.98-6.93 (m, 1H), 6.44-6.23 (m, 4H), 5.27 (s, 2H).

Example 2: Synthesis of Compound A2

Step 1. Synthesis of intermediate 17

Selectfluor (30.8 mg, 0.086 mmol) was added to a solution of intermediate 16 (35 mg, 0.058 mmol) in CH ₃ CN/THF/Py (3.6:1.2:0.4, 0.5 ml) at -60°C. The mixture was stirred at -25°C-35°C for 8 hours. Saturated sodium sulfite solution (2 mL) and EA (5 mL) were added to the reaction solution, stirred for 5 minutes, water (5 mL) was added, and extracted with EA (5 mL) for 3 times. The organic phases were combined, washed with 1N HCl (5 mL), saturated sodium bicarbonate solution (5 mL), and saturated brine (5 mL), respectively, dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by flash preparative chromatography (CH ₃ CN/0.05% TFA in H ₂ O=0-95%) to obtain intermediate 17. LC-MS: m/z 622.1 (M+H) ⁺ .

Step 2. Synthesis of Compound A2

A solution of intermediate 17 (17 mg, 0.027 mmol) in DCM/TFA (4:1, 0.5 mL) was stirred at room temperature for 2 hours. The reaction solution was spin-dried and the residue was purified by prep-HPLC to obtain product A2. LC-MS: m/z 522.1 (M+H) ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.46-12.40 (m, 1H), 9.78 (s, 1H), 8.46 (s, 1H), 7.97-7.96 (m, 1H), 7.95-7.90 (m, 2H), 7.82 (d, J = 2 .0Hz,1H),7.58-7.54(m,1H),6.96(d,J＝2.0Hz,1H),6.54-6.52(m,2H),6.41-6.38(m,1H),6.28(s,1H),5.21(s,2H).

Example 3: Synthesis of Compound A3

Step 1. Synthesis of intermediate 18

Intermediate 8 (49 mg, 0.18 mmol) was dissolved in 2 mL of DMF, sodium hydrogen sulfide (11 mg, 0.27 mmol) was added under ice bath, MOMCl (26 mg, 0.32 mmol) was added dropwise after 5 minutes, and LCMS was monitored after 30 minutes. Saturated ammonium chloride solution (20 ml) was added to the reaction solution, extracted with EA (15 ml*3), the organic phases were combined, dried and concentrated to obtain a crude product, and purified by a normal column to obtain intermediate 18. LC-MS: m/z 316.2 (M+H) ⁺ .

Step 2. Synthesis of intermediate 19

Intermediate 18 was dissolved in 40 mL of ethyl acetate, 400 mg of palladium carbon (400 mg, 0.32 mmol, purity 9.7%) was added, hydrogen was replaced with a hydrogen balloon, refluxed at 60°C for 7 hours, filtered, concentrated to obtain a crude product, and purified by a normal column to obtain intermediate 19. LC-MS: m/z 318.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, Chloroform-d) δ 7.20 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.16 (s, 1H), 5.22 (s, 2H), 5.09 (s, 2H), 4.55 (t, J = 9.0 Hz, 2H), 3.78 (s, 3H), 3.48 (s, 3H), 3.15 (t, J = 9.0 Hz, 2H).

Step 3. Synthesis of intermediate 20

Intermediate 19 (566 mg, 1.79 mmol) was dissolved in 15 mL of methanol, p-toluenesulfonic acid monohydrate (136 mg, 714 mmol) was added under ice bath, reacted overnight at room temperature, concentrated to obtain a crude product, and purified by forward column to obtain intermediate 20. LC-MS: m/z 274.1 (M+H) ⁺ .

Step 4. Synthesis of intermediate 21

The intermediate 20 (476 mg, 1.74 mmol) was dissolved in 7 mL of DMF, triethylamine (527 mg, 5.22 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (809 mg, 2.27 mmol) were added under ice bath, and the mixture was reacted at room temperature for 3 hours. After the reaction of the raw materials was completed by TLC monitoring, _H2O (100 ml) was added to the reaction solution, and the mixture was extracted with EA (100 ml*3). The organic phases were combined, dried and concentrated to obtain the intermediate 21.

Step 5. Synthesis of intermediate 22

Intermediate 21 was dissolved in 15 mL of dioxane and 1.5 mL of water, and intermediate 1 (640 mg, 2.26 mmol), potassium carbonate (481 mg, 3.48 mmol) and Pd(dppf)Cl ₂ were added, nitrogen was replaced, and the mixture was reacted at 105°C overnight. After cooling, H ₂ O (100 ml) was added to the reaction solution, and the mixture was extracted with EA (100 ml*3). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by a normal column to obtain intermediate 22. LC-MS: m/z 413.1 (M+H) ⁺ .

Step 6. Synthesis of intermediate 23

Intermediate 22 (25 mg, 0.061 mmol) was dissolved in 3 mL of trifluoroacetic acid, sealed, reacted at 105° C. overnight, concentrated to obtain a crude product, and purified by a forward column to obtain intermediate 23. LC-MS: m/z 293.1 (M+H) ⁺ .

Step 7. Synthesis of intermediate 24

K ₂ CO ₃ (106 mg, 0.77 mmol) and lithium bromide (187 mg, 0.77 mmol) were added to a DMF (4 mL) solution of intermediate 23 (150 mg, 0.51 mmol) and stirred at 80°C for 40 min. The temperature was lowered to 50°C, tert-butyl bromoacetate was dissolved in 1 mL of DMF and added dropwise to the reaction solution, and the reaction was carried out at 50°C overnight. After cooling, H ₂ O (100 ml) was added to the reaction solution, and the mixture was extracted with EA (100 ml*3). The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by a normal column to obtain intermediate 24. LC-MS: m/z 407.2 (M+H) ⁺ .

Step 8. Synthesis of intermediate 25

Intermediate 24 (253 mg, 0.62 mmol) was dissolved in THF/MeOH (4 mL/4 mL), RaneyNi (catalytic amount) and 6 mL of hydrazine hydrate were added to the reaction solution, and the reaction solution was stirred at 85°C for 1 h. The reaction solution was filtered, the filter cake was washed with MeOH (5 mL*2), and the filtrate was dried to obtain the crude intermediate 25. LC-MS: m/z 377.2 (M+H) ⁺ .

Step 9. Synthesis of intermediate 26

Intermediate 25 (200 mg, 0.53 mmol) was dissolved in a mixed solvent of TFA (2 mL) and DCM (4 mL) and stirred at 25°C for 2 hours. The reaction solution was concentrated, the solvent was removed, and the crude product was separated and purified by reverse phase column (biotage, C-18, 40 g, UV254, MeCN/0.05% TFA aqueous solution = 0-40%) to obtain intermediate 26. LC-MS: m/z 321.1 (M+H) ⁺ .

Step 10. Synthesis of intermediate 27

Intermediate 26 (135 mg, 0.42 mmol) and trimethyl orthoformate (267 mg, 2.52 mmol) were added to AcOH (2 mL) and stirred for 30 min. NaN ₃ (164 mg, 2.52 mmol) was added to the reaction solution and stirred overnight. The reaction solution was directly purified by reverse phase column (biotage, C-18, 40 g, UV254, MeCN/0.05% TFA aqueous solution = 0-35%)

The intermediate 27 was obtained. LC-MS: m/z 374.1 (M+H) ⁺ .

The remaining steps were similar to the synthesis of compound A1 in Example 1 to obtain A3, LC-MS: m/z 506.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.73 (s, 1H), 7.92–7.82 (m, 3H), 7.78 (d, J=1.6 Hz, 1H), 7.53 (s, 1H), 6.49–6.40 (m, 1H), 6.36 (s, 1H), 5.23 (s, 2H), 4.14 (t, J=8.9 Hz, 2H), 3.30 (s, 2H).

Example 4: Synthesis of Compound A4

Step 1. Synthesis of intermediate 28

2-Bromo-4-chloroaniline (619 mg, 3.00 mmol) and water (12 mL) were added to a 100 mL round-bottom flask. Subsequently, 3.7 mL of concentrated hydrochloric acid was added, and the reaction solution was cooled to -5°C. At -5°C, an aqueous solution (1.5 mL) of NaNO ₂ (228 mg, 3.30 mmol) was added to the above reaction solution, and the temperature was maintained for 1 hour. Then, an aqueous solution (1.5 mL) of NaN ₃ (215 mg, 3.30 mmol) was added, and the reaction was continued at -5°C for 0.5 hour. The reaction solution was extracted with EA (3*40 mL), and the organic phases were combined, washed with saturated NaHCO ₃ aqueous solution (100 mL), water (100 mL) and saturated brine (100 mL) in sequence, dried over Na ₂ SO ₄ , filtered and concentrated to obtain intermediate 28. LC-MS: UV has absorption, MS has no response.

Step 2. Synthesis of intermediate 29

In a 100 mL round-bottom flask, intermediate 28 (1150 mg, 4.98 mmol), 3,3-diethoxyprop-1-yne (956 mg, 7.47 mmol) and toluene (10 mL) were added, the temperature was raised to 110°C, and the reaction was stirred for 16 hours. LC-MS showed that the product was generated and the reaction was completed. The reaction solution was spin-dried and purified by normal phase column (PE/EA=0-50%) to obtain intermediate 29. LC-MS: m/z 362.0 (M+H) ⁺ .

Step 3. Synthesis of intermediate 30

HCl (20 mL) and dioxane (20 mL) were added to a 100 mL round-bottom flask, and intermediate 29 (1200 mg, 3.34 mmol) was added to the above mixed solution, and the temperature was raised to 30°C and the reaction was carried out for 16 hours. LC-MS detection showed that the product was generated and the reaction was completed. The reaction solution was diluted with water (40 mL) and extracted with EA (200 mL). The organic phase was washed with water (100 mL*2) and saturated sodium chloride (100 mL*2) in sequence, then dried with Na ₂ SO ₄ , filtered, and concentrated to obtain intermediate 30. LC-MS: m/z 288.0 (M+H) ⁺ .

Step 4. Synthesis of intermediate 31

In a 100 mL round-bottom flask, intermediate 30 (950 mg, 3.33 mmol), DAST (1072 mg, 6.66 mmol) and DCM (20 mL) were added and reacted at room temperature for 2 hours. LC-MS detection showed that the product was generated, and the reaction was terminated. The reaction solution was poured into a saturated NaHCO ₃ aqueous solution (60 mL) at 0°C, extracted with DCM (60 mL*2), and the organic phases were combined, washed with water (100 mL) and saturated brine (100 mL) in turn, dried over anhydrous Na ₂ SO ₄ , and concentrated. The crude product was purified by normal phase column (PE/EA=0-15%) to obtain intermediate 31. LCMS: m/z 310.0 (M+H) ⁺ .

Step 5. Synthesis of intermediate 32

Intermediate 9 (478 mg, 1.2 mmol), intermediate 31 (400 mg, 1.3 mmol), K ₂ CO ₃ (327 mg, 2.4 mmol) and Pd(dppf)Cl ₂ (65 mg) were dissolved in 28 mL of 1,4-dioxane and 9 mL of water, and the reaction was stirred at 125°C for 5 minutes. Bis-pinacol borate (1.8 g, 7.1 mmol) was dissolved in 3 mL of 1,4-dioxane and added to the reaction solution, and the reaction was stirred at 125°C for 10 minutes. The reaction solution was poured into 20 mL of water, extracted with ethyl acetate (20 mL*3), the organic phases were combined, washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product, which was purified by a normal column (EA/PE=2/3) to obtain intermediate 32. LCMS: m/z 483.0 (M+H) ⁺ .

The remaining steps were similar to the synthesis of compound A1 in Example 1 to obtain A4, LC-MS: m/z 553.2 (M+H)+; ¹ HNMR (400 MHz, DMSO-d6) δ12.04 (s, 1H), 8.82 (t, J=1.6 Hz, 1H), 7.92-7.83 (m, 2H), 7.81 (d, J=2.1 Hz, 2H), 7.72 (d, J=2.1 Hz, 1H), 7.23-7.10 (m, 1H), 7.06-6.94 (m, 1H), 6.94-6.81 (m, 1H), 6.37-6.21 (m, 2H), 6.19 (d, J=2.5 Hz, 2H), 5.20 (s, 2H).

Example 5: Synthesis of Compound A5

A5 was synthesized similarly to compound 1 in Example A1, LC-MS: m/z 555.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.11 (s, 1H), 8.85 (d, J=1.5 Hz, 1H), 7.99 (dd, J=10.5, 8.2 Hz, 1H), 7.85-7.73 (m, 3H), 7.26 (t, J=54.1 Hz, 1H), 7.09 (d, J=3.8 Hz, 1H), 6.36 (dd, J=8.2, 2.1 Hz, 1H), 6.27 (d, J=7.9 Hz, 2H), 5.10 (s, 2H), 4.12 (t, J=9.0 Hz, 2H), 3.30 (t, J=9.0 Hz, 2H).

Example 6: Synthesis of Compound A6

Step 1. Synthesis of intermediate 33

In a 250 mL three-necked round-bottom flask, add 2,2,2-trifluoroethylamine hydrochloride (4050 mg, 30.0 mmol) and NaNO ₂ (2277 mg, 33 mmol) and protect with argon. Then add toluene (60 mL) degassed with argon, put the reaction solution in an ice bath, cool to 0°C, and stir for 30 minutes. Then add water (6 mL) degassed with argon. After the addition, react at 0°C for 2 hours, then heat to 10°C and react for another 30 minutes. After the reaction is completed, place the reaction solution in a refrigerator (about -18°C) and freeze for 16 hours. Then transfer the organic phase in the reaction solution to a 250 mL dry round-bottom flask, add anhydrous K ₂ CO ₃ (3000 mg), stir and dry for 1 hour to obtain a dry toluene solution of intermediate 33.

Step 2. Synthesis of intermediate 34

2-Bromo-4-chloroaniline (2500 mg, 12.2 mmol), formic acid (2245 mg, 48.8 mmol) and sodium formate (415 mg, 6.1 mmol) were added to a 100 mL round-bottom flask. The reaction was stirred at room temperature for 16 hours. The reaction solution was diluted with EA (50 mL), washed with water (3*50 mL) and saturated NaHCO ₃ aqueous solution (50 mL) in sequence, dried over Na ₂ SO ₄ , filtered and concentrated to obtain product 34. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.82 (s, 1H), 8.36 (d, J＝1.3 Hz, 1H), 8.05 (d, J＝8.8 Hz, 1H), 7.80 (d, J＝2.4 Hz, 1H), 7.46 (dd, J＝8.6, 2.4 Hz, 1H).

Step 3. Synthesis of intermediate 35

In a 250 mL three-necked round-bottom flask, intermediate 34 (2600 mg, 11.2 mmol), triethylamine (3393 mg, 33.6 mmol) and anhydrous THF (30 mL) were added. The system was protected with nitrogen and cooled to 0°C in an ice bath. While maintaining the system temperature, POCl ₃ (2050 mg, 13.4 mmol) was dissolved in anhydrous THF (10 mL) and slowly added dropwise to the above reaction solution. After the addition, the temperature was maintained at 0°C and the reaction was allowed to react for 1 hour. LC-MS showed that a new product was generated and the reaction was completed. At 0°C, the reaction solution was poured into a saturated potassium carbonate aqueous solution (60 mL), extracted with methyl tert-butyl ether (2*50 mL), dried with Na ₂ SO ₄ , filtered and concentrated. Purified by normal phase column (PE/DCM=0-30%) to obtain product 35. ¹ H NMR (400MHz, CDCl ₃ ) δ7.68 (d, J = 2.1 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 8.5, 2.1 Hz, 1H).

Step 4. Synthesis of intermediate 36

In a 100 mL round-bottom flask, intermediate 35 (1650 mg, 7.6 mmol), intermediate 33 (30 mL, 0.3-0.4 M toluene solution), silver carbonate (416 mg, 1.52 mmol) were added. Molecular sieves (900 mg) and DMF (10 mL), heated to 40 ° C, reacted for 16 hours. LC-MS showed that the product was generated, and the reaction was terminated. The reaction was filtered, the toluene in the filtrate was dried, and then diluted with water (50 mL) and EA (50 mL). Extracted with EA (50 mL*3), the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated. The crude product was purified by normal phase column (PE/DCM=0-50%) to obtain intermediate 36. LCMS: m/z 328.0 (M+H) ⁺ .

Step 5. Synthesis of intermediate 37

Intermediate 9 (562 mg, 1.4 mmol), intermediate 36 (500 mg, 1.5 mmol), K ₂ CO ₃ (384 mg, 2.8 mmol) and Pd(dppf)Cl ₂ (65 mg) were dissolved in 28 mL of 1,4-dioxane and 9 mL of water, and the reaction was stirred at 125°C for 5 minutes. Bis-pinacol borate (2.1 g, 8.4 mmol) was dissolved in 3 mL of 1,4-dioxane and added to the reaction solution, and the reaction was stirred at 125°C for 10 minutes. The reaction solution was poured into 20 mL of water, extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and dried to obtain a crude product, which was purified by a normal column (EA/PE=2/3) to obtain Intermediate 37. LCMS: m/z 501.0 (M+H) ⁺ .

The remaining steps were similar to the synthesis of compound A4 in Example 4 to obtain A6, LC-MS: m/z 571.2 (M+H) ⁺ ; 1HNMR (400 MHz, DMSO-d6) δ9.23 (s, 1H), 7.87 (s, 3H), 7.81 (dd, J = 10.3, 8.4 Hz, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.21 (s, 1H), 7.15 (s, 1H), 7.03-6.88 (m, 2H), 6.43 (s, 1H), 6.31 (d, J = 7.8 Hz, 2H), 5.30 (s, 2H).

Example 7: Synthesis of Compound A7

Step 1. Synthesis of intermediate 38

Intermediate 9 (500 mg, 1.2 mmol), 2-bromo-4-chlorobenzonitrile (290 mg, 1.3 mmol), K ₂ CO ₃ (340 mg, 2.4 mmol) and Pd(dppf)Cl ₂ (65 mg) were dissolved in 28 mL of 1,4-dioxane and 9 mL of water, and the reaction was stirred at 125°C for 5 minutes. Bis-pinacol borate (1.89 g, 7.2 mmol) was dissolved in 5 mL of 1,4-dioxane and added to the reaction solution, and the reaction was stirred at 115°C for 10 minutes. The reaction solution was poured into 20 mL of water, extracted with ethyl acetate (20 mL*3), the organic phases were combined, washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, and dried to obtain a crude product, which was purified by a normal column (EA/PE=2/3) to obtain Intermediate 38. LC-MS: m/z 391.2 (M+H) ⁺ .

The remaining steps were similar to the synthesis of compound A4 in Example 4 to obtain A7, LC-MS: m/z 461.0 (M+H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d6) δ12.13 (s, 1H), 8.09–8.01 (m, 2H), 7.93–7.85 (m, 2H), 7.78 (dd, J=8.4, 2.1 Hz, 1H), 7.10 (d, J=2.1 Hz, 1H), 7.04 (dd, J=4.0, 2.1 Hz, 1H), 6.47 (d, J=9.0 Hz, 1H), 6.27 (dd, J=8.3, 2.2 Hz, 1H), 6.20 (s, 2H), 5.29 (s, 2H).

Effect embodiment:

1. Biological activity of the compounds of the present invention in inhibiting coagulation factor XIa (FXIa)

1. Test Method

Coagulation factor XIa protease (FXIa) decomposes specific substrates to produce yellow p-nitroaniline (pNA), which has strong absorption at 405 nM. The inhibitory activity of the compound on coagulation factor XIa is determined by detecting the absorbance of the compound at 405 nM.

2. Reagents, consumables and instruments

The coagulation factor XIa protease used in the experiment was purchased from Abcam, catalog number ab62411; the coagulation factor XIa specific substrate was purchased from HYPHEN BioMed, catalog number Biophen cs-21(66); tris-HCl was purchased from Invitrogen, catalog number 15567-027; NaCl was purchased from ABCONE, catalog number S39168; and Tween 20 was purchased from Amersco, catalog number 0777-1L.

Buffer: 100 mM tris-HCl, 200 mM NaCl, 0.02% Tween 20, pH = 7.4.

ECHO liquid workstation was purchased from Labcyte, model ECHO550; Bravo liquid workstation was purchased from Agilent, model 16050-101; multifunctional microplate reader was purchased from PerkinElmer, model EnVision; 384-well compound plate was purchased from Labcyte, model LP-0200; 384-well experimental plate was purchased from PerkinElmer, model 6007650.

3. Compound Preparation

The compounds were dissolved in 100% DMSO, 20 mM, and stored at room temperature in a nitrogen cabinet.

4. Test methods:

a. Use 100% DMSO to dilute the 20mM test compound to 2mM and the reference compound to 0.4mM; use the Bravo liquid workstation to dilute the compound 3-fold in a series of 10 concentration points.

b. Use ECHO liquid handling station to transfer 10 nL of compound to the corresponding 384-well experimental plate, duplicate wells; the final concentration of compound reaction is 1000, 333.3, 111.1, 37.0, 12.3, 4.1, 1.37, 0.46, 0.15, 0.05 nM. The final concentration of reference compound reaction is 200, 66.7, 22.2, 7.4, 2.47, 0.82, 0.27, 0.09, 0.03, 0.01 nM.

c. Transfer 10 nL DMSO to the high signal control wells and transfer 10 nL 0.4 mM reference compound to the low signal control wells.

d. Prepare 0.1 μg/mL FXIa enzyme solution with buffer, add 10 μL enzyme solution to 384-well test plate; prepare 5 mM substrate solution with buffer, add 10 μL substrate solution to 384-well test plate. The final concentration of FXIa is 0.05 μg/mL, and the final concentration of substrate is 2.5 mM.

e. Centrifuge the 384-well assay plate and incubate at 37°C for 15 minutes.

f. Use EnVision to measure absorbance at 405 nM.

In this example, the half-maximal inhibitory activity (IC ₅₀ ) of the compounds of the present invention on FXIa was determined as shown in Table 1, wherein:

Table 1. IC ₅₀ values (nM) of the compounds of the present invention for inhibition of FXIa

serial number FXIa IC ₅₀ serial number FXIa IC ₅₀ serial number FXIa IC ₅₀ A1 3.72 A2 1.63 A3 1.55

It can be seen that the compounds of the present invention have significant FXIa inhibitory activity.

II. Test of the Anticoagulant Effect of the Compounds of the Invention on Human Blood in Vitro

1. Test Method

After the activated partial thromboplastin time (APTT) assay reagent is mixed with plasma, the optical density changes until the coagulation point. The clotting time (CT) is measured by optical turbidimetry using a semi-automatic coagulation analyzer. The in vitro anticoagulant activity of the compound on human blood is determined by detecting the clotting time of plasma treated with different concentrations of the compound, and the concentration corresponding to the prolongation of the clotting time of the compound is calculated.

2. Reagents, consumables and instruments

The human plasma used in the experiment was from Huiyuan Biotechnology (Shanghai) Co., Ltd.; the activated partial thromboplastin time assay kit was purchased from Taizhou Zhongqinshidi Biotechnology Co., Ltd., catalog number SS00220005.

The semi-automatic coagulation analyzer was purchased from Shenzhen Shengxinkang Technology Co., Ltd., model SK5004; the measuring cup was purchased from Shenzhen Shengxinkang Technology Co., Ltd. Bravo liquid workstation was purchased from Agilent, model 16050-101; and the 384-well compound plate was purchased from Labcyte, model number LP-0200.

3. Compound Preparation

The compounds were dissolved in 100% DMSO, 20 mM, and stored at room temperature in a nitrogen cabinet.

4. Test methods

a. Incubate the NaCl reagent in the kit half an hour in advance and allow the APTT reagent to equilibrate to room temperature.

b. Use Bravo liquid handling station to dilute the compound 2-fold in a series of 14 concentration points.

c. Add 0.75 μL of compound to the measuring cup, double-dip; add 50 μL of plasma, add 50 μL of APTT reagent, mix well, and place in the coagulation analyzer and incubate at 37°C for 3 minutes.

d. Start the APTT assay, add 50 μL NaCl to initiate the reaction, and calculate the coagulation time.

e. 100% DMSO was used instead of the compound to measure the control clotting time, and the final DMSO concentration was 0.5%.

5. Data Processing

Graphpad Prism was used to perform curve fitting data and calculate CT2.0, i.e., the compound concentration corresponding to 2 times the aPTT of the blank control. The inhibition of human blood coagulation by the compounds of the present invention is shown in Table 2 below, where:

Table 2. CT2.0 (μM) of the compounds of the present invention

serial number CT2.0(μM) serial number CT2.0(μM) serial number CT2.0(μM) A1 3.24 A2 1.92 A3 2.40

The compounds of the present invention have significant anticoagulant activity.

All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims (10)

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, R ₁ is selected from _R2 is selected from F, Cl, Br and I; _R3 is H; R ₄ are independently selected from H, F, Cl, Br and NH ₂ ; R ₅ is independently selected from H, F, Cl, Br and I; Ring A is pyridyl; Ring B is imidazolyl; n is 2; m is selected from 0 or 1; represent 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ₂ is Cl. 3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein _R4 is independently selected from H, F and _NH2 . 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ₅ is independently selected from H and F. 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit for 6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from 7. A compound of the following formula or a pharmaceutically acceptable salt thereof, selected from 8. A pharmaceutical composition, wherein the pharmaceutical composition comprises the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. 9. Use of the compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the preparation of a FXIa inhibitor. 10. Use of the compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and/or treating a disease mediated by FXIa.