CN112028877B - Alkoxy pyridone compound and preparation method and application thereof - Google Patents

Abstract

The invention belongs to the field of pharmaceutical chemistry. Specifically, the invention relates to a series of inhibitors of Factor XIa (FXIa) with a novel structure, and a preparation method and application thereof. The structure is shown in the following general formula (I). The compounds or stereoisomers, racemates, geometric isomers, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts and pharmaceutical compositions thereof can be used for treating or/and preventing related diseases mediated by Factor XIa (FXIa).

Description

Alkoxy pyridone compound and preparation method and application thereof

The following priority is claimed in the present application:

CN201910479984.9, application date: 6 months and 4 days in 2019.

Technical Field

The invention belongs to the field of pharmaceutical chemistry. Specifically, the present invention relates to novel compounds which are inhibitors of Factor XIa (Factor XIa, abbreviated as FXIa) having a novel structure, or stereoisomers, racemates, geometric isomers, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing the same.

Background

Thromboembolic disorders are diseases that result from abnormal blood clots that form within blood vessels during the life of humans and animals. The causes of thrombosis are three: i.e. damaged blood vessels, altered blood flow and stasis of blood flow; is a group of complications caused by many different diseases and different causes. Due to differences of various basic diseases and different thromboembolic sites, the clinical manifestations of thrombotic diseases are myocardial infarction, stroke, Deep Venous Thrombosis (DVT), pulmonary embolism, atrial fibrillation, cerebral infarction and the like, especially the myocardial infarction, cerebral infarction and pulmonary infarction which are the main causes of embolism and infarction are the first causes of various deaths, and nearly 1200 million people are seized in the world every year and nearly one fourth of the total deaths in the world.

The human blood coagulation process consists of intrinsic pathway (intrinsic pathway), extrinsic pathway (extrinsic pathway) and common pathway (common pathway), which is a coagulation cascade of fibrin formation through sequential activation and then amplification of a series of coagulation factors. The intrinsic pathway (also called contact activation pathway) and the extrinsic pathway (also called tissue Factor pathway) initiate the generation of coagulation Factor Xa (Factor Xa, abbreviated as FXa), and then thrombin IIa (Factor IIa, abbreviated as FIIa) is generated through the common pathway, finally fibrin is formed. Procoagulant blood (hemostasis) and anticoagulant blood (antithrombosis) oppose each other and maintain relative equilibrium in the human blood system. When the function of the anticoagulation fibrinolysis system in vivo is reduced and the blood coagulation and anticoagulation functions in blood are out of balance, blood coagulation occurs, thereby causing thrombus or embolism.

Along with the elucidation of the mechanism of thrombosis, antithrombotic drugs which have been studied and developed mainly include three major classes of anticoagulants (e.g., warfarin, heparin, etc.), antiplatelet aggregation drugs (e.g., aspirin, clopidogrel, etc.), and thrombolytic drugs (e.g., urokinase, reteplase, etc.). The market of domestic anticoagulant drugs is rapidly increased, wherein the traditional varieties such as heparin drugs still occupy the main share, but the market scale gradually tends to be stable. The novel therapeutic drugs, namely direct thrombin (FIIa) inhibitors (such as dabigatran etexilate and the like) and activated blood coagulation factor Xa (FXa) inhibitors (such as rivaroxaban, apixaban and the like), show strong market activity and are strong competitors of heparin drugs. The use of activated blood coagulation factor (FXa) inhibitors is rapidly increasing because of their efficacy and safety in preventing and treating thromboembolic disorders such as stroke, pulmonary embolism, and Venous Thromboembolism (VTE). But with an increase in hospitalization and mortality associated with bleeding, which is a major complication of anticoagulant therapy. In 2016, approximately 117,000 hospitalized patients died due to FXa inhibitor-related bleeding in the united states alone, which is equivalent to approximately 2000 bleeding-related deaths per month. Therefore, it is of great importance to develop anticoagulant drugs with a low bleeding tendency.

Factor xi (fxi), a plasma serine protease zymogen essential for the maintenance of the intrinsic pathway, is activated to produce activated factor xia (fxia), which plays a key role in the amplification of the coagulation cascade. In the coagulation cascade, thrombin can feedback-activate FXI, which in turn promotes the massive production of thrombin, thereby amplifying the coagulation cascade. Therefore, drugs directed against FXI targets can block the intrinsic pathway and inhibit the amplification of the coagulation cascade, thus having an antithrombotic effect. In recent years, clinical data related to human coagulation Factor XI (FXI) deficiency or FXI level increase and thrombotic disease occurrence and antithrombotic experimental studies of animal FXI deficiency or knockout or inhibition show that FXI inhibition is a new target for antithrombotic prevention and treatment, and the risk of hemorrhage is possibly lower than that of direct FXa inhibitors.

Human FXI deficiency, also known as hemophilia C, is characterized by mild bleeding phenotype, rare spontaneous bleeding, and rare cases of joint and intramuscular bleeding, which means that there is less risk of bleeding when FXI is inhibited. Secondly, the incidence of ischemic stroke and deep venous thrombosis in FXI-deficient patients is obviously reduced, which indicates that FXI inhibition is beneficial to reducing the incidence risk of ischemic stroke and deep venous thrombosis. Thirdly, in the thrombophilia study of 474 patients and controls, the risk of DVT development was 2.2-fold higher in the population with high FXI levels than in the other populations, indicating that high FXI levels are a risk factor for DVT development and that FXI levels are positively correlated with DVT development. Other researches show that the risk of cerebral apoplexy and venous thrombosis can be obviously increased by the increase of FXI level, and thrombotic diseases can be possibly reduced by inhibiting FXI.

FXI knockout mice can survive healthily, have no difference in fertility and hemostatic function from wild mice, and also exhibit prolonged activated partial thromboplastin time (aPTT) and normal Prothrombin Time (PT) as in FXI-deficient patients. The mouse FXI gene knockout can inhibit arterial and venous thrombosis, and compared with several clinically applied antithrombotic medicaments, the antithrombotic effect is equal to or even more effective than that of high-dose heparin, and is more effective than other medicaments such as aspirin, clopidogrel or argatroban; moreover, these antithrombotic agents may cause a small amount of bleeding, and the tail bleeding time of mice in which the FXI gene was knocked out was not different from that of wild type. This suggests that FXI may be an antithrombotic target with little hemorrhagic side effects. The reported FXI inhibitors mainly comprise monoclonal antibodies, antisense oligonucleotides, chemical small molecules, polypeptides or proteins, polypeptide mimics and the like. At present, FXIa monoclonal antibody MAA-868 of Norway and BAY1213790 of Bayer have already entered clinical phase II research, and FXIa antisense oligonucleotide ISIS416858/BAY2306001/IONIX-FXIRx developed by Ionis and Bayer cooperation are currently in clinical phase II research. BMS and a small molecule oral FXIa inhibitor BMS-986177 developed by the cooperation of the strong life have completed a plurality of phase I clinical studies and enter a phase II clinical test; a small-molecule oral FXIa inhibitor ONO-7684 developed by Nippon Xiaoye corporation enters a clinical phase I study. The clinical phase I trial of the intravenous small molecule FXIa inhibitor BMS-962122 of BMS has been completed. The monoclonal antibody and the antisense oligonucleotide need to be injected and administered, and have the defects of high price, slow response, difficult control and the like, and the chemical micromolecule has the advantages of relatively good oral bioavailability, better patient compliance and the like. Therefore, the research and development of safe, effective, good-specificity and strong-activity novel FXIa micromolecule inhibitor medicines can possibly make up the defect that the existing clinical anticoagulant and antithrombotic medicines are easy to generate hemorrhagic complications and meet the clinical unmet requirements.

Plasma Kallikrein (PK) is a trypsin-like serine protease zymogen present in Plasma, similar to the factor XIa gene with up to 58% amino acid sequence similarity. In blood, most of plasma kallikrein exists in the form of a complex with High Molecular Weight Kininogen (HMWK). Plasma kininase is involved in blood coagulation, fibrinolysis and kinin production, and has a role in blood coagulation and many inflammatory diseases. Activated Factor XII (Factor XIIa, FXIIa) cleaves prekallikrein (prekallikrein) to form kallikrein (PK), which promotes the cleavage of HWMK to Bradykinin (Bradykinin), thereby promoting blood coagulation. The plasma kallikrein inhibitor is possibly used for treating diseases such as Hereditary Angioneurotic Edema (HAE) and advanced diabetic macular edema (advanced diabetic macular edema). The plasma kininase inhibitor macromolecular protein drug Ecallantide (Kalbitor) has been approved by FDA to treat HAE, however, no small-molecule plasma kininase inhibitor is approved to be on the market at present, and the development of a safe and effective new Kallikrein small-molecule inhibitor drug can also meet the clinical unmet demand.

Disclosure of Invention

Through repeated experimental research, the inventor reasonably designs and synthesizes a series of small molecular compounds with novel structures shown in the following general formula (I), and the small molecular compounds have high inhibitory activity on the blood coagulation factor XIa (FXIa). The compounds or stereoisomers, racemates, geometric isomers, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts and pharmaceutical compositions thereof can be used for treating or/and preventing related diseases mediated by FXIa.

The compound of the invention has high FXIa inhibition activity, and provides a new treatment option for treating diseases such as thromboembolism and the like.

The invention provides a compound shown in formula (I), an optical isomer or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

T₁selected from N and CH;

T₂、T₃are each independently selected from N and C (R)₁₂)；

T₄Selected from N and C (R)₄)；

R₁Is selected from C_1-6An alkyl group, a 5-to 6-membered heteroaryl group and a 5-to 6-membered heterocyclic group, wherein C_1-6Alkyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl is optionally substituted with 1,2 or 3R;

R₂selected from H, F, Cl, Br, I, NH₂And Me;

R₃selected from H, F, Cl, Br, I and NH₂；

R₄And R₅Each independently selected from H, halogen, OH, NH₂、C_1-3Alkyl radical, C_1-3alkyl-O-, C_3-6cycloalkyl-O-and 3-to 6-membered heterocycloalkyl-O-, C_1-3Alkyl radical, C_1-3alkyl-O-, C_3-6cycloalkyl-O-or 3-6 membered heterocycloalkyl-O-is optionally substituted with 1,2 or 3R, and R₄And R₅At least one of them is selected from OH and C_1-3alkyl-O-, C_3-6cycloalkyl-O-or 3-to 6-membered heterocycloalkyl-O-;

l is selected from the group consisting of a single bond and-CH₂-；

R₆Selected from H, halogen, OH, NH₂、C_1-6Alkyl radical, C_3-6Cycloalkyl and 3-to 6-membered heterocycloalkyl, said C_1-6Alkyl radical, C_3-6Cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with 1,2 or 3R;

R₇selected from H, F, Cl, Br, I, NH₂NHMe and Me;

R₈selected from H, F, Cl, Br, I, NH₂NHMe and Me;

R₉selected from H, F, Cl, Br, I, NH₂NHMe and Me;

R₁₀selected from H, F, Cl, Br, I, NH₂NHMe and Me;

or, R₈And R₉Are connected together to form a 5-6 membered ring;

R₁₂selected from H, F, Cl, Br, I, NH₂And Me;

r is respectively and independently selected from H, F, Cl, Br, I and NH₂、CN、OH、C_1-6Alkyl and C_1-6Heteroalkyl group of said C_1-6Alkyl or C_1-6Heteroalkyl is optionally substituted with 1,2, or 3R';

r' is respectively and independently selected from H, Me, F, Cl, Br, I and NH₂And CN;

said C is_1-6A heteroalkyl group, a 3-to 6-membered heterocycloalkyl group, a 5-to 6-membered heterocyclic group or a 5-to 6-membered heteroaryl group comprising 1, b,2 or 3 heteroatoms or groups of heteroatoms independently selected from-O-, -NH-, -S-, -C (═ O) O-, -S (═ O)2-, and N.

In some embodiments of the present invention, each of the above R is independently selected from H, F, Cl, Br, I, NH₂、CN、OH、C_1-3Alkyl radical, C_1-3Alkoxy and C_1-3Alkylamino radical, said C_1-3Alkyl radical, C_1-3Alkoxy or C_1-3Alkylamino is optionally substituted with 1,2 or 3R' and the other variables are as defined herein.

In some embodiments of the present invention, each of the above R is independently selected from H, F, Cl, Br, I, NH₂、CN、OH、Me、

Other variables are as defined herein.

In some embodiments of the invention, R is as defined above₁Is selected from C_1-3Alkyl, tetrazolyl, 1,2, 3-triazolyl, 4, 5-dihydroisoxazolyl and isoxazolyl, wherein C is_1-3Alkyl is optionally substituted with 1,2 or 3R, tetrazolyl or 1,2, 3-triazolyl is optionally substituted with R, the other variables being as defined herein.

In some embodiments of the invention, R is as defined above₁Is selected from

Other variables are as defined herein.

In some embodiments of the invention, R is as defined above₄And R₅Each independently selected from H, F, Cl, Br, I, OH, NH₂、Me、

The above-mentioned

Optionally substituted with 1,2 or 3R, the other variables being as defined herein.

In some embodiments of the invention, R is as defined above₄And R₅Each independently selected from H, F, Cl, Br, I, OH, NH₂、Me、

Other variables are as defined herein.

In some embodiments of the invention, R is as defined above₅Selected from H, OH,

Other variables are as defined herein.

In some embodiments of the invention, R is as defined above₄Selected from H, F, Me and

other variables are as defined herein.

In some embodiments of the invention, the structural unit

Is selected from

Other variablesAs defined herein.

In some embodiments of the invention, R is as defined above₆Selected from H, F, Cl, Br, I, OH, NH₂、Me、

The Me is,

Optionally substituted with 1,2 or 3R, the other variables being as defined herein.

In some embodiments of the invention, R is as defined above₆Selected from H, F, Cl, Br, I, OH, NH₂、Me、

Other variables are as defined herein.

In some embodiments of the invention, the structural unit

Selected from H, F, Me,

Other variables are as defined herein.

In some embodiments of the invention, the structural unit

Is selected from

Other variables are as defined herein.

In some embodiments of the invention, the structural unit

Is selected from

Other variables are as defined herein.

The present invention also provides a compound of the formula, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from:

the invention also provides a pharmaceutical composition. In some embodiments of the invention, the pharmaceutical composition comprises a compound described above or a pharmaceutically acceptable salt thereof.

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

The invention also provides application of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing an XIa inhibitor. The above XIa inhibitors are useful for the treatment of cardiovascular diseases.

The invention also provides application of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing medicaments for preventing and/or treating diseases mediated by the XIa factor.

In some embodiments of the invention, the factor XIa-mediated disease is selected from cardiovascular and cerebrovascular diseases.

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

In some embodiments of the invention, the thromboembolic disorder is selected from Hereditary Angioneurotic Edema (HAE), advanced diabetic macular edema (advanced myocardial edema), myocardial infarction, angina, reocclusion and restenosis following angioplasty or aortic coronary bypass, disseminated intravascular coagulation, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism, or deep vein thrombosis.

Definitions and explanations

The following terms and symbols used in the present application have the meanings as described below, unless otherwise indicated in the context.

A dash ("-") that is not between two letters or symbols indicates a point of attachment for a substituent. E.g. C_1-6Alkylcarbonyl-refers to C attached to the rest of the molecule through a carbonyl group_1-6An alkyl group. However, when the attachment site of a substituent is apparent to those skilled in the art, for example, a halogen substituent, "-" may be omitted.

With dotted lines at the valency of the group

When, for example, in

The wavy line in (a) indicates the point of attachment of the group to the rest of the molecule.

The term "hydrogen" as used herein refers to the group-H.

The term "hydroxy" as used herein refers to the group-OH.

The term "halo" or "halogen" as used herein refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

The term "cyano" as used herein refers to the group-CN.

The term "alkyl" as used herein refers to a straight or branched chain saturated monovalent hydrocarbon radical having from 1 to 8 carbon atoms, such as from 1 to 6 carbon atoms, such as from 1 to 4 carbon atoms, such as from 1,2 or 3 carbon atoms. For example, "C_1-8Alkyl "means an alkyl group having 1 to 8 carbon atoms. Similarly, "C_1-6Alkyl "represents an alkyl group having 1 to 6 carbon atoms; "C_1-4Alkyl "represents an alkyl group having 1 to 4 carbon atoms; "C_1-3Alkyl "means an alkyl group having 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl ("Me"), ethyl ("Et"), propyl such as n-propyl ("n-Pr") or isopropyl ("i-Pr"), butyl 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.

The term "heteroalkyl," as used herein, by itself or in conjunction with another term, means a stable straight or branched chain alkyl radical, or combination thereof, consisting of a number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from-C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O)₂-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)₂N (h) -and-S (═ O) n (h) -. In some embodiments, the heteroalkyl is C_1-6A heteroalkyl group; in yet other embodiments of the present invention, the substrate is,the heteroalkyl group is C_1-3A heteroalkyl group. The heteroatom or heteroatom group may be located at any internal position of the heteroalkyl group, including the position of attachment of the alkyl group to the remainder of the molecule, but the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used conventionally to refer to those alkyl groups that are attached to the remainder of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively. Examples of heteroalkyl groups include, but are not limited to, -OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH₂(CH₃)₂、-CH₂-CH₂-O-CH₃、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃、-N(CH₃)(CH₂CH₃)、-CH₂-CH₂-NH-CH₃、-CH₂-CH₂-N(CH₃)-CH₃、-SCH₃、-SCH₂CH₃、-SCH₂CH₂CH₃、-SCH₂(CH₃)₂、-CH₂-S-CH₂-CH₃、-CH₂-CH₂、-S(＝O)-CH₃、-CH₂-CH₂-S(＝O)₂-CH₃And (d). Up to two heteroatoms may be consecutive, e.g. -CH₂-NH-OCH₃。

The term "alkoxy" as used herein refers to the group-O-alkyl, wherein alkyl is as defined above. For example, "C_1-8Alkoxy "denotes-O-C_1-8Alkyl, i.e., alkoxy having 1 to 8 carbon atoms. Similarly, "C_1-6Alkoxy "denotes-O-C_1-6Alkyl, i.e., alkoxy having 1 to 6 carbon atoms; "C_1-4Alkoxy "denotes-O-C_1-4Alkyl, i.e., alkoxy having 1 to 4 carbon atoms; "C_1-3Alkoxy "denotes-O-C_1-3Alkyl, i.e., alkoxy having 1 to 3 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, such as n-propoxy or isopropoxy, butoxy, such as n-butoxy, isobutoxy, t-butoxy, pentyloxy, hexyloxy, and the like. Regardless of the term "alkaneThe definition applies whether oxy "is used alone or as part of another group.

The term "alkylamino" or "alkylamino" as used herein refers to "N-alkylamino" wherein the amino groups are each independently substituted by an alkyl group, wherein the alkyl group has the meaning as described herein. In some of these embodiments, the alkylamino group is a C_1-6Lower alkylamino groups in which the alkyl group is attached to the nitrogen atom. In other embodiments, the alkylamino group is C_1-3Lower alkylamino groups of (a). Suitable alkylamino groups can be monoalkylamino groups, examples of which include, but are not limited to, N-methylamino, N-ethylamino, and the like.

The term "cycloalkyl" as used herein refers to a saturated monovalent monocyclic or bicyclic hydrocarbon group having 3 to 12 ring carbon atoms, for example having 3 to 8 ring carbon atoms, for example having 3 to 6 ring carbon atoms, for example 3 to 4 ring carbon atoms. For example, "C_3-12Cycloalkyl "denotes cycloalkyl having 3 to 12 ring carbon atoms. Similarly, "C_3-8Cycloalkyl "denotes cycloalkyl having 3 to 8 ring carbon atoms; "C_3-6Cycloalkyl "denotes cycloalkyl having 3 to 6 ring carbon atoms; "C_3-4Cycloalkyl "denotes cycloalkyl having 3 to 4 ring carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, and the like.

As used herein, the term "3-12 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 3 to 12 ring atoms, 1,2,3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O))_pAnd p is 1 or 2). The said compounds include monocyclic, bicyclic and tricyclic ring systems, wherein the bicyclic and tricyclic ring systems include spiro, fused and bridged rings. Furthermore, with respect to the "3-12 membered heterocycloalkyl", the heteroatom may occupy the position of the heterocycloalkyl linkage to the rest of the molecule. The 3-12 membered heterocycloalkyl group includes 3-10 membered, 3-8 membered, 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4 membered5-and 6-membered heterocycloalkyl, and the like. Examples of 3-12 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, and the like), piperazinyl (including 1-piperazinyl, and 2-piperazinyl, and the like), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, dioxepanyl, and the like.

As used herein, the term "3-10 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 3 to 10 ring atoms, 1,2,3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O))_pAnd p is 1 or 2). They include monocyclic, bicyclic, and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spirocyclic, bicyclic, and bridged rings. Furthermore, with respect to the "3-10 membered heterocycloalkyl", the heteroatom may occupy the position of the heterocycloalkyl linkage to the rest of the molecule. The 3-to 10-membered heterocycloalkyl group includes 3-to 8-membered, 3-to 6-membered, 3-to 5-membered, 4-to 6-membered, 5-to 6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups and the like. Examples of 3-10 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, and the like), piperazinyl (including 1-piperazinyl, and 2-piperazinyl, and the like), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, dioxepanyl, and the like.

The term "3-8 membered heterocycloalkyl" as used herein "By itself or in combination with other terms mean a saturated cyclic group consisting of 3 to 8 ring atoms, 1,2,3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O))_pAnd p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings. Furthermore, with respect to the "3-8 membered heterocycloalkyl", the heteroatom may occupy the position of the heterocycloalkyl linkage to the rest of the molecule. The 3-8 membered heterocycloalkyl group includes 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5-membered, and 6-membered heterocycloalkyl groups and the like. Examples of 3-8 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, and the like), piperazinyl (including 1-piperazinyl, and 2-piperazinyl, and the like), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, dioxepanyl, and the like.

As used herein, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms denotes 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, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O))_pAnd p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings. Furthermore, with respect to the "3-6 membered heterocycloalkyl", the heteroatom may occupy the position of the heterocycloalkyl linkage to the rest of the molecule. The 3-6 membered heterocycloalkyl group includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl groups and the like. Examples of 3-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetra-azetidinyl)Hydrothien-2-yl, tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, etc.

As used herein, the term "4-6 membered heterocycloalkyl" by itself or in combination with other terms denotes 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, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O))_pAnd p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings. Furthermore, with respect to the "4-6 membered heterocycloalkyl", the heteroatom may occupy the position of the heterocycloalkyl linkage to the rest of the molecule. The 4-6 membered heterocycloalkyl group includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl groups and the like. Examples of 4-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, and the like), 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, homopiperidinyl, and the like.

As used herein, the term "5-6 membered heterocycloalkyl" by itself or in combination with other terms denotes 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, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O))_pAnd p is 1 or 2). Which comprises a sheetAnd bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings. Furthermore, with respect to the "5-6 membered heterocycloalkyl", the heteroatom may occupy the position of the heterocycloalkyl linkage to the rest of the molecule. The 5-6 membered heterocycloalkyl group includes 5-and 6-membered heterocycloalkyl groups. Examples of 5-6 membered heterocycloalkyl include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 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, homopiperidinyl, and the like.

As used herein, the term "3-5 membered heterocycloalkyl" by itself or in combination with other terms denotes 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, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S (O))_pAnd p is 1 or 2). Furthermore, with respect to the "3-5 membered heterocycloalkyl", the heteroatom may occupy the position of the heterocycloalkyl linkage to the rest of the molecule. The 3-5 membered heterocycloalkyl group includes 4-5 membered, 4-membered, and 5-membered heterocycloalkyl groups and the like. Examples of 3-5 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, and the like), or tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), and the like.

As used herein, the term "4-5 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated monocyclic group consisting of 4 to 5 ring atoms, 1,2,3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S (O))_pAnd p is 1 or 2). Furthermore, as to the "4-to 5-membered heterocycloalkyl", hetero atomMay occupy the position of the attachment of the heterocycloalkyl group to the rest of the molecule. The 4-5 membered heterocycloalkyl group includes 4-and 5-membered heterocycloalkyl groups. Examples of 4-5 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, and the like), or tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), and the like.

As used herein, the term "3-4 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated monocyclic group consisting of 3 to 4 ring atoms, 1,2,3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S (O))_pAnd p is 1 or 2). Furthermore, with respect to the "3-4 membered heterocycloalkyl", the heteroatom may occupy the position of the heterocycloalkyl linkage to the rest of the molecule. The 3-4 membered heterocycloalkyl group includes 3-and 4-membered heterocycloalkyl groups. Examples of 3-4 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, and the like.

The term "aryl" as used herein refers to a carbocyclic hydrocarbon group consisting of a ring or the fusion of rings having from 6 to 14 ring carbon atoms, e.g., from 6 to 12 ring carbon atoms, e.g., from 6 to 10 ring carbon atoms, wherein at least one ring is aromatic. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, 1,2,3, 4-tetrahydronaphthyl, indenyl, with phenyl and naphthyl being preferred. Accordingly, the term "aromatic ring" as used herein refers to a ring of an aryl group as defined above.

The term "heteroaryl" as used herein refers to:

monocyclic aromatic hydrocarbon groups having 5,6 or 7 ring atoms, for example having 6 ring atoms, which contain in the ring one or more, for example 1,2 or 3, for example 1 or 2, ring heteroatoms independently selected from N, O and S (for example N), the remaining ring atoms being carbon atoms; and

bicyclic aromatic hydrocarbon groups having 8 to 12 ring atoms, for example having 9 or 10 ring atoms, comprising one or more, for example 1,2,3 or 4, for example 1 or 2 ring heteroatoms independently selected from N, O and S (for example N) in the ring, the remaining ring atoms being carbon atoms, wherein at least one ring is aromatic.

When the total number of S and O atoms in the heteroaryl group exceeds 1, these S and O heteroatoms are not adjacent to each other.

Heteroaryl also includes those wherein the N-ring heteroatom is in the form of an N-oxide, such as pyrimidinyl N-oxide.

In some embodiments, the ring heteroatom in the heteroaryl groups described above is an N atom, and such heteroaryl groups are referred to as "nitrogen-containing heteroaryl groups". Nitrogen-containing heteroaryl groups also include those wherein the N-ring heteroatom is in the N-oxide form, such as pyridyl N-oxide.

Examples of heteroaryl groups include, but are not limited to: pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-6-yl), pyridyl N-oxide; a pyrazinyl group; a pyrimidinyl group; pyrazolyl (e.g., pyrazol-5-yl, pyrazol-1-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl); an imidazolyl group;

an azole group; different from each other

An azole group; a thiazolyl group; an isothiazolyl group; a thiadiazolyl group; a tetrazolyl group; a triazolyl group; a thienyl group; a furyl group; a pyranyl group; a pyrrolyl group; a pyridazinyl group; benzo [ d ] carbonyl]A thiazolyl group; benzodioxolyl groups, e.g. benzo [ d][1,3]Dioxolyl; benzo (b) is

Azolyl, e.g. benzo [ d ]]

An azole group; imidazopyridinyl radicals, e.g. imidazo [1,2-a]A pyridyl group; triazolopyridyl radicals, e.g. 1,2,4]Triazolo [4,3-a]Pyridyl and [1,2,4 ]]Triazolo [1,5-a]A pyridyl group; (ii) an indazolyl group; 2H-indazolyl; pyrrolopyrimidinyl radicals, e.g. pyrrolo [3,4-d]Pyrimidinyl, 7H-pyrrolo [2,3-d ] compounds]A pyrimidinyl group; pyrazolopyrimidinyl radicals, e.g. pyrazolesAnd [1,5-a ]]A pyrimidinyl group; tetrazolopyridinyl radicals, e.g. tetrazolo [1,5-a]A pyridyl group; benzothienyl; a benzofuranyl group; a benzimidazolinyl group; an indolyl group; indolinyl; purinyl groups, such as 9H-purinyl and 7H-purinyl; a quinolyl group; an isoquinolinyl group; 1,2,3, 4-tetrahydroquinolinyl and 5,6,7, 8-tetrahydroisoquinolinyl.

Examples of nitrogen-containing heteroaryl groups include, but are not limited to: a pyrrolyl group; a pyrazolyl group; an imidazolyl group; a pyridyl group; a pyrazinyl group; pyrimidinyl, N-pyrimidinyl oxide; a pyridazinyl group; pyrrolopyrimidyl groups such as pyrrolo [3,4-d ] pyrimidyl, 7H-pyrrolo [2,3-d ] pyrimidyl; purinyl groups, such as 9H-purinyl and 7H-purinyl; a quinolyl group; an indolyl group; and indazolyl groups. Accordingly, the term "heteroaryl ring" as used herein refers to a ring of heteroaryl as defined above.

As used herein, "aryl", "aromatic" follows the Houckel's rule, wherein the number of pi electrons is equal to 4n +2, n is zero or any positive integer up to 6.

The term "5-6 membered ring" as used herein refers to a ring structure comprising 5-6 atoms, wherein one or more of the atoms in the ring may or may not be independently optionally replaced by a heteroatom, the ring may be fully saturated or contain one or more degrees of unsaturation, may be aromatic, and the ring may be optionally substituted with a substituent, such as C_1-6Alkyl substitution, for example, the term "5-to 6-membered ring" as used herein includes, but is not limited to, pyrrolyl, 2-methyl-1, 2-dihydro-3H-pyrazol-3-onyl, pyridyl, piperidin-2-onyl and the like.

The term "5-6 membered heterocyclyl" as used herein refers to a ring structure comprising 5-6 atoms, wherein one or more atoms of the ring are independently optionally replaced by a heteroatom, and the ring may be fully saturated or contain one or more unsaturations, but is in no way aromatic. For example, the term "5-6 membered heterocyclyl" as used herein includes, but is not limited to, 4, 5-dihydroisoxazole and the like.

The term "carbonyl" as used herein refers to the group-C (O) -, which may also be denoted as-CO-.

As used hereinThe term "amino" refers to the group-NH₂。

The term "alkylamino" or "monoalkylamino" as used herein refers to the group alkyl-NH-, wherein alkyl is as defined herein.

The term "optionally" as used herein means that the subsequently described event may or may not occur, and that the description includes instances where said event occurs and instances where it does not. 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 pattern.

The term "substituted" or "substituted with … …" as used herein 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 group of substituents, 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 with oxygen. Combinations of substituents and/or variables are permissible only if such combinations result in chemically correct and stable compounds. A chemically correct and stable compound means that the compound is sufficiently stable to be isolated from the reaction mixture and to determine the chemical structure of the compound, and can subsequently be formulated into a formulation that has at least practical utility. For example, as used herein, the term "substituted" or "substituted" without explicitly listing substituents means that one or more hydrogen atoms on a given atom or group are independently substituted with one or more, e.g., 1,2,3, or 4, substituents independently selected from: deuterium (D), halogen, -OH, mercapto, cyano, -CD₃Alkyl (preferably C)_1-6Alkyl group), alkoxy group (preferably C)_1-6Alkoxy), haloalkyl (preferably halo C)_1-6Alkyl), haloalkoxy (preferably halo C)_1-6Alkoxy), -C (O) NR_aR_band-N (R)_a)C(O)R_band-C (O) OC_1-4Alkyl (wherein R_aAnd R_bEach independently selected from hydrogen and C_1-4Alkyl, halo C_1-4Alkyl), carboxyl (-COOH), cycloalkyl (preferably 3-8 membered cycloalkyl), heterocyclyl (preferably 3-8 membered heterocyclyl), aryl, heteroaryl, aryl-C_1-6Alkyl-, heteroaryl-C_1-6Alkyl-, -OC_1-6Alkylphenyl, -C_1-6alkyl-OH (preferably-C)_1-4alkyl-OH), -C_1-6alkyl-SH, -C_1-6alkyl-O-C_1-2、-C_1-6alkyl-NH₂(preferably-C)_1-3alkyl-NH₂)、-N(C_1-6Alkyl radical)₂(preferably-N (C)_1-3Alkyl radical)₂)、-NH(C_1-6Alkyl) (preferably-NH (C)_1-3Alkyl)), -N (C)_1-6Alkyl) (C_1-6Alkylphenyl), -NH (C)_1-6Alkylphenyl), nitro, -C (O) OC_1-6Alkyl (preferably-C (O) OC_1-3Alkyl), -NHC (O) (C)_1-6Alkyl), -NHC (O) (phenyl), -N (C)_1-6Alkyl radical C (O) (C)_1-6Alkyl), -N (C)_1-6Alkyl group C (O) (phenyl), -C (O) C_1-6Alkyl, -C (O) heteroaryl (preferably-C (O) -5-7 membered heteroaryl), -C (O) C_1-6Alkylphenyl, -C (O) C_1-6Haloalkyl, -OC (O) C_1-6Alkyl (preferably-OC (O) C)_1-3Alkyl), alkylsulfonyl (e.g., -S (O)₂-C_1-6Alkyl), alkylsulfinyl (- (S (O) -C)_1-6Alkyl), -S (O)₂-phenyl, -S (O)₂-C_1-6Haloalkyl, -S (O)₂NH₂、-S(O)₂NH(C_1-6Alkyl), -S (O)₂NH (phenyl), -NHS (O)₂(C_1-6Alkyl), -NHS (O)₂(phenyl) and-NHS (O)₂(C_1-6Haloalkyl), wherein said alkyl, cycloalkyl, phenyl, aryl, heterocyclyl and heteroaryl are each optionally further substituted with one or more substituents selected from the group consisting of: halogen, -OH, -NH₂Cycloalkyl, 3-8 membered heterocyclyl, C_1-4Alkyl radical, C_1-4Haloalkyl-, -OC_1-4Alkyl, -C_1-4alkyl-OH, -C_1-4alkyl-O-C_1-4Alkyl, aryl, heteroaryl, and heteroaryl,-OC_1-4Haloalkyl, cyano, nitro, -C (O) -OH, -C (O) OC_1-6Alkyl, -CON (C)_1-6Alkyl radical)₂、-CONH(C_1-6Alkyl), -CONH₂、-NHC(O)(C_1-6Alkyl), -NH (C)_1-6Alkyl radical C (O) (C)_1-6Alkyl), -SO₂(C_1-6Alkyl), -SO₂(phenyl), -SO₂(C_1-6Haloalkyl), -SO₂NH₂、-SO₂NH(C_1-6Alkyl), -SO₂NH (phenyl), -NHSO₂(C_1-6Alkyl), -NHSO₂(phenyl) and-NHSO₂(C_1-6Haloalkyl). When an atom or group is substituted with a plurality of substituents, the substituents may be the same or different.

Unless otherwise specified, Cn-n + m or Cn-Cn + m includes any one particular case of n to n + m carbons, e.g., C_1-6Comprising C₁、C₂、C₃、C₄、C₅And C₆Also included are any ranges of n to n + m, e.g. C_1-6Comprising C_1-3、C_1-6、C_1-4、C_3-6、C_3-5、C_2-5And C_1-5Etc.; similarly, n-to n + m-members represent n to n + m ring atoms, and for example, 5-to 6-membered rings include 5-membered rings and 6-membered rings.

The term "pharmaceutically acceptable" as used herein refers to 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 or base addition salts of compounds of formula (I) suitable for administration to a subject, including but not limited to: acid addition salts of the compounds of formula (I) with inorganic acids, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, and the like; and acid addition salts of the compounds of formula (I) with organic acids, for example formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, waterSalicylates, stearates and substituted amides of the formula HOOC- (CH)₂)_nSalts with alkanedicarboxylic acids of-COOH (wherein n is 0 to 4), and the like. "pharmaceutically acceptable salts" also include the base addition salts of the compounds of formula (I) bearing an acidic group with pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium and ammonium.

Furthermore, if the compounds described herein are obtained in the form of an acid addition salt, the free base form thereof can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is in the form of the free base, its acid addition salts, in particular the pharmaceutically acceptable acid addition salts, can be obtained by dissolving the free base in a suitable solvent and treating the solution with an acid, according to the usual procedures for preparing acid addition salts from basic compounds. Those skilled in the art will be able to determine, without undue experimentation, the various synthetic procedures which may be used to prepare non-toxic pharmaceutically acceptable acid addition salts.

The compounds of the invention may exist in the form of solvates. The term "solvate" means a solvent addition form comprising 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, where the water retains its H₂The molecular state of O, such combination being capable of forming one or more hydrates, such as hemihydrate, monohydrate and dihydrate.

The term "prodrug" as used herein refers to an active or inactive compound that is chemically modified to form the compound of the present invention by physiological effects in vivo such as hydrolysis, metabolism, and the like, after administration to a subject. The suitability and techniques involved in making and using prodrugs are well known to those skilled in the art. Exemplary prodrugs are, 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 which are convertible by solvolysis under physiological conditions to the parent carboxylic acid, for example, 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, carboxy, lower alkoxycarbonyl) -lower alkyl esters, α - (lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl) -lower alkyl esters, such as pivaloyloxymethyl ester, and the like, as 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 thus exist in two or more stereoisomers. The compounds according to the invention can therefore be present as individual stereoisomers (e.g. enantiomers, diastereomers) and mixtures thereof in any proportion, for example racemates, and, where appropriate, as tautomers and geometrical isomers thereof.

The term "stereoisomer" as used herein refers to compounds having the same chemical constitution, but which differ in the spatial arrangement of the atoms or groups. Stereoisomers include enantiomers, diastereomers, and conformers, among others.

The term "enantiomer" as used herein refers to two stereoisomers of a compound that are nonsuperimposable mirror images of each other.

The term "diastereomer" as used herein refers to a stereoisomer 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, spectroscopic properties, or biological activities. Mixtures of diastereomers may be separated by high resolution analytical methods such as electrophoresis and chromatography such as HPLC.

Stereochemical definitions and conventions may be compiled following the s.p. parker, McGraw-Hill Dictionary of Chemical terminologies (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 an optically active form, 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 denote the absolute configuration of a molecule with respect to its chiral center. The prefixes d and l or (+) and (-) are used to denote the sign of a compound to rotate plane polarized light, where (-) or l denotes that the compound is left-handed. Compounds with a prefix of (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is commonly referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur in chemical reactions or processes without stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers without optical activity.

The racemic mixture can be used as such or resolved into individual isomers. The resolution can result in a stereochemically pure compound or in an enriched mixture of one or more isomers. Methods for separating isomers are well known (see Allinger n.l. and Eliel e.l., "Topics in stereospecificity", volume 6, Wiley Interscience, 1971), including physical methods such as chromatography using chiral adsorbents. The individual isomers can be prepared in chiral form from chiral precursors. Alternatively, the individual isomers may be separated chemically from the mixture by forming diastereomeric salts with chiral acids (e.g., the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α -bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractional crystallization of the salts, and subsequent liberation of one or both of the resolved bases, optionally repeating this process, to yield one or two isomers substantially free of the other isomer, i.e., the desired stereoisomer in optical purity, e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% by weight. Alternatively, the racemate may be covalently linked to a chiral compound (an auxiliary) to give diastereomers, as is well known to those skilled in the art.

The term "tautomer" or "tautomeric form" as used herein refers to structural isomers of different energies that may be interconverted via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by recombination of some of the bonded electrons.

The term "treatment" as used herein refers to the administration of one or more pharmaceutical substances, in particular a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described herein, to an individual suffering from a disease or having symptoms of said disease, for the purpose of curing, alleviating, altering, healing, ameliorating, improving or affecting said disease or symptoms of said disease. The term "prevention" as used herein refers to the administration of one or more pharmaceutical substances, in particular a compound of formula (I) as described herein and/or a pharmaceutically acceptable salt thereof, to an individual having a predisposition to the disease, in order to prevent the individual from suffering from the disease. The terms "treating", "contacting" and "reacting" when referring to a chemical reaction refer to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and/or desired product. It will be appreciated that the reaction that produces the indicated and/or the desired product may not necessarily result directly from the combination of the two reagents that were initially charged, i.e., one or more intermediates that are formed may be present in the mixture that ultimately result in the formation of the indicated and/or the desired product.

The term "effective amount" as used herein refers to an amount generally sufficient to produce a beneficial effect in an individual. An effective amount of a compound of the 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, medical history of the individual, health of the individual, degree of responsiveness of the individual to the drug, etc.).

The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention.

Technical and scientific terms used herein that are not specifically defined have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

Examples

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures in the following examples, if no specific conditions are indicated, are generally carried out according to the conditions customary for such reactions, or according to the conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are percentages and parts by weight. Unless otherwise specified, the ratio of liquids is by volume.

The test materials and reagents used in the following examples are commercially available without specific reference.

In the following examples of the present invention,¹the H-NMR spectra were recorded on a Bluker AVANCE III HD 400MHz NMR spectrometer;¹³C-NMR spectra were recorded on a Bluker AVANCE III HD 400MHz NMR spectrometer with chemical shifts expressed in delta (ppm); mass spectra were recorded on a Shimadzu LCMS-2020(ESI format) or Agilent 6215(ESI) mass spectrometer; reversed-phase preparative HPLC separation is a full-automatic purification system guided by Gilson GX281 ultraviolet

Prep C18OBDTM 19 x 250mm 10 μm column)/or Waters QDa guided full automatic purification system

Prep C18OBD 29 x 250mm 10 μm column). Chiral analytical HPLC is performed using a Waters UPCC supercritical fluid analysis System (

OD-H4.6X 250mm 5 μm column or

AS-3 0.3cm*100mm 3μm columns); the chiral separation SFC is performed by using a Waters-SFC80 supercritical fluid purification system (

OD 2.5 × 25cm,10 μm column or

AS 2.5 × 25cm,10 μm column).

Wherein, the Chinese name table of the reagent represented by the chemical formula or English letter abbreviation is as follows:

AcOH or HOAc represents acetic acid or acetic acid; AcONH₄、NH₄OAc or CH₃COONH₄Represents ammonium acetate or ammonium acetate; AlMe₃Represents trimethylaluminum; AlCl₃Represents aluminum trichloride; aq represents an aqueous solution; ar represents argon; BF (BF) generator₃-Et₂O represents boron trifluoride-diethyl ether solution; BoC represents tert-butoxycarbonyl; BoC₂O represents di-tert-butyl dicarbonate; b (O)ⁱPr)₃Represents triisopropylborane; br represents a broad peak; br₂Represents liquid bromine; DEG C represents centigrade degree; CAN represents cerium ammonium nitrate; CD (compact disc)₃OD represents deuterated methanol; CDCl₃Represents deuterated chloroform; CDI represents N, N' -carbonyldiimidazole; CH (CH)₃COOK or AcOK for potassium acetate; CHCl₃Represents trichloromethane; CH (CH)₃I represents methyl iodide; CO 2₂Represents carbon dioxide; conc. represents concentrate; cs₂CO₃Represents cesium carbonate; CuI represents cuprous iodide; d represents a doublet; DAST represents diethylaminosulfur trifluoride; DCM represents dichloromethane; DEA stands for diethanolamine; DIAD represents diisopropyl azodicarboxylate; DIBAL stands for diisobutylaluminum hydride; dioxane or 1,4-Dioxane represents Dioxane, Dioxane; DIPEA or DIEA represents N, N-diisopropylethylamine; DMAP represents 4-dimethylaminopyridine or N, N-dimethyl-4-aminopyridine; DME represents dimethoxyethane; DMEA represents N, N-dimethylethanolamine; DMF represents dimethylformamide; DMSO represents dimethyl sulfoxide; DPPA represents diphenylphosphoryl azide; EA or EtOAc stands for ethyl acetate; EDCI represents 1-ethyl- (3-dimethylaminopropyl) carbodiimide; ELSD stands for evaporative light scattering detector(ii) a ESI stands for electrospray ionization; et (Et)₂O represents diethyl ether; EtOH or C₂H₅OH represents ethanol; et (Et)₃N represents triethylamine; et (Et)₃SiH represents triethylsilane; EtI stands for iodoethane; FA represents formic acid; fe represents iron; g represents g; h represents hour; h₂Represents hydrogen; h₂O represents water; h₂SO₄Represents sulfuric acid; HATU represents 1- [ bis (dimethylamino) methylene]-1H-1,2, 3-triazolo [4,5-b]Pyridinium 3-oxide hexafluorophosphate; HBr stands for hydrobromic acid; HCl represents hydrogen chloride or hydrochloric acid; HCO₂H represents formic acid; HOBt represents 1-hydroxybenzotriazole; HPLC for high performance liquid chromatography;ⁱPrOH or IPA represents isopropanol; k₂CO₃Represents potassium carbonate; k₃PO₄Represents potassium phosphate; KOAc represents potassium acetate; LCMS stands for liquid chromatography-mass spectrometry combination; LDA represents lithium diisopropylamide; LiBr stands for lithium bromide; LiOH represents lithium hydroxide; m represents a multiplet; m represents molar concentration; m/z represents mass-to-charge ratio; MeCN, ACN or CH₃CN represents acetonitrile; MeI or CH₃I represents methyl iodide; MW or W represents microwave; MeOH represents methanol; min represents min; mg represents mg; mL represents mL; mmol represents millimole; mol represents mol; MOMCl represents chloromethyl methyl ether; n is a radical of₂Represents nitrogen; n is a radical of₂H₄Represents hydrazine; NH (NH)₂NH₂·H₂O represents hydrazine hydrate; na (Na)₂CO₃Represents sodium carbonate; NaBH₃CN or NaBH₃(CN) represents sodium cyanoborohydride; NaBH₄Represents sodium borohydride; NaH represents sodium hydride; NaHCO 2₃Represents sodium bicarbonate; NaN₃Represents sodium azide; NaNO₂Represents sodium nitrite; NaOH represents sodium hydroxide; NBS represents N-bromosuccinimide; n-BuLi represents n-butyllithium; NCS represents N-chlorosuccinimide; NH (NH)₄Cl represents ammonium chloride; NH (NH)₄OH represents ammonium hydroxide and ammonia water; NMP stands for N-methyl-2-pyrrolidone; Pd/C stands for Pd/C₂dba₃Represents tris (dibenzylideneacetone) dipalladium; pd (dppf) Cl₂Or PdCl₂(dppf) represents 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride; pd (PPh)₃)₄Represents tetrakis (triphenylphosphine) palladium (0); PE represents petroleum ether; PhMgBr stands for phenylmagnesium bromide; PPh₃Represents triphenylphosphine; py represents pyridine; RaneyNi stands for Raney nickel; r.t. or RT for room temperature; ruphospalladacycle represents chloro (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1' -biphenyl) [2- (2-aminoethylphenyl)]Palladium (II); s represents a single peak; selectfluor stands for 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2]Octane bis (tetrafluoroborate); sfc (supercritical Fluid chromatography) represents supercritical Fluid chromatography; SOCl₂Represents thionyl chloride;^tBuNC stands for 2-isocyano-2-methylpropane; t represents a triplet; t-BuONa represents sodium tert-butoxide; t is₃P represents 1-propyl phosphoric anhydride; TEA for triethylamine; TMEDA represents tetramethylethylenediamine; tf₂O represents trifluoromethanesulfonic anhydride; TLC for thin layer chromatography; TFA or CF₃COOH represents trifluoroacetic acid; THF represents tetrahydrofuran; TMSI stands for trimethyl sulfoxide iodide; toluene or tol, for Toluene; trimethoxymethane or Trimethylotropmate represents trimethyl orthoformate; X-Phos represents 2-dicyclohexyl phosphonium-2, 4, 6-triisopropyl biphenyl.

Synthesis of intermediates

Intermediate 5: synthesis of 4- (5-chloro-2-nitrophenyl) -5-methoxypyridin-2 (1H) -one (5)

Step 1 Synthesis of (2, 5-dimethoxypyridin-4-yl) boronic acid (2)

To a 500mL three-necked flask, the compound 12, 5-dimethoxypyridine (10.0g, 71.86mmol) and anhydrous THF (250mL) were added and cooled to-78 ℃. At this temperature, LDA (72mL, 2M in THF) was slowly added dropwise. After the addition was completed, the reaction was stirred at-78 ℃ for 1.5 hours. Then, B (O)ⁱPr)₃(20.272g, 107.79mmol) was slowly added dropwise to the above reaction mixture. After all the addition was completed, the temperature was raised to room temperature, and the reaction was carried out for 16 hours. LC-MS detection indicated the reaction was complete. Quenching with water (50mL), spin-drying the organic solvent in the reaction solution, diluting with water (100mL), cooling to 0 deg.C, adjusting pH to about 7 with 1N hydrochloric acid aqueous solution, and separating out solid. Filtering, washing the solid with water (2 × 30mL), and drying to obtain the target product, namely, the compound 2(2, 5-dimethoxypyridin-4-yl) boronic acid, as a white solid, 10.5g, yield: 79.9 percent. LCMS M/z184.2(M + H)⁺。

Step 2.4- (5-chloro-2-nitrophenyl) -2, 5-dimethoxypyridine (4) Synthesis

To a 250mL eggplant-shaped bottle was added (2, 5-dimethoxypyridin-4-yl) boronic acid (2) (3.000g, 16.40mmol), the compound 32-bromo-4-chloro-1-nitrobenzene (3.525g, 14.91mmol), K₃PO₄(9.495g, 44.73mmol), 1,4-dioxane (75mL), and water (25 mL). Pd (dppf) Cl₂(1200mg, 1.64mmol) was added to the above mixture. The reaction system is heated to 100 ℃ under the protection of nitrogen and reacted overnight. LC-MS detection indicated the reaction was complete. The reaction solution was spin-dried and purified by normal phase column (PE/EA 15% to 25%) to obtain the target compound 4, 3.431g, yellow solid, yield: 70.4 percent. LCMS M/z 295.0(M + H)⁺。

And step 3: synthesis of 4- (5-chloro-2-nitrophenyl) -5-methoxypyridin-2 (1H) -one (5)

To a 500mL round bottom flask were added 4- (5-chloro-2-nitrophenyl) -2, 5-dimethoxypyridine (4) (3.413g, 11.58 mmol) and the pyridinium salt of hydrobromic acid (37.079g, 231.6 mmol). DMF (120mL) was then added. The reaction solution was stirred at 100 ℃ for 3 hours. LC-MS detection shows that the reaction is finished. The reaction mixture was cooled to room temperature, and EA (250mL) was added thereto to precipitate a solid. Filtration and cake washing with EA (10mL × 2). The filter cake is pyridinium hydrobromideThe filtrate was concentrated to about 10mL, and H was added to the filtrate₂And O, separating out a solid, filtering, washing a filter cake with water (10mL & ltx.2), wherein the filter cake is the target compound, and drying the filter cake in a vacuum drying oven to obtain a target product 5 which is a yellow green solid and has the yield of 3.100g and 95.7%. LCMS M/z 281.0(M + H)⁺。

Intermediate 9: synthesis of 4- (5-chloro-2- (difluoromethyl) phenyl) -5-methoxypyridin-2 (1H) -one (9)

Step 1.2 Synthesis of bromo-4-chloro-1- (difluoromethyl) benzene (7)

DAST (6.321mL, 47.81mmol) was added to a solution of compound 6(7g, 31.91mmol) in DCM (105mL) at 0 deg.C and stirred at room temperature for 16 h. TLC showed the reaction was complete. The reaction was concentrated, diluted with EA (100mL) and sequentially with saturated NaHCO₃Washed (50mL) with saturated NaCl (50mL), dried and concentrated to give 2-bromo-4-chloro-1- (difluoromethyl) benzene (7) as a colorless oily liquid, 5.54g, 71.9% yield.¹H NMR(400MHz,DMSO)δ7.95(s,1H),7.70(d,J＝8.4Hz,1H),7.65(dd,J＝8.4,1.9Hz,1H),7.14(t,J＝54.1Hz,1H).

Step 2.4- (5-chloro-2- (difluoromethyl) phenyl) -2, 5-dimethoxypyridine (8) Synthesis

To a 250mL eggplant-shaped bottle was added 2-bromo-4-chloro-1- (difluoromethyl) benzene (7) (800mg, 3.313mmol), (2, 5-dimethoxypyridin-4-yl) boronic acid (2) (550mg, 3.006mmol), K₃PO₄(2.109g, 9.939mmol), 1,4-dioxane (25mL) and water (8 mL). Pd (dppf) Cl₂(220mg, 0.331mmol) was added to the above mixture. After the reaction system is protected by nitrogen gas exchange for three times, the reaction system is heatedThe temperature was raised to 100 ℃ and the reaction was carried out overnight. LC-MS (MC19-113 and 028-R1) detection indicated the reaction was complete. The reaction solution was spin-dried and purified with normal phase silica gel column (PE/EA ═ 15% to 35%) to give 4- (5-chloro-2- (difluoromethyl) phenyl) -2, 5-dimethoxypyridine (8), 540mg, white solid, yield: 54.4 percent. LCMS M/z 300.1(M + H)⁺。

Step 3.4- (5-chloro-2- (difluoromethyl) phenyl) -5-methoxypyridin-2 (1H) -one (9) Synthesis

To a 100mL round-bottomed flask were added 4- (5-chloro-2- (difluoromethyl) phenyl) -2, 5-dimethoxypyridine (8) (540mg, 1.802mmol) and the pyridinium salt of hydrobromic acid (5.769g, 36.04 mmol). DMF (20mL) was then added. The reaction solution was stirred at 100 ℃ for 3 hours. LC-MS detection shows that the reaction is finished. The reaction mixture was cooled to room temperature, and EA (40mL) was added thereto to precipitate a solid. Filtration and cake washing with EA (5mL × 2). The filter cake was pyridinium hydrobromide, the filtrate was concentrated to about 10mL, and H was added to the filtrate₂O, a solid precipitated, and was filtered, and the filter cake was washed with water (5mL × 2) to obtain the desired compound, and the filter cake was dried in a vacuum oven to obtain 4- (5-chloro-2- (difluoromethyl) phenyl) -5-methoxypyridin-2 (1H) -one (9) as a yellow solid, 420mg, and a yield of 81.7%. LCMS M/z 285.9(M + H)⁺。

Intermediate 14: synthesis of 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (14)

Step 1.1 Synthesis of 1-azido-2-bromo-4-chlorobenzene (10)

A100 mL round bottom flask was charged with 2-bromo-4-chloroaniline (619mg, 3.00mmol) and water (12)mL). Then, 3.7mL of concentrated HCl was added and the reaction was cooled to-5 ℃. At-5 deg.C, adding NaNO₂An aqueous solution (1.5mL) (228mg, 3.30mmol) was added to the reaction mixture and the temperature was maintained for 1 hour. Then adding NaN₃(215mg, 3.30mmol) of an aqueous solution (1.5mL) was added and the reaction was continued at-5 ℃ for 0.5 h. The reaction was extracted with EA (3X 40mL), the organic phases were combined and saturated NaHCO was used₃The aqueous solution (100mL), water (100mL) and saturated brine (100mL) were washed successively with Na₂SO₄Drying, filtration and concentration gave 600mg of 1-azido-2-bromo-4-chlorobenzene (10) as a yellow solid in yield: 85 percent. LC-MS: UV absorption and MS no response.

Step 2.1 Synthesis of- (2-bromo-4-chlorophenyl) -4- (tributylstannyl) -1H-1,2, 3-triazole (11)

1-azido-2-bromo-4-chlorobenzene (10) (600mg, 2.57mmol), tributyl (ethynyl) stannane (971mg, 3.08mmol) and toluene (12mL) were added to a 100mL round bottom flask, and the reaction was allowed to warm to 110 ℃ for 16 hours. LC-MS showed the product to be formed. The reaction solution was concentrated and purified by normal phase column (PE/EA ═ 0 to 100%) to give 1.13g of 1- (2-bromo-4-chlorophenyl) -4- (tributylstannyl) -1H-1,2, 3-triazole (11) as a yellow oil, yield: 80 percent. LCMS M/z 547.7(M + H)⁺。

Step 3 Synthesis of (2-bromo-4-chlorophenyl) -4-chloro-1H-1, 2, 3-triazole (12)

A100 mL round-bottom flask was charged with 1- (2-bromo-4-chlorophenyl) -4- (tributylstannyl) -1H-1,2, 3-triazole (11) (1.0g, 1.83mmol), NCS (366mg, 2.74mmol), and acetonitrile (20mL), and the temperature was raised to 60 ℃ for 16 hours. LC-MS shows that most of the raw materials are consumed, products are generated, and the reaction is finished. The reaction solution was spin dried and the crude product was purified on normal phase column (PE/EA ═ 0-100%) to give (2-bromo-4-chlorophenyl) -4-chloro-1H-1, 2, 3-triazole(12)300mg, white solid, yield: 50 percent. LCMS M/z 293.5(M + H)⁺。

Step 4.4 Synthesis of 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -2, 5-dimethoxypyridine (13)

In a 100mL round-bottom flask was added the compound (2-bromo-4-chlorophenyl) -4-chloro-1H-1, 2, 3-triazole (12) (300mg, 1.02mmol), (2, 5-dimethoxypyridin-4-yl) boronic acid (2) (224mg, 1.22mmol), K₃PO₄(540mg, 2.55mmol), dioxane (5mL) and water (0.5 mL). Then Pd (dppf) Cl is added₂(74mg, 0.10 mmol). The mixture is ventilated and protected by nitrogen, and the temperature is raised to 100 ℃ for reaction for 16 hours. LC-MS showed the reaction was complete. The reaction solution was spin-dried, and the crude product was purified with a normal phase column (PE/EA ═ 0 to 100%) to give the target product 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -2, 5-dimethoxypyridine (13)250mg as a pale yellow oil, yield: and 69 percent. LCMS M/z 352.1(M + H)⁺。

Step 5.4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (14) Synthesis

A50 mL round-bottomed flask was charged with 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -2, 5-dimethoxypyridine (13) (250mg, 0.71mmol), pyridinium hydrobromide (1139mg, 7.12mmol) and DMF (2mL), and the temperature was raised to 100 ℃ for reaction for 3 hours. LC-MS shows that the reaction is finished and the product is generated. The reaction solution was spin dried, 20mL of an aqueous dispersion solid was added, filtered, and the filter cake was dried to give the desired product 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (14)200mg as a pale yellow solid, yield: 83 percent. LCMS M/z337.1(M + H)⁺。

Intermediate 17: synthesis of tert-butyl (4- (2-bromoacetyl) phenyl) carbamate (17)

Step 1 Synthesis of N- (4- (2-bromoacetyl) phenyl) acetamide (15)

In a 250mL round bottom flask was added N-phenylacetamide (4.1g, 30.37mmol), 2-bromoacetyl bromide (7106mg, 35.53mmol) and DCM (50mL) and cooled to 0 ℃. At 0 ℃ AlCl₃(9020mg, 68.33mmol) was added to the above reaction mixture in three portions. After the addition, the temperature was raised to 50 ℃ to react for 16 hours. LC-MS detection indicated the reaction was complete. After the reaction solution is cooled to room temperature, pouring the reaction solution into ice water for quenching, filtering, washing a filter cake with water, and drying to obtain a solid, namely N- (4- (2-bromoacetyl) phenyl) acetamide (15), an off-white solid, 4.7g, yield: 61 percent. LCMS M/z 298.9(M + H +41)⁺。

Step 2 Synthesis of (4- (2-bromoacetyl) aniline (16)

Into a 250mL round bottom flask was added N- (4- (2-bromoacetyl) phenyl) acetamide (15) (4.0g, 15.68mmol), H₂SO₄(50mL, 6N) and methanol (50mL), heated to 80 ℃ and reacted for 2.5 hours. LC-MS detection indicated the reaction was complete. The organic solvent in the reaction solution is dried by spinning and NaHCO is used₃Adjusting the pH value of the saturated aqueous solution to be alkalescent, separating out solids, filtering and drying to obtain solids. The solid was purified on normal phase column (PE/DCM 0-100%, DCM/EA 0-100%) to give (4- (2-bromoacetyl) aniline (16)1.80g, yellow solid, yield: 54%. LCMS: M/z 216.1(M + H)⁺。

Step 3 Synthesis of tert-butyl (4- (2-bromoacetyl) phenyl) carbamate (17)

To a 100mL round bottom flask was added (4- (2-bromoacetyl) aniline (16) (500mg, 2.35mmol), di-tert-butyl dicarbonate (5120mg, 23.5mmol), methanol (20mL) and THF (5mL), the temperature was raised to 70 ℃ and the reaction was carried out for 20 hours, LC-MS detection showed disappearance of the starting material and completion of the reaction, the reaction mixture was spun dry and purified with a normal phase column (PE/DCM 0-100%) to give tert-butyl (4- (2-bromoacetyl) phenyl) carbamate (17)200mg as a white solid with 27% yield, UV absorption on LCMS, but the MS response was weak.¹H NMR(400MHz,CDCl₃)δ7.99–7.91(m,2H),7.51–7.45(m,2H),4.41(s,2H),1.53(s,9H).

Intermediate 19: synthesis of 3-bromoacetyl-6-aminopyridine (19)

Step 1.3 Synthesis of acetyl-6-aminopyridine (18)

3-acetyl-6-chloropyridine (2g, 12.86mmol) was added to the NH₄OH (30mL), the reaction mixture was stirred at 130 ℃ for 16 h. LC-MS showed the reaction was complete. The reaction solution was spin-dried to obtain 2.3g of a crude product of 3-acetyl-6-aminopyridine (18) as a yellow solid, which was used directly for the next reaction. LCMS M/z 137.2(M + H)⁺。

Step 2.3 Synthesis of Bromoacetyl-6-aminopyridine (19)

3-acetyl-6-aminopyridine (18) (1g, crude) was dissolved in AcOH (75mL), HBr (1.188g, 14.67mmol) and Br were added to the solution₂(0.4mL, 8.079mmol), stirring the reaction mixture at 20 ℃ for 48H, adding H to the reaction mixture₂O (100 mL). Extracting with EA (100mL of 3), combining the organic phases, washing the organic phase with saturated aqueous NaCl solution (50mL), anhydrous Na₂SO₄Dried and purified by silica gel column to give 3-bromoacetyl-6-aminopyridine (19) as a yellow solid, 300mg, yield: 25 percent. LCMS: m/z 215.1; 217.1(M + H)⁺。

Intermediate 22: synthesis of tert-butyl (5- (2-bromoacetyl) -6-fluoropyridin-2-yl) carbamate (22)

Step 1. (6-fluoro-5-iodopyridin-2-yl) carbamic acid tert-butyl ester

6-fluoro-5-iodopyridin-2-amine (22.2g, 93.28mmol), di-tert-butyl dicarbonate (22.4g, 102.61mmol), DMAP (1.14g, 9.328mmol) and acetonitrile (444mL) were added to a 1L round-bottomed flask at room temperature and reacted for 4 hours. TLC detection showed disappearance of starting material. The reaction solution was filtered to remove solids, the filtrate was concentrated, and purified by normal phase column (PE/EA ═ 0 to 5%) to give tert-butyl (6-fluoro-5-iodopyridin-2-yl) carbamate (20) as a colorless gum, 15.2g, yield: 48 percent. LCMS M/z 282.9(M-56+ H)⁺。

Step 2 Synthesis of tert-butyl (5- (1-ethoxyvinyl) -6-fluoropyridin-2-yl) carbamate (21)

To a 250mL round bottom flask was added (6-fluoro-5-iodopyridin-2-yl) carbamic acid tert-butyl ester (20) (15.2g, 44.95mmol), tributyl (1-ethoxyvinyl) stannane (18.9g, 52.33mmol), Pd (PPh) at room temperature₃)₄(1.22g, 1.056mmol) and DMF (75 mL). And under the protection of argon, heating to 120 ℃ and reacting for 16 hours. LC-MS detection indicated the reaction was complete. EA (300mL) was added to the reaction solutionAnd 1M aqueous potassium fluoride (600mL) was stirred for 30min, whereupon a solid precipitated and was filtered. The filtrate was extracted with EA (2X 200mL), separated, the organic phases combined and washed with anhydrous Na₂SO₄And (5) drying. Purification on normal phase column (PE/EA ═ 0-5%) gave tert-butyl (5- (1-ethoxyvinyl) -6-fluoropyridin-2-yl) carbamate (21), 5.0g, white solid, yield: 39 percent. LCMS M/z 227.2(M-56+ H)⁺。

Step 3 Synthesis of tert-butyl (5- (2-bromoacetyl) -6-fluoropyridin-2-yl) carbamate (22)

To a 250mL round-bottomed flask was added (5- (1-ethoxyvinyl) -6-fluoropyridin-2-yl) carbamic acid tert-butyl ester (21) (5.0g, 17.7mmol), THF (60mL) and water (20mL), stirred, cooled to 0 ℃ on an ice bath. NBS (3.14g, 17.7mmol) was added portionwise at 0 ℃. After the addition, the reaction was maintained at 0 ℃ for 30 min. LC-MS detection indicated that the reaction was complete. The reaction was extracted with EA (3 × 100mL) and the organic phases were combined. The organic phase was saturated NaHCO₃Washed with aqueous solution (2 x 200mL) anhydrous Na₂SO₄Drying and concentrating to obtain a crude product. The crude product was purified on normal phase column (PE/EA ═ 0-20%) to give tert-butyl (5- (2-bromoacetyl) -6-fluoropyridin-2-yl) carbamate (22), 2.9g, white solid, yield: 49 percent. LCMS M/z 276.9(M-56+ H)⁺。

Intermediate 24: synthesis of methyl (R) -2-bromo-3-cyclopropylpropionate (24)

Step 1 Synthesis of (R) -2-bromo-3-cyclopropylpropionic acid (23)

(R) -2-amino-3-cyclopropylpropionic acid (3010mg, 23.30 m) was added to a 250mL eggplant-shaped bottle at room temperaturemol) and 50mL of water, 20mL of HBr (40% in water) are subsequently added, the reaction is stirred at room temperature until the reaction is clear, the reaction is cooled to-5 ℃ and 50mL of an aqueous solution of sodium nitrite (1930mg,27.97mmol) are added dropwise to the solution at this temperature. After the completion of the dropwise addition, the reaction was warmed to room temperature and stirred for 16 hours. LC-MS detection shows that most of the raw materials disappear and the product is generated. The reaction solution was extracted with ether (100mL × 3), and the combined organic phases were washed with saturated aqueous sodium chloride solution (200mL × 1), and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered off, and the filtrate was concentrated to give (R) -2-bromo-3-cyclopropylpropionic acid (23) as a yellow oil, 3500mg, yield 78%.¹H NMR(400MHz,CDCl₃)δ4.41–4.33(m,1H),2.06–1.71(m,2H),0.94–0.83(m,1H),0.61–0.51(m,2H),0.25–0.15(m,2H).

Step 2 Synthesis of (R) -methyl 2-bromo-3-cyclopropylpropionate (24)

To a 250mL eggplant-shaped bottle was added 90mL of methanol at 0 ℃ and 9mL of thionyl chloride was added dropwise to the methanol, and after completion of the addition, the mixture was stirred at 0 ℃ for 0.5 hour, and (R) -2-bromo-3-cyclopropylpropionic acid (23) (3500mg,18.13mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. LC-MS detection showed disappearance of the starting material. The reaction solution was concentrated (bath temperature less than 20 ℃), and purified with silica gel column (wet loading, biotage,80g, silica gel column, UV254, dichloromethane 0-20% in petroleum ether) to give (R) -methyl 2-bromo-3-cyclopropylpropionate (24) as a pale yellow oil, 2800mg, 74% yield.¹H NMR(400MHz,CDCl₃)δ4.33(t,J＝7.6Hz,1H),3.81(s,3H),2.00–1.96(m,2H),0.86–0.79(m,1H),0.58–0.47(m,2H),0.22–0.11(m,2H).

Intermediate 25: synthesis of methyl 2-bromo-3-cyclobutylpropionate (25)

Analogously to the synthesis of intermediate 24 with (S) -2-amino-3-cyclobutylpropionic acid is synthesized as a starting material, and the product is a light yellow oil.¹H NMR(400MHz,DMSO-d₆)δ4.40(t,J＝7.4Hz,1H),3.69(s,3H),2.37-2.30(m,1H),2.16-2.10(m,1H),2.04-1.96(m,3H),1.81–1.65(m,4H).

Intermediate 26: synthesis of 4-chloro-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (26)

To a 250mL round-bottomed flask, at room temperature, were added compound 4(30g, 145.3mmol) and 5(55.3g, 218.0mmol), KOAc (36.6g, 373.0mmol), Pd (dppf) Cl₂(3.2g, 4.4mmol) and DMSO (90 mL). Under the protection of nitrogen, the temperature is raised to 80 ℃ and the reaction lasts for 22 hours. LC-MS detection indicated the reaction was complete. The reaction mixture was allowed to stand and cooled to room temperature, water (250mL) was added to precipitate a solid, and the mixture was filtered. The filtered solid was slurried with DCM (150mL), filtered again and the filtrate concentrated to give the crude product. The crude product was purified using normal phase column (PE/EA 0-20%) to give 29g of product (impure), twice purified using normal phase column (PE/DCM 0-40%) to give 4-chloro-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (26) as a white solid, 12g, yield: 32 percent. LCMS M/z 172.0(M-82+ H)⁺。

Intermediate 32: synthesis of 1- (4-chloro-2- (5-methoxy-2-oxo-1, 2-dihydropyridin-4-yl) phenyl) -1H-1,2, 3-triazole-4-carbonitrile (32)

Step 1.1 Synthesis of tert-butyl 1- (2-bromo-4-chlorophenyl) -1H-1,2, 3-triazole-4-carboxylate (27)

Intermediate 10(2400mg,10.32mmol) and tert-butyl propiolate (3mL,21.85mmol) were dissolved in 50mL of toluene and the reaction was stirred at 110 deg.CAfter 16 hours, the reaction was cooled to room temperature, and the reaction mixture was concentrated to give a crude product, which was purified by column chromatography (biotage,40g, silica gel column, UV254, DCM in PE 0-100%) to give the desired product 27(2700mg, yield: 73%) as a white semisolid. LCMS M/z 401.0(M + H + CH)₃CN)⁺。

Step 2.1- (2-bromo-4-chlorophenyl) -1H-1,2, 3-triazole-4-carboxylic acid (28) Synthesis

Intermediate 27(2430mg,6.77mmol) was dissolved in a mixed solvent consisting of 10mL TFA and 10mL DCM, the reaction was stirred at room temperature for 1 hour, the reaction was concentrated to give crude product, which was slurried with 5mL DCM, filtered, and the filter cake was dried to give the desired product 28(1700mg, yield: 82%) as a white solid. LCMS M/z 304.0(M + H)⁺。

Step 3.1- (2-bromo-4-chlorophenyl) -1H-1,2, 3-triazole-4-carboxamide (29) Synthesis

Intermediate 28(1200mg,3.97mmol) was dissolved in 8mL of DMF, followed by the addition of HATU (1809mg,4.76mmol) and TEA (1011mg,9.92mmol), the reaction was stirred at room temperature for 1 hour, 2mL of aqueous ammonia was added, the reaction was stirred at room temperature for 1 hour, 70mL of water was added, filtration was carried out, the filter cake was washed with water (3mLX3), and drying was carried out to give the desired product 29(1000mg, yield: 83%) as a white solid. LCMS M/z303.0(M + H)⁺。

Step 4.1 Synthesis of 1- (4-chloro-2- (2, 5-dimethoxypyridin-4-yl) phenyl) -1H-1,2, 3-triazole-4-carboxamide (30)

Intermediate 29(500mg,1.66mmol), intermediate 2(333mg,1.82mmol), K₂CO₃(573mg,4.14mmol) and Pd (dppf) Cl₂(121mg,0.17mmol) was added to 1Reacting in a mixed solvent of 0mL of 1,4-dioxane and 1mL of water at 100 ℃, under the protection of nitrogen, stirring for 16 hours, concentrating the reaction to obtain a crude product, purifying the crude product by column chromatography (biotage,40g, silica gel column, UV254, EA in DCM is 0-100%), obtaining a target product 30(360mg, yield: 60%) and a yellow solid. LCMS M/z 360.1(M + H)⁺。

Step 5.1 Synthesis of 1- (4-chloro-2- (2, 5-dimethoxypyridin-4-yl) phenyl) -1H-1,2, 3-triazole-4-carbonitrile (31)

Intermediate 30(360mg,1.00mmol) was dissolved in 20mL EA, followed by addition of T₃P (1910mg,3.00mmol) (50% w/w in ethyl acetate) and TEA (303mg,3.00mmol) were reacted at 120 ℃ with microwave stirring for 1.5 hours, the reaction solution was cooled and concentrated to obtain crude product, which was purified by column chromatography (biotage,40g, silica gel column, UV254, EA in DCM 0-100%) to obtain the target product 31(280mg, yield: 82%) as a white solid. LCMS M/z 342.1(M + H)⁺。

Step 6.1 Synthesis of 1- (4-chloro-2- (5-methoxy-2-oxo-1, 2-dihydropyridin-4-yl) phenyl) -1H-1,2, 3-triazole-4-carbonitrile (32)

Intermediate 31(280mg,0.82mmol) was dissolved in 3mL of DMF, pyridinium hydrobromide (2621mg,16.38mmol) was added and the reaction stirred at 100 ℃ for 3 hours, then the reaction solution was cooled to room temperature, 10mL of EA was added, filtered, the filtrate was concentrated, then 40mL of water was added, filtered, the filter cake was washed with water (3mLX3) and dried to give the desired product 32(200mg, yield: 80%) as a white solid. LCMS M/z 328.1(M + H)⁺。

Intermediate 33: synthesis of 2-diazo-1, 1, 1-trifluoroethane (33)

In a 250mL three-necked round bottom flask, 2,2, 2-trifluoroethylamine hydrochloride (4050mg, 30.0mmol) and NaNO were added₂(2277mg, 33mmol) under argon. Toluene (60mL) degassed with argon was then added, and the reaction was cooled to 0 ℃ in an ice bath and stirred for 30 minutes. Water (6mL) degassed with argon was added. After the addition, the reaction was carried out at 0 ℃ for 2 hours, then the temperature was raised to 10 ℃ and the reaction was carried out for 30 minutes. After the reaction was completed, the reaction mixture was frozen in a refrigerator (about-18 ℃ C.) for 16 hours. The organic phase in the reaction was then transferred to a 250mL dry round bottom flask and anhydrous K was added₂CO₃(3000mg) and stirred for 1 hour to give a dry intermediate, 33 in toluene, 60mL, about 0.3-0.4M. This solution was used directly in the next step.

Intermediate 38: synthesis of 4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (38)

Step 1. Synthesis of N- (2-bromo-4-chlorophenyl) carboxamide (34)

A100 mL round bottom flask was charged with 2-bromo-4-chloroaniline (2500mg, 12.2mmol), formic acid (2245mg, 48.8mmol), and sodium formate (415mg, 6.1 mmol). The reaction was then stirred at room temperature for 16 hours. The reaction was diluted with EA (50mL), diluted with water (3 × 50mL), saturated NaHCO₃The aqueous solution (50mL) was washed successively with Na₂SO₄Drying, filtering and concentrating to obtain the target product 34, 2600mg, grey solid, yield: 91 percent.¹H NMR(400MHz,DMSO-d₆)δ9.82(s,1H),8.36(d,J＝1.3Hz,1H),8.05(d,J＝8.8Hz,1H),7.80(d,J＝2.4Hz,1H),7.46(dd,J＝8.6,2.4Hz,1H).

Step 2.2 Synthesis of 2-bromo-4-chloro-1-isocyanobenzene (35)

Intermediate 34(2600mg, 11.2mmol), triethylamine (3393mg, 33.6mmol) and anhydrous THF (30mL) were added to a 250mL three-necked round bottom flask and the system was cooled to 0 ℃ in an ice bath under nitrogen. Maintaining the temperature of the system, adding POCl₃(2050mg, 13.4mmol) was dissolved in anhydrous THF (10mL) and added dropwise slowly to the above reaction mixture. After the addition, the temperature was maintained at 0 ℃ for 1 hour. LC-MS shows that a new product is generated and the reaction is finished. The reaction was poured into saturated aqueous potassium carbonate (60mL) at 0 deg.C, extracted with methyl tert-butyl ether (2X 50mL), and Na₂SO₄Drying, filtering and concentrating. Purification on normal phase column (PE/DCM ═ 0-30%) gave the title product 35, 1750mg, black solid, yield: 72 percent.¹H NMR(400MHz,CDCl₃)δ7.68(d,J＝2.1Hz,1H),7.39(d,J＝8.5Hz,1H),7.34(dd,J＝8.5,2.1Hz,1H).

Step 3.1- (2-bromo-4-chlorophenyl) -4- (trifluoromethyl) -1H-1,2, 3-triazole (36) Synthesis

A100 mL round bottom flask was charged with intermediate 35(1650mg, 7.6mmol), 33(30mL, 0.3-0.4M in toluene), silver carbonate (416mg, 1.52mmol), 4A molecular sieves (900mg) and DMF (10mL), warmed to 40 ℃ and reacted for 16 h. LC-MS showed the product to be formed and the reaction was terminated. The reaction was filtered and the toluene in the filtrate was spun dry and then diluted with water (50mL) and EA (50 mL). Extracting with EA (3X 50mL), combining the organic phases, washing with saturated brine (200mL), anhydrous Na₂SO₄Drying and concentrating. The crude product was purified on normal phase column (PE/DCM ═ 0-50%) to afford the desired product 36, 920mg, yellow oil, yield: 37 percent. LCMS M/z 328.0(M + H)⁺。

Step 4.4 Synthesis of 4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -2, 5-dimethoxypyridine (37)

In a 100mL round-bottom flask was added compound 36(920mg, 2.83mmol), 2(518mg, 2.83mmol), K₃PO₄(1500mg, 7.07mmol), dioxane (32mL) and water (8 mL). Then Pd (dppf) Cl is added₂(204mg, 0.28 mmol). The mixture is ventilated and protected by nitrogen, and the temperature is raised to 100 ℃ for reaction for 2 hours. LC-MS showed the reaction was complete. The reaction was spun dry and the crude product was purified on normal phase column (PE/EA ═ 0-30%) to afford the desired product 37, 679mg, yellow oil, yield: 62 percent. LCMS M/z 385.1(M + H)⁺。

Step 5.4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (38) Synthesis

A50 mL round-bottom flask was charged with compound 37(679mg, 1.77mmol), pyridinium hydrobromide (5658mg, 35.36mmol) and DMF (10mL), and the reaction was warmed to 100 ℃ for 3 hours. LC-MS shows that the reaction is finished and the product is generated. After the reaction solution is spin-dried as much as possible, 50mL of water-dispersed solid is added, filtration is carried out, a filter cake is dried, and a target product 38, 575mg and yellow solid are obtained, wherein the yield is as follows: 88 percent. LCMS M/z 371.1(M + H)⁺。

Intermediate 43: synthesis of 4- (5-chloro-2- (4- (difluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (43)

Step 1.1 Synthesis of 1- (2-bromo-4-chlorophenyl) -4- (diethoxymethyl) -1H-1,2, 3-triazole (39)

At 100mAn L round bottom flask was charged with intermediate 10(1150mg, 4.98mmol), 3, 3-diethoxyprop-1-yne (956mg, 7.47mmol) and toluene (10mL), heated to 110 ℃ and stirred for reaction for 16 h. LC-MS shows the product formation and the reaction is complete. The reaction was spun dry and purified on normal phase column (PE/EA 0-50%) to give intermediate 39, 1.40g, yellow oil, yield: 78 percent. LCMS M/z 362.0(M + H)⁺。

Step 2.1 Synthesis of- (2-bromo-4-chlorophenyl) -1H-1,2, 3-triazole-4-carbaldehyde (40)

HCl (20mL) and dioxane (20mL) were added to a 100mL round bottom flask, then Compound 39(1200mg, 3.34mmol) was added to the above mixed solution, and the temperature was raised to 30 ℃ for 16 hours. LC-MS detection shows that the product is generated and the reaction is finished. The reaction mixture was diluted with water (40mL) and extracted with EA (200 mL). The organic phase was washed successively with water (2 x 100mL) and saturated sodium chloride (2 x 100mL), then with Na₂SO₄Drying, filtration and concentration gave intermediate 40, 950mg, yellow solid, yield: 99 percent. LCMS M/z 288.0(M + H)⁺。

Step 3.1- (2-bromo-4-chlorophenyl) -4- (difluoromethyl) -1H-1,2, 3-triazole (41) Synthesis

A100 mL round-bottomed flask was charged with intermediate 40(950mg, 3.33mmol), DAST (1072mg, 6.66mmol) and DCM (20mL) and reacted at room temperature for 2 hours. LC-MS detection shows that a product is generated, and the reaction is finished. The reaction mixture was poured into 0 ℃ saturated aqueous sodium bicarbonate (60mL), extracted with DCM (2X 60mL), the organic phases were combined, washed with water (100mL) and saturated brine (100mL) in that order, anhydrous Na₂SO₄Drying and concentrating. The crude product was purified on normal phase column (PE/EA ═ 0-15%) to afford the desired product 41, 579mg, white solid, yield: 56 percent. LCMS M/z 310.0(M + H)⁺。

Step 4.4 Synthesis of 4- (5-chloro-2- (4- (difluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -2, 5-dimethoxypyridine (42)

A100 mL round bottom flask was charged with intermediate 41(579mg, 1.88mmol), intermediate 2(344mg, 1.88mmol), K₃PO₄(996mg, 4.70mmol), dioxane (16mL) and water (4 mL). Then Pd (dppf) Cl is added₂(138mg, 0.19 mmol). The mixture is ventilated and protected by nitrogen, and the temperature is raised to 100 ℃ for reaction for 2 hours. LC-MS detection indicated the reaction was complete. The reaction was spun dry and the crude product was purified on normal phase column (PE/EA ═ 0-50%) to afford the target product 42, 405mg, dark yellow solid, yield: 59 percent. LCMS M/z 367.1(M + H)⁺。

Step 5.4- (5-chloro-2- (4- (difluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (43) Synthesis

A50 mL round-bottomed flask was charged with intermediate 42(405mg, 1.11mmol), pyridinium hydrobromide (3552mg, 22.20mmol) and DMF (5mL), and the reaction was warmed to 100 ℃ for 3 hours. LC-MS detection shows that the reaction is finished and the product is generated. After the reaction solution was spin-dried as much as possible, 50mL of water-dispersed solid was added, filtered, and the filter cake was dried to obtain the target product 43, 304mg, light brown solid, yield: 78 percent. LCMS M/z353.1(M + H)⁺。

Intermediate 49: synthesis of 2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-cyclopropylpropionic acid (47)

Step 1.6 Synthesis of chloro-4-iodo-3-methoxypyridazine (44)

A1000 mL three-necked flask was charged with 2,2,6, 6-tetramethylpiperidine (26mL, 152.78mmol) and anhydrous THF (500mL) and cooled to-30 ℃. At this temperature, n-BuLi (96mL, 1.6M) was slowly added dropwise. After the addition, the temperature was raised to 0 ℃ and the reaction was stirred for 1 hour. Then, the temperature was reduced to-78 ℃ and a solution of 3-chloro-6-methoxypyridazine (10g,69.44mmol) in THF (50mL) was slowly added dropwise. The reaction solution was stirred for 30 minutes. A solution of iodine (8g, 62.50mmol) in THF (10mL) was slowly added dropwise to the reaction. The temperature is kept at minus 78 ℃, and the reaction is stirred for 2 hours. LC-MS detection indicated the reaction was complete. After quenching with saturated sodium thiosulfate solution (20mL) at-78 deg.C, warm to room temperature. Water (100mL) was added, extracted with DCM (100mL × 3), the organic phase washed with 50mL saturated brine, dried over sodium sulfate and filtered. The filtrate was concentrated to give a crude product. The crude product was purified on normal phase column (DCM: PE ═ 0-50%) to give a white solid, washed with methanol (50mL) and filtered to give the product 6-chloro-4-iodo-3-methoxypyridazine (44) as a white solid, 2.2g, yield: 12 percent. LCMS M/z 270.9(M + H)⁺。

Step 2.5 Synthesis of 5-iodo-6-methoxypyridazin-3 (2H) -one (45)

Intermediate 44(2.2g, 8.14mmol) and AcOH (10mL) were added to a 100mL eggplant-shaped bottle. The reaction is heated to 100 ℃ and stirred for 2 h. LC-MS detection indicated the reaction was complete. 30mL of water was added and extracted with EA (30 mL. multidot.3). The organic phase was washed with 20mL of saturated brine, dried over sodium sulfate and filtered. The filtrate was concentrated to give crude which was washed with methanol (50mL) to give the product 5-iodo-6-methoxypyridazin-3 (2H) -one (45), 410mg, white solid, yield: 20 percent. LCMS M/z 252.9(M + H)⁺。

Step 3.3 Synthesis of methyl 3-cyclopropyl-2- (4-iodo-3-methoxy-6-oxopyridazin-1 (6H) -yl) propanoate (46)

To a 100mL round-bottomed flask was added 5-iodo-6-methoxypyridazin-3 (2H) -one (45) (410mg, 1.63mmol), DMF (5mL) and DME (20mL) at room temperature. NaH (60%) (41mg, 1.71mmol) was added to the above solution, and after 5 minutes at room temperature, LiBr (283mg, 3.25mmol) was added to the above reaction solution and reacted in an ultrasonic water bath at room temperature for 10 minutes. Intermediate 24(471mg, 2.28mmol) was then dissolved in DME (1mL) and added dropwise to the reaction. After the addition was complete, the reaction was warmed to 65 ℃ and reacted for 16 hours. LC-MS detection shows that the target product is generated, and the reaction is finished. The reaction was cooled to room temperature, quenched with 10mL of water, and the organic solvent was spun off. Neutralized with 1M aqueous hydrochloric acid, extracted with EA (3 × 50mL), the organic phases combined, dried and concentrated. The crude product was concentrated and purified using normal phase column (PE: EA ═ 0-50%) to give methyl 3-cyclopropyl-2- (4-iodo-3-methoxy-6-oxopyridazin-1 (6H) -yl) propanoate (46), 350mg, yellow oil, yield: 57 percent. According to the results of the chiral column analysis, the product was completely racemized. LCMS M/z 379.0(M + H)⁺。

Step 4.2 Synthesis of methyl 2- (4- (2-amino-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-cyclopropylpropionate (47)

To a 50mL eggplant-shaped bottle were added intermediate 46(350mg, 0.93mmol), intermediate 26(281mg, 1.11mmol), and K₂CO₃(384mg, 2.78mmol), 1,4-dioxane (5mL) and water (0.5 mL). Then Pd (dppf) Cl₂(68mg, 0.09mmol) was added to the above mixture. The reaction system is heated to 100 ℃ under the protection of nitrogen and reacted overnight. LC-MS detection indicated the reaction was complete. Filtration through celite, EA (3 × 50mL), merging of the organic phases, drying and concentration, purification on normal phase column (PE/EA 0-100%) gave 47, 260mg, yellow oil, yield: 75 percent. LCMS M/z 378.0(M + H)⁺。

Step 5.2- (4- (2-amino-5-chlorophenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-cyclopropylpropionic acid (48) Synthesis

Intermediate 47(260mg, 0.68mmol) was dissolved in THF/H₂O (5mL/5mL), LiOH. H was added to the reaction mixture₂O (115mg, 2.75mmol), and the reaction mixture was stirred at room temperature for 2 h. LC-MS showed no residue of starting material and formation of target compound. Neutralized with 1M aqueous hydrochloric acid, extracted with EA (3 × 50mL), the organic phases combined, dried and concentrated. The concentrated crude product was purified by reverse phase column to give the desired product 48, 200mg, yellow solid, yield: 80 percent. LCMS M/z 364.0(M + H)⁺。

Step 6.2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -3-cyclopropylpropionic acid (49) Synthesis

Intermediate 48(200mg, 0.55mmol) and trimethyl orthoformate (175mg, 1.65mmol) were added to AcOH (5mL) and stirred for 30 min. Adding NaN into the reaction solution₃(107mg) was stirred at 30 ℃ overnight. LC-MS detection shows that the target compound is generated, and the raw materials are completely reacted. The reaction solution is cooled to 0 ℃, and saturated NaNO is slowly added₂Aqueous solution until no bubbles are generated. Extract with EA (30mL x3), combine the organic phases, dry and concentrate. Purification over a reverse phase column afforded intermediate 49 as a white solid, 150mg, yield 65%. LCMS M/z 417.2(M + H)⁺。

Intermediate 50: synthesis of 2- (5-chloro-2-nitrophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane (50)

2-bromo-4-chloro-1-nitrobenzene (compound 3, 4729mg, 20.00mmol) is combinedSubstance 5(6095mg, 24.00mmol), KOAc (3926mg,40.00mmol) was added to 1,4-dioxane (40 mL). Pd (dppf) Cl₂(1463mg, 2.00mmol) was added to the above mixture. The reaction system is heated to 100 ℃ under the protection of nitrogen and reacted overnight. The reaction solution was spin dried and purified by column chromatography (biotage,80g, silica gel column, UV254, DCM in petroleum ether 0-50%)) to give intermediate 50, 3000mg, yellow solid, yield: 53 percent.¹H NMR(400MHz,DMSO-d₆)δ8.21(d,J＝8.8Hz,1H),7.78(dd,J＝8.8,2.4Hz,1H),7.71(d,J＝2.3Hz,1H),1.35(s,12H).

Intermediate 56: synthesis of 4- (5-chloro-2-nitrophenyl) -5-ethoxypyridin-2 (1H) -one (56)

Step 1.2 Synthesis of methoxy-5- (methoxymethoxy) pyridine (51)

3-hydroxy-6-methoxypyridine (900mg, 7.19mmol) was dissolved in 10ml of anhydrous DMF and sodium hydride (345mg, 8.63mmol) (60% w/w in mineral oil) was added at 0 ℃ and the reaction mixture was stirred at room temperature for 45 minutes, MOMCl (0.6ml,8.27mmol) was added dropwise to the reaction mixture and the reaction was stirred at room temperature overnight. Quenching with water, extracting with ethyl acetate (100ml X3), combining organic phases, washing with saturated saline (300ml X4), drying with anhydrous sodium sulfate, filtering, and spin-drying to obtain a crude product, and purifying the crude product by column chromatography (biotage,40g, silica gel column, UV254, ethyl acetate 0-8% in petroleum ether)) to obtain an intermediate 51, a colorless oily substance, 856mg, and a yield of 70%. LCMS M/z 170.2(M + H)⁺。

Step 2.4 Synthesis of iodo-2-methoxy-5- (methoxymethoxy) pyridine (52)

Intermediate 51(856mg,5.06mmol) was dissolved in 13ml of anhydrous THF, TMEDA (706mg,6.08mmol) was added followed by n-butyllithium (2.3ml,5.82mmol) (2.5M in n-hexane) at-78 deg.C, the reaction was stirred at-78 deg.C for 1 hour, iodine (1670mg,6.58mmol) was dissolved in 5ml of anhydrous tetrahydrofuran, added dropwise to the reaction system, the reaction was stirred at-78 deg.C for 1 hour, then warmed to room temperature overnight. The reaction was quenched with water, extracted with ethyl acetate (60ml X3), the combined organic phases washed with saturated brine (100ml), dried over anhydrous sodium sulfate, filtered, and spun-dried to give a crude product which was purified by column chromatography (biotage,40g, silica gel column, UV254, ethyl acetate 0-7% in petroleum ether)) to give intermediate 52, a pale yellow semi-solid, 1400mg, purity 86%. LCMS M/z 296.1(M + H)⁺.

Step 3.3 Synthesis of 3-hydroxy-4-iodo-6-methoxypyridine (53)

Intermediate 52(1400mg,4.74mmol) was dissolved in 7mL of anhydrous THF at room temperature, followed by the addition of 10mL of 3N HCl, and the reaction was stirred at 60 ℃ for 3 hours, then allowed to warm to room temperature overnight. Diluting with ethyl acetate (50mL) and water (50mL), separating the layers, adding more solid into the water phase, and adding NaHCO into the water phase₃To pH 4, extraction with ethyl acetate (50mL X3), combined organic phases washed with 100mL saturated brine, dried over anhydrous sodium sulfate, filtered, spun dried to give crude product, which was purified by column chromatography (biotage,120g, C-18, UV214, acetonitrile 5-95% in 0.05% TFA in water)) to afford intermediate 53 as a white solid, 970mg, 76% yield over two steps, purity 82%. LCMS M/z 252.0(M + H)⁺.

Step 4.2 Synthesis of methoxy-4-iodo-5-ethoxypyridine (54)

Intermediate 53(650mg, 2.59mmol) was dissolved in 17ml acetone and K was added at 0 deg.C₂CO₃(716mg,5.18mmol) and iodoethane (525mg,3.37mmol), and the reaction was stirred at 85 ℃ for 16 hours. The reaction solution was cooled to room temperature and concentrated to give crude product which was purified by column chromatography (biotage,40g, silica gel column, UV254, ethyl acetate in petroleum ether 0-7%)) to give intermediate 54 as a white solid, 600mg, 83% yield. LCMS M/z 280.0(M + H)⁺.

Step 5.4- (5-chloro-2-nitrophenyl) -5-ethoxy-2-methoxypyridine (55) Synthesis

Intermediate 54(600mg, 2.15mmol), intermediate 50(670mg, 2.36mmol), K₂CO₃(743mg,5.37mmol) was added to 1,4-dioxane (10mL) and water (2 mL). Pd (dppf) Cl₂(157mg, 0.22mmol) was added to the above mixture. The reaction system is heated to 100 ℃ under the protection of nitrogen and reacted overnight. The reaction solution was spin dried and purified by column chromatography (biotage,40g, silica gel column, UV254, ethyl acetate in petroleum ether 0-100%)) to give intermediate 55, 320mg, yellow solid, yield: 48 percent. LCMS M/z 309.1(M + H)⁺.

Step 6.4- (5-chloro-2-nitrophenyl) -5-ethoxypyridin-2 (1H) -one (56) Synthesis

Compound 55(320mg, 1.04mmol) and the pyridinium salt of hydrobromic acid (3317mg, 20.73mmol) were added to DMF (8 mL). The reaction solution was stirred at 100 ℃ for 3 hours. The reaction mixture was cooled to room temperature, and EA (50mL) was added thereto to precipitate a solid. Filtration and cake washing with EA (10mL × 2). The filter cake was dispersed in 50mL of water, filtered, washed with water (10mL x 2) to give the desired compound as a filter cake, and dried to give the desired product 56 as a pale yellow solid, 240mg, 78% yield. LCMS M/z 295.1(M + H)⁺。

Intermediate 57: synthesis of 4- (5-chloro-2-nitrophenyl) -5-isopropoxy-2 (1H) -one (57)

Similar to the synthesis of intermediate 56, the intermediate is synthesized from 3-hydroxy-6-methoxypyridine, 2-iodopropane and the like.

Example a 1: synthesis of 1- ((5- (6-amino-2-fluoropyridin-3-yl) -1H-imidazol-2-yl) methyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (A1)

Step 1 Synthesis of tert-butyl 2- (4- (5-chloro-2-nitrophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) acetate (58)

Will K₂CO₃(170mg, 1.60mmol) and tert-butyl 2-bromoacetate (250mg,1.28mmol) were added to a solution of 4- (5-chloro-2-nitrophenyl) -5-methoxypyridin-2 (1H) -one (intermediate 5) (300mg, 1.07mmol) in DMF (5mL) and stirred at 55 ℃ for 3H. LC-MS showed the reaction was complete. Adding H to the reaction solution₂O (20mL), extracted with EA (15mL × 3), the organic phases combined, dried and concentrated to give the crude product which was purified by forward column to give tert-butyl 2- (4- (5-chloro-2-nitrophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) acetate (58) as a yellow-green solid, 280mg, 66% yield. LCMS M/z 395.0(M + H)⁺。

Step 2: synthesis of tert-butyl 2- (4- (2-amino-5-chlorophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) acetate (59)

Reacting tert-butyl 2- (4- (5-chloro-2-nitrophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) acetate (58)(230mg, 0.58mmol) was dissolved in THF/C₂H₅To OH (8mL/8mL), Raney Ni (catalytic amount) and hydrazine hydrate (290mg, 5.8mmol) were added and the reaction was stirred at 90 ℃ for 1 h. LC-MS showed no residue of starting material and formation of target compound. The reaction was filtered through celite, the filter cake was washed with MeOH (5mL × 2), the filtrate was dried, dissolved in DMSO and purified by reverse phase chromatography to give intermediate 59 as a yellow solid, 194mg, 91.5% yield. LCMS M/z 337.0(M + H)⁺。

And step 3: synthesis of 2- (4- (2-amino-5-chlorophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) acetic acid (60)

Tert-butyl 2- (4- (2-amino-5-chlorophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) acetate (59) (194mg, 0.53mmol) was dissolved in dioxane hydrochloride solution (4N,2mL) and the reaction was stirred at 25 ℃ for 2H. LC-MS detection shows that the reaction is finished. The reaction mixture was concentrated, and the solvent was removed. The crude product was dissolved in methanol and purified by reverse phase column chromatography to give 2- (4- (2-amino-5-chlorophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) acetic acid (60) as a yellow solid, 150mg, yield: 91 percent. LCMS M/z 309.1(M + H)⁺。

And 4, step 4: synthesis of 2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) acetic acid (61)

2- (4- (2-amino-5-chlorophenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) acetic acid (60) (150mg, 0.486mmol), trimethyl orthoformate (206mg, 1.944mmol) was added to AcOH (4mL) and stirred for 30 min. Adding NaN into the reaction solution₃(126mg, 1.944mmol) and stirred overnight. LC-MS shows that the target compound is generated and the raw materials are completely reacted. The reaction solution is dried by spinning and purified by a reverse phase column to obtain 2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) ethylAcid (61) as a white solid, 150mg, yield 85.3%. LCMS M/z 723.1(2M + H)⁺。

And 5: synthesis of tert-butyl (5- (2- ((4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) methyl) -1H-imidazol-5-yl) -6-fluoropyridin-2-yl) carbamic acid (62)

2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) acetic acid (61) (150mg, 0.415mmol), intermediate 22(137mg, 0.415mmol) was added to NMP (2mL) at room temperature, DIPEA (107mg, 0.83mmol) was added dropwise over ice, and the mixture was stirred at room temperature for 30 min. LC-MS detection shows that the reaction is finished. 10mLEA was added to the reaction solution with saturated NH₄Aqueous Cl (10mL) was washed and the aqueous phase was extracted with EA (10mL × 2). The organic phases were combined and washed with saturated aqueous NaCl solution (10mL), Na₂SO₄Drying, concentrating, dissolving the concentrated residue with toluene/glacial acetic acid (2mL/0.2mL), and adding CH to the reaction solution₃COONH₄(320mg, 4.15mmol) and stirred at 100 ℃ overnight. LC-MS showed the reaction was complete and solvent was spun dry and purified by forward chromatography to give tert-butyl (5- (2- ((4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) methyl) -1H-imidazol-5-yl) -6-fluoropyridin-2-yl) carbamic acid (62) as a yellow solid in 100mg, 40.6% yield. LCMS M/z 594.2(M + H)⁺。

Step 6: synthesis of 1- ((5- (6-amino-2-fluoropyridin-3-yl) -1H-imidazol-2-yl) methyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (A1)

Intermediate 62(100mg, 0.14mmol) was dissolved in dioxane (2mL) and stirred at room temperature. Then dioxane hydrochloride (4M, 2mL) was added to the above solution, methanol (0.5mL) was added, and the reaction was stirred at room temperatureFor 16 hours. LC-MS detection shows that the reaction is finished. The reaction mixture was concentrated, and the solvent was removed. Dissolving the crude product in methanol, adjusting pH to alkalescence with anhydrous sodium carbonate, filtering, and concentrating the filtrate to obtain crude product. The crude product was purified by reverse phase preparative isolation to give example A1 (acid method), 9.11mg, total yield: 10.8 percent. LCMS M/z 494.1(M + H)⁺；¹H NMR(400MHz,DMSO-d₆)δ12.07(s,1H),9.68(s,1H),8.37(s,1H),8.06–7.92(m,1H),7.82(d,J＝1.2Hz,2H),7.74(t,J＝1.3Hz,1H),7.37(s,1H),7.15–7.05(m,1H),6.50(s,1H),6.37(dd,J＝8.2,2.0Hz,1H),6.34–6.19(m,2H),5.08(s,2H),3.25(s,3H).

Example a 2: synthesis of 1- (1- (5- (6-amino-2-fluoropyridin-3-yl) -1H-imidazol-2-yl) ethyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (A2)

Analogously to the synthesis of example A1, from intermediate 5,

Methyl (2-bromopropionate) and 22. The first step, starting from intermediate 5 and methyl 2-bromopropionate, was carried out by substituting K in A1 with NaH₂CO₃As a base, react at 65 ℃ for 16 hours; the other step operations are substantially identical to the corresponding steps in the synthesis of a 1. LCMS M/z 508.2(M + H)⁺；¹H NMR(400MHz,DMSO-d₆)δ12.70–12.01(m,1H),9.66(s,1H),8.11–7.92(m,1H),7.84–7.73(m,3H),7.17(s,2H),6.50(s,1H),6.46–6.21(m,3H),6.20–6.12(m,1H),3.19(s,3H),1.67(d,J＝7.1Hz,3H).

Example a 3: synthesis of 1- (1- (5- (4-aminophenyl) -1H-imidazol-2-yl) propyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (A3).

Similar to the examplesSynthesis of A2, from intermediate 5,

(ethyl 2-bromobutyrate) and intermediate 17. LCMS M/z 503.2(M + H)⁺；¹H NMR(400MHz,DMSO-d₆)δ12.49–12.06(m,1H),9.67(s,1H),7.85–7.78(m,2H),7.75(s,1H),7.48–7.01(m,4H),6.62–6.50(m,2H),6.47(s,1H),6.12–5.88(m,1H),5.32–4.78(m,2H),3.26–3.21(m,3H),2.19–1.94(m,2H),0.78(t,J＝7.2Hz,3H).

Example a 4: synthesis of 1- (1- (5- (6-amino-2-fluoropyridin-3-yl) -1H-imidazol-2-yl) propyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (A4)

Analogously to the synthesis of example A2, from intermediate 5,

(ethyl 2-bromobutyrate) and intermediate 22. LCMS M/z 522.3(M + H)⁺。¹H NMR(400MHz,DMSO-d₆)δ12.38(s,1H),9.67(s,1H),7.99(t,J＝9.6Hz,1H),7.81(s,2H),7.75(s,1H),7.39(s,1H),7.12(d,J＝3.6Hz,1H),6.47(s,1H),6.37(dd,J＝8.2,1.4Hz,1H),6.32–6.19(m,2H),6.01(t,J＝7.6Hz,1H),3.22(s,3H),2.18–1.97(m,2H),0.78(t,J＝7.3Hz,3H).

Example a 5: synthesis of 1- (1- (5- (6-aminopyridin-3-yl) -1H-imidazol-2-yl) -2-cyclopropylethyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (A5)

Similar to the synthesis of example a2, synthesized from intermediates 5, 24 and 19, without the final Boc protecting group removal one step in the synthesis of a 2. Racemization is carried out in the reaction process, and the final product is a racemized product through chiral analysis. LCMS: m-z 530.2(M+H)⁺；¹H NMR(DMSO-d₆,400MHz)δ12.26(s,1H),9.66(s,1H),8.23(d,J＝47.1Hz,2H),7.65(dd,J＝93.8,75.9Hz,4H),7.38–7.36(m,2H),6.56–6.39(m,2H),6.19(s,1H),5.84(s,2H),3.23(s,3H),2.15(dd,J＝13.4,6.6Hz,1H),1.81(s,1H),0.56(s,1H),0.33(d,J＝7.6Hz,2H),0.03–-0.03(m,2H).

Example a 6: synthesis of 1- (1- (5- (6-amino-2-fluoropyridin-3-yl) -1H-imidazol-2-yl) -2-cyclopropylethyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (A6)

Synthesized in analogy to the synthesis of example a2, from intermediates 5, 24 and 22. LCMS M/z 548.3(M + H)⁺。¹H NMR(400MHz,DMSO-d₆)δ12.38(s,1H),9.66(s,1H),8.34(s,0.5H),8.02(s,1H),7.84-7.79(m,2H),7.73(t,J＝1.4Hz,1H),7.36(s,1H),7.14(s,1H),6.47(s,1H),6.37(dd,J＝8.2,2.1Hz,1H),6.28-6.16(m,2H),3.23(s,3H),2.19-2.14(m,1H),1.92-1.78(brs,1H),0.58-0.54(m,1H),0.37-0.30(m,2H),0.12–0.00(m,2H).

Examples a7 and A8: synthesis of 1- (1- (5- (6-amino-2-fluoropyridin-3-yl) -1H-imidazol-2-yl) -2-cyclopropylethyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (R or S absolute configuration)

Example A6 purification on a chiral column (

AS-H10 μm2.5 × 25cm) to give compounds a7(2.01mg, retention time 5.63 min) and A8(2.48mg, retention time 9.62 min).

A7:LCMS m/z 548.3(M+H)⁺；¹H NMR(400MHz,DMSO-d₆)δ12.35(s,1H),9.66(s,1H),8.34(s,0.5H),8.02(s,1H),7.84-7.79(m,2H),7.73(t,J＝1.4Hz,1H),7.36(s,1H),7.14(s,1H),6.47(s,1H),6.37(dd,J＝8.2,2.1Hz,1H),6.28-6.16(m,2H),3.23(s,3H),2.19-2.14(m,1H),1.92-1.78(brs,1H),0.58-0.54(m,1H),0.37-0.30(m,2H),0.12–0.00(m,2H)。

A8:LCMS m/z 548.3(M+H)⁺；¹H NMR(400MHz,DMSO-d₆)δ12.36(s,1H),9.66(s,1H),8.34(s,0.5H),8.02(s,1H),7.84-7.79(m,2H),7.73(t,J＝1.4Hz,1H),7.36(s,1H),7.14(s,1H),6.47(s,1H),6.37(dd,J＝8.2,2.1Hz,1H),6.28-6.16(m,2H),3.23(s,3H),2.19-2.14(m,1H),1.92-1.78(brs,1H),0.58-0.54(m,1H),0.37-0.30(m,2H),0.12–0.00(m,2H).

Example a 9: synthesis of 1- (1- (5- (6-amino-2-fluoropyridin-3-yl) -4-fluoro-1H-imidazol-2-yl) -2-cyclopropylethyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (A9)

Step 1 Synthesis of tert-butyl (5- (2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-cyclopropylethyl) -4-fluoro-1H-imidazol-5-yl) -6-fluoropyridin-2-yl) carbamic acid (64)

The starting compound tert-butyl (5- (2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-cyclopropylethyl) -1H-imidazol-5-yl) -6-fluoropyridin-2-yl) carbamic acid (63) was synthesized from intermediates 5, 24 and 22 in analogy to step 5 of the synthesis of example a 1.

The starting compound (360mg,0.55mmol) was dissolved in a mixed solution of 0.8mL tetrahydrofuran and 2.5mL acetonitrile followed by the addition of 0.1mL pyridine, the addition of a selective fluoro reagent (295mg,0.83mmol) at-18 deg.C, stirring for 2 hours at this temperature, and LC-MS detection showed the disappearance of most of the starting material and the formation of the product. The reaction was diluted with 20mL ethyl acetate, followed by addition of saturated sodium sulfite solution (20mL), stirring for 1 hour, addition of water 20mL, extraction with ethyl acetate (40mL x3), combined organic phases washed successively with 1N HCl (100mL x 1), saturated sodium bicarbonate solution (100mL x 1), saturated aqueous sodium chloride solution (100mL x 1), and dried over anhydrous sodium sulfate. For treatingThe anhydrous sodium sulfate was filtered off, the filtrate was concentrated, and the crude product was purified by column chromatography (biotage,40g, silica gel column, UV254, ethyl acetate 0-100% in dichloromethane) to give tert-butyl (5- (2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-cyclopropylethyl) -4-fluoro-1H-imidazol-5-yl) -6-fluoropyridin-2-yl) carbamic acid (64) (163mg, yield: 44%) as a pale yellow solid. LCMS M/z 666.2(M + H)⁺。

Step 2.1 Synthesis of 1- (1- (5- (6-amino-2-fluoropyridin-3-yl) -4-fluoro-1H-imidazol-2-yl) -2-cyclopropylethyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (A9)

Tert-butyl (5- (2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-cyclopropylethyl) -4-fluoro-1H-imidazol-5-yl) -6-fluoropyridin-2-yl) carbamic acid (64) (140mg,0.21mmol) was dissolved in a mixed solution of 3mL dichloromethane and 1mL trifluoroacetic acid at room temperature and stirred for 2 hours at room temperature with LC-MS detection showing disappearance of starting material. The reaction mixture was concentrated and purified by prep-HPLC to give the objective product A9(72mg, yield: 60%). LCMS M/z 566.2(M + H)⁺；¹H-NMR(400MHz,DMSO-d₆)δ12.54(s,1H),9.67(s,1H),7.84-7.74(m,3H),7.60-7.56(m,1H),7.19(s,1H),6.56-6.16(m,5H),3.24(s,3H),2.11-2.05(m,1H),1.87-1.82(m,1H),0.57-0.54(m,1H),0.37-0.32(m,2H),0.03-0.04(m,2H).

Step 3 chiral resolution of A9 gave examples A10 and A11

1- (1- (5- (6-amino-2-fluoropyridin-3-yl) -4-fluoro-1H-imidazol-2-yl) -2-cyclopropylethyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (A9) (70mg) was, by hand, the racemic compound which was purified by chiral column (Chi: (Chi)

AS-H10 um2.5 × 25cm) chiral resolution yielded examples a10 (retention time 4.70 min) and a11 (retention time 9.27 min).

A10:LCMS m/z 566.2(M+H)⁺；¹H NMR(400MHz,DMSO-d₆)δ12.54(s,1H),9.67(s,1H),7.82-7.75(m,3H),7.60-7.56(m,1H),7.19(s,1H),6.56-6.16(m,5H),3.24(s,3H),2.11-2.05(m,1H),1.87-1.82(m,1H),0.57-0.54(m,1H),0.37-0.32(m,2H),0.03-0.04(m,2H)。

A11:LCMS m/z 566.2(M+H)⁺；¹H NMR(400MHz,DMSO-d₆)δ12.54(s,1H),9.67(s,1H),7.84-7.74(m,3H),7.60-7.56(m,1H),7.19(s,1H),6.56-6.16(m,5H),3.24(s,3H),2.11-2.05(m,1H),1.87-1.82(m,1H),0.57-0.54(m,1H),0.37-0.32(m,2H),0.03-0.04(m,2H)。

Example a 12: synthesis of 1- (1- (5- (6-amino-2-fluoropyridin-3-yl) -1H-imidazol-2-yl) -2-cyclobutylethyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (A12)

Synthesized in analogy to the synthesis of example a2, from intermediates 5, 25 and 22. LCMS M/z 562.3(M + H)⁺；¹H NMR(400MHz,DMSO-d₆)δ12.35(s,1H),9.66(s,1H),8.02(s,1H),7.77(d,J＝28.4Hz,3H),7.39(s,1H),7.14(s,1H),6.49–6.00(m,5H),3.25(s,3H),2.28–2.07(m,3H),1.89(d,J＝6.9Hz,2H),1.76(dd,J＝16.2,9.1Hz,2H),1.62(dt,J＝18.2,9.0Hz,2H).

Example a 13: synthesis of 1- (1- (5- (6-amino-2-fluoropyridin-3-yl) -1H-imidazol-2-yl) -2-cyclopropylethyl) -4- (5-chloro-2- (difluoromethyl) phenyl) -5-methoxypyridin-2 (1H) -one (A13)

Synthesized in analogy to the synthesis of example a2, from intermediates 9, 24 and 22.

Step 1.2- (4- (5-chloro-2- (difluoromethyl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -3-cyclopropylpropionic acid (65) Synthesis

Intermediate 9(200mg, 0.700mmol), DMF (3mL) and DME (1.5mL) were added to a 25mL eggplant-shaped flask while stirring at room temperature under a nitrogen blanket. Sodium hydride solid (102mg, 0.735mmol) (60% w/w mineral oil) was then added. The reaction was stirred at room temperature for 5 minutes, then anhydrous lithium bromide (122mg,1.40mmol) was added, and after 10 minutes of sonication in ultrasound, a solution of intermediate 24(188mg, 0.910mmol) in 0.5mL of DME was slowly added dropwise to the reaction. After the dropwise addition, the mixture is stirred for 16 hours at 60 ℃, LC-MS detection shows that the carboxylic acid and the ester exist, meanwhile, the raw materials are basically consumed, the reaction liquid is cooled to room temperature, LiOH (147mg,3.50mmol) and 3mL of water are added, stirring is carried out at the room temperature for 2 hours, and LC-MS shows that the ester is completely converted into the carboxylic acid. The reaction mixture was concentrated, diluted with 20mL of water, extracted with ethyl acetate (20mL × 2), the organic phase was discarded, the pH of the aqueous phase was adjusted to 3 to 4 with 1N HCl, extracted with ethyl acetate (20mL × 3), the combined organic phases were washed with saturated brine (20mL × 1), and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered off, the filtrate was concentrated to give a crude product, which was purified with a reverse phase column to give 2- (4- (5-chloro-2- (difluoromethyl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -3-cyclopropylpropionic acid (65) as a yellow powdery solid, 240mg, yield: 86.2 percent. LCMS M/z 398.0(M + H)⁺. According to example a5, intermediate 65 is the racemic product.

Step 2 Synthesis of tert-butyl (5- (2- (1- (4- (5-chloro-2- (difluoromethyl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-cyclopropylethyl) -1H imidazol-5-yl) -6-fluoropyridin-2-yl) carbamic acid (66)

2- (4- (5-chloro-2- (difluoromethyl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -3-cyclopropylpropionic acid (65) (100,0.251mmol), intermediate 22(84mg,0.251mmol) was dissolved in 2mL of NMP followed by DIPEA (65mg,0.502mmol) and the reaction stirred at room temperature for 0.5H and LC-MS showed substantial consumption of starting material and ester formation, the reaction was diluted with 20mL of water, extracted with ethyl acetate (20mL 3), the combined organic phases were washed successively with water (60mL 1), brine (60mL 1), dried over anhydrous sodium sulfate, filtered, the filtrate was dried to give intermediate (crude) which was dissolved in 2mL of toluene and 0.2mL of acetic acid, ammonium acetate (193mg,2.502mmol) was stirred at 100 deg.C for 16 hours and LC-MS showed the formation of the product. The reaction solution was concentrated. The crude product was purified by silica gel column to give tert-butyl (5- (2- (1- (4- (5-chloro-2- (difluoromethyl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-cyclopropylethyl) -1H imidazol-5-yl) -6-fluoropyridin-2-yl) carbamic acid (66) as a yellow oil, 90mg, 56.82% yield. LCMS M/z 630.2(M + H)⁺。

Step 3.1 Synthesis of 1- (1- (5- (6-amino-2-fluoropyridin-3-yl) -1H-imidazol-2-yl) -2-cyclopropylethyl) -4- (5-chloro-2- (difluoromethyl) phenyl) -5-methoxypyridin-2 (1H) -one (A13)

Tert-butyl (5- (2- (1- (4- (5-chloro-2- (difluoromethyl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-cyclopropylethyl) -1H imidazol-5-yl) -6-fluoropyridin-2-yl) carbamic acid (66) (90mg,0.134mmol) was dissolved in 2mL of 1,4-dioxane at room temperature, followed by the addition of 2mL of HCl in 1,4 dioxane (4N) and 10 drops of methanol until the reaction was clear and the reaction was stirred at room temperature for 2 days. LC-MS detection shows that the reaction is finished. Concentrating the reaction solution, dissolving in 2mL of methanol, adding sodium carbonate to pH 8, filtering, and directly preparing the filtrate (alkaline preparation) to obtain 1- (1- (5- (6-amino-2-fluoropyridin-3-yl) -1H-imidazol-2-yl) -2-cyclopropylethyl) -4- (5-chloro-2- (difluoromethyl) phenyl) -5-methoxyPyridin-2 (1H) -one (A13), 17.12mg, yield 22.4%. LCMS M/z530.2(M + H)⁺。¹H NMR(400MHz,DMSO)δ12.48(d,J＝57.0Hz,1H),8.15–8.06(m,1H),7.85–7.62(m,3H),7.46(s,1H),7.15(d,J＝26.8Hz,1H),6.78(t,J＝56.0Hz,2H),6.49–6.18(m,5H),3.54(d,J＝13.9Hz,3H),2.30–2.18(m,1H),1.98–1.85(m,1H),0.64(s,1H),0.36(d,J＝7.5Hz,2H),0.10(t,J＝15.9Hz,2H).

Example a 14: synthesis of 1- (1- (5- (6-amino-2-fluoropyridin-3-yl) -1H-imidazol-2-yl) -2-cyclopropylethyl) -4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (A14)

Synthesized in analogy to the synthesis of example a13, from intermediates 14, 24 and 22. LCMS M/z 581.2(M + H)⁺；¹H NMR(400MHz,DMSO-d₆)δ12.54–12.27(m,1H),8.65–8.56(m,1H),8.10–7.99(m,1H),7.86–7.72(m,2H),7.69(d,J＝2.2Hz,1H),7.42–7.28(m,1H),7.18–7.02(m,1H),6.45–6.41(m,1H),6.37(dd,J＝8.2,2.0Hz,1H),6.31–6.26(m,2H),6.25–6.14(m,1H),3.29–3.22(m,3H),2.20–2.05(m,1H),1.99–1.83(m,1H),0.64–0.50(m,1H),0.42–0.27(m,2H),0.08–0.00(m,2H).

Example a 15: synthesis of 1- (2- (1- (1- (5- (6-amino-2-fluoropyridin-3-yl) -1H-imidazol-2-yl) -2-cyclopropylethyl) -5-methoxy-2-oxo-1, 2-dihydropyridin-4-yl) -4-chlorophenyl) -1H-1,2, 3-triazole-4-carbonitrile (A15)

Synthesized from intermediates 32, 24 and 22 in analogy to the synthesis of example a 14. LCMS M/z 572.2(M + H)⁺；¹H NMR(400MHz,DMSO-d₆)δ12.37(s,1H),9.32(s,1H),8.06-8.01(m,1H),7.84–7.74(m,3H),7.35-7.30(m,1H),7.16–7.06(m,1H),6.48–6.17(m,5H),3.25(s,3H),2.18-2.10-(m,1H),1.96-1.89(m,1H),0.60-0.56(m,1H),0.39-0.34(m,2H),0.06-0.014(m,2H).

Example a 16: synthesis of 1- (1- (5- (6-amino-2-fluoropyridin-3-yl) -1H-imidazol-2-yl) -2-cyclopropylethyl) -4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (A16)

Synthesized from intermediates 38, 24, and 22 in analogy to the synthesis of example a 14. LCMS M/z 615.2(M + H)⁺；¹H NMR(400MHz,DMSO-d₆)δ9.16(s,1H),7.94(t,J＝8.8Hz,1H),7.88–7.79(m,2H),7.72(s,1H),7.31(s,2H),6.83–6.29(m,4H),6.12(s,1H),3.23(s,3H),2.22–1.94(m,2H),0.62–0.48(m,1H),0.39–0.29(m,2H),0.12–-0.00(m,2H).

Example a 17: synthesis of 1- (1- (5- (6-amino-2-fluoropyridin-3-yl) -1H-imidazol-2-yl) -2-cyclopropylethyl) -4- (5-chloro-2- (4- (difluoro) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (A17)

Synthesized in analogy to the synthesis of example a14, from intermediates 43, 24 and 22. LCMS M/z 597.2(M + H)⁺；¹H NMR(400MHz,DMSO-d₆)δ8.75(s,1H),7.93(t,J＝9.2Hz,1H),7.86–7.74(m,2H),7.73–7.64(m,1H),7.58–6.94(m,3H),6.93–6.29(m,4H),6.27–5.90(m,1H),3.23(s,3H),2.21–2.02(m,2H),0.64–0.47(m,1H),0.45–0.28(m,2H),0.13–0.00(m,2H).

Example a 18: synthesis of (S) -2- (1- (5- (4-aminophenyl) -1H-imidazol-2-yl) -2-cyclopropylethyl) -5- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -6-methoxypyridazin-3 (2H) -one (A18)

Step 1 Synthesis of tert-butyl (S) - (4- (2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -3-methoxy-6-oxopyridazin-1 (6H) tert-butyl) -2-cyclopropylethyl) -1H-imidazol-5-yl) phenyl) carbamate (67)

Intermediate 49(100mg, 0.24mmol) and intermediate 17(75mg, 0.24mmol) were added to NMP (2mL) at room temperature, DIEA (78mg, 0.60mmol) was added dropwise over an ice bath, and the mixture was stirred at room temperature for 1.5 h. LC-MS detection shows that the reaction is finished. EA (10mL) was added to the reaction mixture, followed by saturated NH₄Aqueous Cl (10mL) was stripped and the aqueous phase was extracted with EA (10mL 2). The organic phases were combined and washed with saturated aqueous NaCl solution (10mL), Na₂SO₄Drying, concentrating, dissolving the concentrated residue with toluene/glacial acetic acid (2mL/0.2mL), and adding NH₄oAc (185mg, 2.40mmol), stirring at 100 ℃ for 3 h. LC-MS showed the reaction was complete and after solvent spin-drying purification by forward chromatography gave 67 as a yellow solid, 80mg, 52% yield. LCMS M/z 650.2(M + H)⁺And 630.3(M + H)⁺。

Step 2 Synthesis of (S) -2- (1- (5- (4-aminophenyl) -1H-imidazol-2-yl) -2-cyclopropylethyl) -5- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -6-methoxypyridazin-3 (2H) -one (A18)

Intermediate 67(60mg, 0.13mmol) was dissolved in DCM (1mL) and stirred at room temperature. Then, dioxane hydrochloride solution (4M, 4mL) was added to the above solution and the reaction was stirred at room temperature for 16 hours. LC-MS detection shows that the raw materials are basically disappeared, and the reaction is finished. The reaction was concentrated and the solvent removed to give crude which was sent to HPLC to give 16.37mg of the target product a18 (prepared by acid method), yield: 24 percent. LCMS M/z530.2(M + H)⁺；¹H NMR(400MHz,DMSO-d₆)δ9.86(s,1H),7.95(s,1H),7.90(d,J＝1.0Hz,2H),7.82(s,1H),7.70(d,J＝8.1Hz,2H),7.23(s,1H),7.00(d,J＝5.9Hz,2H),6.34(s,1H),3.38(s,3H),2.34–2.03(m,2H),0.62(s,1H),0.40(d,J＝8.0Hz,2H),0.15(dd,J＝8.9,4.5Hz,1H),0.05-0.00(s,1H).

Example a 19: synthesis of 2- (1- (5- (6-amino-2-fluoropyridin-3-yl) -1H-imidazol-2-yl) -2-cyclopropylethyl) -5- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -6-methoxypyridazin-3 (2H) -one (A19)

Intermediate 49(100mg, 0.24mmol) and 22(80mg, 0.24mmol) were added to NMP (2mL) at room temperature, DIEA (78mg, 0.60mmol) was added dropwise over an ice bath, and stirred at room temperature for 1.5 h. LC-MS detection shows that the reaction is finished. EA (10mL) was added to the reaction mixture, followed by saturated NH₄Aqueous Cl (10mL) was washed and the aqueous phase was extracted with EA (10mL x 3). The organic phases were combined and washed with saturated aqueous NaCl solution (10mL), Na₂SO₄Drying, concentrating, dissolving the concentrated residue with toluene/glacial acetic acid (3mL/0.3mL), and adding NH₄oAc (185mg, 2.40mmol), stirring at 100 ℃ for 16 h. LC-MS showed the reaction was complete, yielding intermediate 68. After solvent spin-drying and purification by HPLC (formic acid system) the final target product a19 was obtained, 7.33mg, yield 5.5%. LCMS M/z 549.3(M + H)⁺；¹H NMR(400MHz,DMSO-d₆)δ11.93(s,1H),9.82(s,1H),8.31–7.99(m,1H),7.86(t,J＝9.0Hz,3H),7.12(d,J＝13.2Hz,2H),6.45–6.33(m,1H),6.28–6.09(m,3H),3.34(s,3H),2.19–1.94(m,2H),0.58(s,1H),0.36(d,J＝8.1Hz,2H),0.07(s,1H),-0.04(s,1H).

Example a 20: synthesis of 1- ((5- (6-amino-2-fluoropyridin-3-yl) -1H-imidazol-2-yl) methyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-ethoxypyridin-2 (1H) -one (A20)

Synthesized in analogy to the synthesis of example a1, from intermediate 56, tert-butyl 2-bromoacetate and intermediate 22. LCMS M/z 508.3(M + H)⁺；¹H NMR(400MHz,DMSO-d₆)δ12.07(s,1H),9.68(s,1H),8.05-7.98(m,1H),7.84-7.74(m,3H),7.37(s,1H),7.13(s,1H),6.52–6.27(m,4H),5.09(s,2H),3.46-3.44(m,2H),0.97(t,J＝6.9Hz,3H).

Example a 21:

synthesized in analogy to the synthesis of example a1, from intermediate 57, tert-butyl 2-bromoacetate and intermediate 22. LCMS M/z 522.1(M + H)⁺，¹H NMR(400MHz,DMSO-d₆)δ12.43(s,1H),9.67(s,1H),7.95(t,J＝9.6Hz,1H),7.87–7.69(m,3H),7.41(s,1H),7.2(s,1H),6.59–6.22(m,4H),5.14(s,2H),3.95–3.75(m,1H),0.86(d,J＝10.0Hz,6H).

Similarly, further examples were synthesized as follows:

effect embodiment:

biological activity of the compound of the invention on inhibition of coagulation factor XIa (FXIa)

1. Test method

Factor XIa protease (FXIa) cleaves specific substrates to produce yellow p-nitroaniline (pNA), which absorbs strongly at 405 nM. The inhibitory activity of a compound on factor XIa was determined by measuring the absorbance of the compound at 405 nM.

2. Reagent, consumable and instrument

The factor XIa protease used in the experiments was purchased from Abcam, cat No. ab 62411; factor XIa-specific substrates were purchased from HYPHEN BioMed, cat # Biophen cs-21 (66); tris-HCl was purchased from Invitrogen, cat # 15567-; NaCl available from ABCONE, cat # S39168; tween 20 was purchased from Amersham, cat # 0777-1L.

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

The ECHO liquid workstation is purchased from Labcyte, model number ECHO 550; the Bravo liquid workstation was purchased from Agilent, model 16050-; a multifunctional microplate reader was purchased from PerkinElmer, model EnVision; 384 well compound plates were purchased from Labcyte, cat # LP-0200; 384 well assay plates were purchased from PerkinElmer, cat # 6007650.

3. Compound preparation

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

4. The test method comprises the following steps:

a. 20mM test compound was diluted to 2mM using 100% DMSO, and reference compound was diluted to 0.4 mM; compounds were serially diluted using a Bravo liquid workstation 3-fold gradient, 10 concentration points.

b. Transfer 10nL of compound to the corresponding 384 well assay plate, duplicate wells, using the ECHO liquid workstation; the final concentrations of the compounds were 1000, 333.3, 111.1, 37.0, 12.3, 4.1, 1.37, 0.46, 0.15, 0.05 nM. The final reference compound reaction concentrations were 200, 66.7, 22.2, 7.4, 2.47, 0.82, 0.27, 0.09, 0.03, 0.01 nM.

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

d. Preparing FXIa enzyme solution with 0.1 mu g/mL by using buffer solution, and adding 10 mu L of enzyme solution to a 384-hole experimental plate; 5mM substrate solution was prepared using buffer, and 10. mu.L of substrate solution was added to 384-well plates. The final concentration of FXIa was 0.05. mu.g/mL and the final concentration of substrate was 2.5 mM.

e. The 384 well assay plates were centrifuged and incubated at 37 ℃ for 15 minutes.

f. Absorbance was measured at 405nM using EnVision.

In this example, half inhibitory activity (IC) of the compounds of the present invention against FXIa was determined₅₀) As shown in the following table, wherein:

TABLE 1 IC inhibition of FXIa by the compounds of the invention₅₀Value (nM)

Numbering	FXIa IC50	Numbering	FXIa IC50	Numbering	FXIa IC50	Numbering	FXIa IC50
								A1	1.22	A2	1.82	A3	2.12	A4	1.84
A5	2.67	A6	1.56	A7	0.81	A8	45.80
								A9	2.55	A10	29.50	A11	0.73	A12	1.65
A13	>1000	A14	4.21	A15	4.80	A16	16.82
								A17	31.34	A18	35.31	A19	34.30	A20	2.57
A21	72.63	A22	5.30	A23	0.85	A24	5.55
								A25	0.56	A26	1.36	A 27	6.72	A28	0.78
A29	0.67	A30	3.58	A31	0.47	A32	5.02
								A33	0.79	A34	74.06	A 35	0.79	A36	3.58
A37	1.19	A38	0.84	A39	1.27	A40	4.46
								A41	0.89	A42	139.3	A43	>1000	A44	30.61
A45	63.35	A46	197.8	A47	401.7	A48	114.2
								A49	20.56	A50	52.23	A51	3.92

Table 2 IC of inhibition of FXIa by compounds of the invention and compounds reported in patent WO2013093484₅₀Comparison of values (nM)

It can be seen that the activity of the compounds of the present invention is significantly better than that of similar compounds reported in patent WO 2013093484.

Second, testing the in vitro anticoagulant effect of the compound of the invention on human blood

1. Test method

Activated Partial Thrombin Time (APTT) measuring reagent is mixed with plasma and then reacts continuously to change optical density until reaching a freezing point, and a semi-automatic coagulation analyzer is used for measuring the Coagulation Time (CT) by an optical turbidimetry method. The in vitro anticoagulation activity of the compound on human blood is determined by detecting the coagulation time of plasma treated by the compound with different concentrations, and the concentration corresponding to the coagulation time prolongation of the compound is calculated.

2. Reagent, consumable and instrument

The human plasma used in the experiment was from Hai-source Biotechnology (Shanghai) Ltd; the activated partial thromboplastin time assay kit was purchased from saidi biotechnology limited, china, No. SS 00220005.

The semi-automatic coagulation analyzer is purchased from Shengxinkang science and technology Limited, Shenzhen, model SK 5004; the measuring cup is purchased from shenzhen shengxikang science and technology limited. The Bravo liquid workstation was purchased from Agilent, model 16050-; 384 well compound plates were purchased from Labcyte, cat # LP-0200.

3. Compound preparation

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

4. Test method

a. The NaCl reagent in the kit was incubated half an hour in advance and the APTT reagent equilibrated to room temperature.

b. Compounds were serially diluted using a Bravo liquid workstation 2-fold gradient, 14 concentration points.

c. Add 0.75. mu.L of compound in the measuring cup, duplicate wells; adding 50 μ L of plasma, adding 50 μ L of APTT reagent, mixing, and incubating at 37 deg.C for 3 min.

d. The APTT assay was started and the reaction was initiated by the addition of 50. mu.L NaCl and the clotting time was counted.

e. Control clotting times were determined using 100% DMSO instead of compound, final DMSO concentration 0.5%.

5. Data processing

Curve fitting data was performed using Graphpad Prism to calculate the compound concentration corresponding to CT2.0, i.e., 2-fold blank aPTT. In this example, the inhibition of human blood coagulation by the compounds of the invention was determined as shown in the following table, wherein:

TABLE 3 CT2.0 (. mu.M) of the inventive Compounds

Therefore, the compound of the invention has obvious inhibitory activity on human blood coagulation.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (15)

1. A compound represented by formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

T₁is N;

T₂is C (R)₁₂)；

T₃Is N;

T₄selected from N and C (R)₄)；

R₁Is tetrazolyl, 1,2, 3-triazolyl, 4, 5-dihydroisoxazolyl, isoxazolyl, or,

R₂Selected from H, F, Cl, Br, I, NH₂And Me;

R₃selected from H, F, Cl, Br, I and NH₂；

R₄Is selected from H;

R₅selected from C optionally substituted with 1,2 or 3R_1-3alkyl-O-or C_3-6cycloalkyl-O-;

l is selected from the group consisting of a single bond and-CH₂-；

R₆Selected from H, C_1-6Alkyl and C_3-6A cycloalkyl group;

R₇selected from H, F, Cl, Br, I, NH₂And NHMe;

R₈selected from H, F, Cl, Br, I, NH₂And NHMe;

R₉selected from H, F, Cl, Br, I, NH₂And NHMe;

R₁₀selected from H, F, Cl, Br, I, NH₂And NHMe;

R₁₂selected from H, F, Cl, Br, I, NH₂And Me;

each R is independently selected from F.

2. The compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R₅Is selected from

3. The compound, its optical isomer, or its pharmaceutically acceptable salt according to claim 1, wherein the structural unit

Selected from:

4. the compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R₆Selected from H, Me,

5. The compound, its optical isomer, or its pharmaceutically acceptable salt according to claim 1 or 4, wherein the structural unit

Selected from H, Me,

6. The compound, its optical isomer, or its pharmaceutically acceptable salt according to claim 1, wherein the structural unit

Is selected from

7. The compound, its optical isomer, or its pharmaceutically acceptable salt according to claim 1, wherein the structural unit

Is selected from

8. A compound of the formula, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from:

9. a pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition of claim 9, further comprising one or more pharmaceutically acceptable carriers, diluents, or excipients.

11. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 9 or 10 for the preparation of an XIa inhibitor.

12. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 9 or 10 in the manufacture of a medicament for the prevention and/or treatment of a disease mediated by factor XIa.

13. The use according to claim 12, wherein the factor XIa-mediated disease is selected from cardiovascular and cerebrovascular diseases.

14. The use according to claim 13, wherein the cardiovascular and cerebrovascular diseases are selected from thromboembolic diseases.

15. The use according to claim 14, wherein the thromboembolic disorder is selected from hereditary angioneurotic edema, late diabetic macular edema, myocardial infarction, angina, reocclusion and restenosis following angioplasty or aortic coronary bypass, disseminated intravascular coagulation, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism, or deep vein thrombosis.