CN111303146A - 3-cyanopyridine compound, pharmaceutical composition containing same, preparation method and application thereof - Google Patents

Abstract

The application discloses a compound shown as a general formula (I), enantiomers, diastereomers, racemes and mixtures thereof, pharmaceutically acceptable salts thereof, a pharmaceutical composition containing the compound, and applications of the compound in preparation of drugs for preventing or treating thromboembolic diseases, in particular coronary artery syndrome (ACS), stroke, coronary heart disease, atrial fibrillation and other diseases.

Description

3-cyanopyridine compound, pharmaceutical composition containing same, preparation method and application thereof

Technical Field

The invention relates to the field of pharmaceutical chemistry and antithrombotic disease drugs, in particular to a 3-cyanopyridine compound, an enantiomer, a diastereomer, a racemate and a mixture thereof, a pharmaceutically acceptable salt or a pharmaceutical composition containing the compound, a preparation method thereof and application thereof in preparing antithrombotic disease drugs.

Background

Thromboembolic disorders include Acute Coronary Syndrome (ACS), stroke, deep vein thrombosis, pulmonary embolism, ischemic stroke, myocardial infarction, and the like. Statistically, about 1200 million people die of thromboembolic diseases every year worldwide. Thrombotic disease has taken the first place of the global overall mortality of the disease. The existing treatment strategies comprise antiplatelet, anticoagulation and thrombolysis, wherein the antiplatelet drug accounts for about 70 percent of the market share of the antithrombotic drug.

The rupture of atherosclerotic plaques or the implantation of artificial materials in the coronary arteries of a patient causes activation of platelets, which release thromboxane A₂(TXA₂) And Adenosine Diphosphate (ADP), wherein the ADP is combined with a corresponding receptor on the surface of the platelet to further accelerate the adhesion and aggregation of the platelet through a positive feedback mechanism. In Ca²⁺Is mediated by glycoprotein on platelet membrane (GPII)_b/III_a) Binding to fibrinogen causes adjacent platelets to adhere to each other to form a thrombus. Therefore, current antiplatelet drugs act mainly by inhibiting platelet activation by thromboxane a2, adenosine diphosphate or thrombin, and by inhibiting platelet aggregation mediated by GPIIb/IIIa. The inhibition of ADP activation on platelets is the most widely used anti-platelet aggregation drug in clinic at present. ADP is an important platelet agonist in vivo, primarily through binding to the 2G-protein coupled receptors P2Y on the platelet surface₁And P2Y₁₂The combination exerts physiological activity.P2Y₁The receptor is involved in platelet deformation and is widely distributed, whereas P2Y₁₂The receptor can enhance the release of platelet particles, the generation of thromboxane A2 and maintain GPII_bBoth the activation and the stabilization of platelet aggregation play important roles and are distributed mainly on the platelet membrane, therefore, P2Y₁₂Receptor antagonists are the most important field for the development of anti-platelet aggregation drugs (Thrombosi Research, 2014(134), 693-703).

Currently used clinically as P2Y₁₂The antagonist includes clopidogrel, prasugrel, ticagrelor and cangrelor. Clopidogrel is irreversible P2Y₁₂Antagonists, oral prodrugs, require metabolic activation of CYP450 to function. Clopidogrel and aspirin combination have become standard antiplatelet therapies. Nevertheless, there are problems such as slow onset of action, great difference in response to clopidogrel among different human groups due to gene polymorphism, low oral bioavailability, etc. Prasugrel is a third generation irreversible P2Y₁₂Antagonists, which do not require CYP450 enzyme metabolic activation, therefore have a faster onset, higher antiplatelet activity and lower response variability among different populations than clopidogrel, but the high activity brings about a higher risk of bleeding (Thrombosis Research 134(2014) 693-703). Clopidogrel and prasugrel are potent irreversible inhibitors of platelets, which can recover function approximately seven days after withdrawal (platelet regeneration cycle is approximately 7-14 days). Ticagrelor was developed by Asricon as the first reversible direct P2Y₁₂The receptor antagonist can play a role without metabolic activation, the effectiveness is not influenced by gene polymorphism, and the clinical curative effect is better compared with clopidogrel. However, after taking ticagrelor clinically, patients have a black frame warning of increased mortality caused by stroke, and side effects such as dyspnea and ventricular arrest. The side effect may be caused by ticagrelor having ADP structure and inhibiting the equilibrium nuclear glycerol transporter 1 (ENT 1)Off-target effects. AZD1283 is a new generation of reversible non-nuclear glycocalyx small molecule P2Y developed by Aslicon₁₂Receptor antagonists, once in phase II clinical studies, have been shown to have poor absorption and metabolic properties in humans due to the tendency of ester groups to hydrolyze to ineffective carboxyl groups in the molecular structure, resulting in insignificant efficacy without stopping in clinical II (bioorg. med. chem. lett.26(2016) 2739-.

Since prasugrel and ticagrelor were marketed in 2009 and 2011, respectively, both were recommended for first-line treatment of ACS, clopidogrel (the former first-line treatment drug) was recommended only for ACS patients who were both intolerant. The therapeutic guidelines for prasugrel and ticagrelor prescribe a minimum of 12 months, but in clinical practice these potent antiplatelet drugs make long-term treatment difficult due to side effects, particularly the higher risk of bleeding compared to clopidogrel.

Highly activated platelets will be replaced by new platelets within 1-2 weeks after the onset of ACS, a high level of platelet antagonism in the patient may be necessary only days or weeks after the acute onset of ACS, and subsequent stabilization of the condition requires a conversion of the treatment from a high level of platelet inhibitors (prasugrel, ticagrelor) to a moderately stronger, safer inhibitor, which is beneficial in reducing the risk of bleeding from long-term antiplatelet therapy. Therefore, the search for an oral, safe, effective, reversible P2Y₁₂Receptor antagonists remain an urgent clinical need and are of great interest.

Disclosure of Invention

In order to overcome the defects of the existing medicines and develop safer and more effective antiplatelet medicines, the inventor designs and synthesizes a series of compounds by taking AZD1283 as a lead compound, carries out the research on the structure-activity relationship of a system, carries out structure confirmation on all new compounds, and evaluates the in vitro antiplatelet aggregation activity, the pharmacokinetic property, the inhibition activity of CYP (cytochrome) enzyme and the in vivo antithrombotic activity of the compounds. The novel compound overcomes all defects of AZD-1238, has better drug forming property, and is suitable to be used as a novel oral antiplatelet drug for treating thrombotic diseases. On this basis, the inventors have completed the present invention.

In a first aspect of the invention, there is provided a compound of formula (I), enantiomers, diastereomers, racemates, mixtures thereof, and pharmaceutically acceptable salts thereof.

Wherein the content of the first and second substances,

R₁selected from hydrogen or C₁-C₆An alkyl group; preferably selected from hydrogen, methyl, ethyl or propyl;

R₂selected from H, halogen, C₁-C₆Alkyl, hydroxy, C₁-C₆An alkoxy group; preferably H, halogen, C₁-C₃Alkyl, hydroxy, C₁-C₃An alkoxy group;

R₃is selected from substituted or unsubstituted 5-7 membered aromatic heterocyclic group, and the substituent is selected from halogen and C₁-C₆One or more of alkyl, cyano, trifluoromethyl, said aromatic heterocyclic group containing one or more heteroatoms selected from N, O, S; or

Wherein R is₆And R₇Each independently selected from hydrogen and C₁-C₆Alkyl, halogen, or R₆、R₇Together with the linking carbon atom to form a 3-6 membered alicyclic ring, R₈Selected from substituted or unsubstituted C₆-C₁₂Aryl or substituted or unsubstituted C₆-C₁₂Aralkyl, said substituent being selected from halogen, cyano, C₁-C₆Alkyl radical, C₁-C₆One or more, preferably 1,2 or 3, of alkoxy, trifluoromethyl, R₈Preferably selected from substituted or unsubstituted phenyl or substituted or unsubstituted benzyl, andthe substituent is selected from halogen, cyano, C₁-C₃One or more, preferably 1,2 or 3, alkyl, trifluoromethyl;

preferably R₃Selected from unsubstituted or halogen-substituted thienyl, or

Wherein R is₆And R₇Each independently selected from hydrogen and C₁-C₆Alkyl, halogen, or R₆、R₇Together with the linking carbon atom to form a 3-6 membered alicyclic ring, R₉Represents one or more, preferably 1,2 or 3 groups selected from hydrogen, halogen, cyano, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, a substituent in trifluoromethyl; preferably R₃Selected from unsubstituted or fluorine-or chlorine-substituted thienyl, or

Wherein R is₆And R₇Each independently selected from hydrogen and C₁-C₃Alkyl, fluoro, chloro, or R₆、R₇Together with the linking carbon atom to form a 3-6 membered alicyclic ring, R₉Represents hydrogen, fluorine, chlorine, cyano, C₁-C₃One or more, preferably 1,2 or 3, substituents of alkyl, trifluoromethyl;

x is O,

R₄Is H or halogen; preferably H, fluorine or chlorine;

R₅is H or C₁-C₆Alkyl, preferably H, methyl, ethyl or propyl;

n is 0, 1 or 2;

the B ring is a 4-to 8-membered saturated nitrogen heterocycle, preferably a 4-to 6-membered saturated nitrogen heterocycle, such as an azetidine ring, a pyrrolidine ring or a piperidine ring.

Preferably, the compound represented by the general formula (I) of the present invention is a compound of the following general formula (II):

wherein R is₁、R₂、R₃X and n are as defined for formula (I), and Y and Z are each independently methylene, ethylene, propylene and butylene.

Preferably, the compound represented by the general formula (I) of the present invention is the following compound:

wherein R is₁、R₂、R₃X and n are as defined for formula (I).

Preferably, in the general formulae (I) to (V), X is O.

Preferably, in the general formulae (I) to (V), n is 0 or 1.

Preferably, in the formulae (I) to (V), R₁Is hydrogen or methyl.

Preferably, the compound represented by the general formula (I) of the present invention is selected from the compounds in the following table 1.

Table 1 representative compounds of the invention

In one embodiment, the enantiomer is, for example, an enantiomer of

The pharmaceutically acceptable salt can be a pharmaceutically acceptable salt formed by the 3-cyanopyridine compound shown in the general formula (I) and organic base or inorganic base or a pharmaceutically acceptable salt formed by the 3-cyanopyridine compound shown in the general formula (I) and organic acid or inorganic acid. Such organic or inorganic bases include, for example, sodium hydroxide, potassium hydroxide, magnesium hydroxide, ethanolamine, and the like, and such pharmaceutically acceptable salts include, without limitation, alkali metal and alkaline earth metal salts, such as sodium salts, potassium salts, magnesium salts, calcium salts, and the like; an ammonium salt; inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate and the like; organic acid salts such as formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, alkylsulfonate (e.g., methylsulfonate, ethylsulfonate, etc.), arylsulfonate (e.g., benzenesulfonate, p-toluenesulfonate, etc.), and the like.

In one embodiment, the pharmaceutically acceptable salt is, for example, a salt of

According to the invention, C₁-C₆Alkyl refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms, including, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl.

According to the invention, C₁-C₆Alkoxy refers to a straight or branched chain alkoxy group containing 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, tert-butoxy.

According to the invention, C₆-C₁₂Aryl refers to monocyclic or polycyclic aromatic ring groups containing 6 to 12 carbon atoms in the ring and no heteroatoms, including, but not limited to, phenyl, naphthyl.

According to the invention, C₆-C₁₂Aralkyl means containing 6-1Arylalkyl of 2 carbon atoms and no heteroatoms including, but not limited to, benzyl, phenethyl.

According to the present invention, the 5-to 7-membered aromatic heterocyclic group means an aromatic cyclic group having 5 to 7 atoms in the ring and at least one heteroatom selected from O, N, S, and includes, but is not limited to, thienyl, thiazolyl, pyridyl, furyl, pyrrolyl and pyrazolyl.

According to the present invention, the 4-to 8-membered saturated azacyclo refers to a saturated ring containing 4 to 8 atoms in the ring and at least one N atom, and includes, but is not limited to, an azetidine ring, a pyrrolidine ring, a piperidine ring, a homopiperidine ring, a morpholine ring, and the like.

According to the present invention, the 3-6 membered alicyclic ring refers to a saturated ring having 3 to 6 carbon atoms in the ring, and includes, but is not limited to, cyclopropyl ring, cyclobutyl ring, cyclopentyl ring and the like.

According to the invention, the halogen comprises fluorine, chlorine, bromine, iodine.

In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I), enantiomers, diastereomers, racemates thereof and mixtures thereof, or pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier or excipient.

The 3-cyanopyridine derivative provided by the present invention can be used alone or mixed with a pharmaceutically acceptable excipient (e.g., excipient, diluent, etc.) to prepare tablets, capsules, granules, syrups, etc. for oral administration. Or prepared into injections for non-oral administration, and the like.

In another aspect, the present invention provides the use of the compound represented by the above general formula (I), its enantiomer, diastereomer, racemate, mixture thereof, or pharmaceutically acceptable salt thereof, in the preparation of a medicament for preventing or treating thromboembolic diseases, particularly coronary syndrome (ACS), stroke, coronary heart disease, atrial fibrillation, or the like.

In another aspect of the invention, there is provided a process for the preparation of the compounds of formula (I).

The compound represented by the general formula (I) of the present invention can be produced by the method shown in the following scheme, however, the conditions of the method, such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to the following explanation. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains. The method is selected from one of the following routes:

route 1

R₂、R₃、R₅And ring B is as previously defined

(a) Reacting compound A with sulfonamide R₃S(＝O)₂NH₂The compound I-1 is obtained by reaction in a polar aprotic solvent as a solvent, for example, at room temperature for 18 hours, in the presence of a condensing agent such as: mixtures of O-benzotriazol-N, N '-tetramethyluronium tetrafluoroborate (TBTU), 2- (7-azobenzotriazol) -N, N' -tetramethyluronium Hexafluorophosphate (HATU), or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI)/1-Hydroxybenzotriazole (HOBT); the organic base is, for example: triethylamine or diisopropylethylamine; the inorganic base is, for example, sodium bicarbonate, sodium carbonate or potassium bicarbonate; the polar aprotic solvents are for example: dimethylsulfoxide, N-dimethylformamide, tetrahydrofuran or dichloromethane;

(b) removing a tert-butoxycarbonyl protecting group from a compound I-1 in a polar aprotic solvent such as dichloromethane or tetrahydrofuran under the action of an acid to obtain a compound I-2; the acid is, for example, formic acid or dilute hydrochloric acid (2 mol/L);

(c) reacting compound I-3 with trimethyl orthoformate in the presence of an anhydride, for example acetic anhydride or propionic anhydride, for example at 120 ℃ for 3 hours, to give the corresponding compound I-4;

(d) reacting the compound I-4 with cyanoacetamide in a polar protic solvent in the presence of an organic or inorganic base, for example at room temperature, to form the corresponding compound I-5; the organic base is, for example: 20% NaOEt, triethylamine or diisopropylethylamine; the inorganic base is, for example, sodium bicarbonate, sodium carbonate or potassium bicarbonate; the solvent is, for example, methanol or ethanol;

(e) adding acyl chloride and DMF into the compound I-5 in a polar aprotic solvent to perform catalytic reaction, for example, reacting at 70 ℃ overnight to generate a corresponding compound I-6; the polar aprotic solvent is, for example, tetrahydrofuran or dichloromethane; the acid chloride is, for example, acetyl chloride or oxalyl chloride;

(f) reacting compound I-6 with I-2 in a polar protic solvent in the presence of an organic base, e.g., at 72 ℃ for 4 hours, to give the corresponding compound I-7; the organic base is, for example, triethylamine or diisopropylethylamine; the polar protic solvent is, for example, methanol or ethanol;

(g) compound I-7 with Ammonia or C₁-C₆An aqueous alkylamine solution in a polar solvent, for example at room temperature for 5 hours, to produce compound I-I; the polar solvent is, for example, methanol or ethanol;

compounds 1 and 2 of the present application can be prepared, for example, from scheme 1;

route 2

R₂、R₃、R₄And ring B is as previously defined

(a) Reaction of 1, 3-cyclohexanedione with N, N-dimethylformamide dimethyl acetal (DMF-dimethyl acetal), for example at 60 ℃ for example 3h (h), gives the corresponding compound II-1;

(b) reacting compound II-1 with malononitrile in a polar aprotic solvent in the presence of an inorganic base, e.g. at 80 ℃ for e.g. 8 hours, to form the corresponding compound II-2; the polar aprotic solvent may be acetonitrile, 1, 4-dioxane, tetrahydrofuran, or Dimethylformamide (DMF); the inorganic base is, for example, ammonium acetate or sodium bicarbonate;

(c) reacting compound II-2 with a halogenating (e.g., fluorinating or chlorinating) reagent in a polar aprotic solvent to form compound II-3; the fluorinating agent is, for example, 1-chloromethyl-4-fluoro-1, 4-diazobicyclo 2.2.2 octane bis (tetrafluoroborate), and the chlorinating agent is, for example, NCS; the polar aprotic solvent may be acetonitrile, 1, 4-dioxane, tetrahydrofuran, or Dimethylformamide (DMF);

(d) adding acyl chloride and DMF into the compound II-3 in a polar solvent to perform catalytic reaction, for example, reacting overnight at 70 ℃ to generate a corresponding compound II-4; the polar solvent is, for example, tetrahydrofuran or dichloromethane; the acid chloride is, for example, acetyl chloride or oxalyl chloride;

(e) reacting compound II-4 with compound I-2 obtained in scheme 1 in a polar protic solvent in the presence of an organic base, e.g. at 60-72 ℃ to form compound I-II; the polar protic solvent is, for example, methanol or ethanol; the organic base is, for example, triethylamine or diisopropylethylamine;

compounds 3 and 4 of the present application can be prepared, for example, from scheme 2;

route 3

R₁、R₂、R₃And ring B is as previously defined

(a) Reacting the compound III-1 with benzyl alcohol in a polar solvent in the presence of strong base to obtain a compound III-2; the polar solvent is tetrahydrofuran or dichloromethane for example; strong bases such as sodium hydride, sodium hydroxide or potassium hydroxide;

(b) the compound III-2 is reacted in a polar protic solvent, such as methanol or ethanol, under the action of Pd/C, for example, at room temperature for 6 hours, and the benzyl protecting group is removed to obtain a compound III-3;

(c) reacting compound III-3 with TBSCl in a polar aprotic solvent in the presence of an organic base, e.g., at room temperature for, e.g., 5 hours, to form the corresponding compound III-4; the organic base is, for example: imidazole, pyridine, triethylamine or diisopropylethylamine; the polar aprotic solvent may be: 1, 4-dioxane, toluene, tetrahydrofuran, Dimethylformamide (DMF);

(d) reaction of compound III-4 with N, N-dimethylformamide dimethyl acetal, for example at 60 ℃ for 3 hours, to give the corresponding compound III-5;

(e) reacting compound III-5 with cyanoacetamide in a polar aprotic solvent in the presence of an organic base, e.g. at room temperature for e.g. 12 hours, to form the corresponding compound III-6; the polar aprotic solvent may be: acetonitrile, 1, 4-dioxane, tetrahydrofuran, Dimethylformamide (DMF); organic bases are for example: sodium methoxide or sodium ethoxide;

(f) reacting compound III-6 with a fluorinating agent in a polar aprotic solvent, e.g., at room temperature for, e.g., 18 hours, to form the corresponding compound III-7; the fluorinating agent can be tetrabutylammonium fluoride; the polar aprotic solvent may be: 1, 4-dioxane, tetrahydrofuran, Dimethylformamide (DMF);

(g) hydrolyzing compound III-7 in a polar solvent, such as ethanol or methanol, in the presence of a strong base, such as at room temperature, to provide compound III-8; strong bases such as sodium hydroxide or potassium hydroxide;

(h) reacting compound III-8 in the presence of phosphorus oxychloride, for example at 100 ℃ for, for example, 4 hours, to form the corresponding compound III-9;

(i) reacting compound III-9 with compound I-2 obtained in scheme 1 in a polar protic solvent in the presence of an organic base, e.g. at 60-72 ℃ to form compound I-III; the polar protic solvent is, for example, methanol or ethanol; the organic base is, for example: triethylamine or diisopropylethylamine;

compounds 5-14, 43 of the present application can be prepared, for example, in scheme 3;

route 4

Ring B and R₃As defined above

(a) Reacting compound IV-1 with benzyloxychloromethane in a polar aprotic solvent in the presence of a strong base, for example under ice bath conditions for 12 hours, to give compound IV-2; the nonpolar solvent is, for example, tetrahydrofuran; strong bases such as sodium hydride or n-butyllithium;

(b) the compound IV-2 is reacted in a polar protic solvent, such as methanol or ethanol, in the presence of Pd/C, for example at room temperature for 6 hours, and the benzyl protecting group is removed to obtain a compound IV-3;

(c) reacting compound IV-3 with TBSCl in a polar aprotic solvent in the presence of an organic base, e.g., at room temperature for, e.g., 5 hours, to form the corresponding compound IV-4; the organic base is, for example: imidazole, pyridine, triethylamine or diisopropylethylamine; the polar aprotic solvent may be: 1, 4-dioxane, toluene, tetrahydrofuran, Dimethylformamide (DMF);

(d) reaction of compound IV-4 with N, N-dimethylformamide dimethyl acetal, for example at 60 ℃ for, for example, 4 hours, gives the corresponding compound IV-5;

(e) reacting compound IV-5 with cyanoacetamide in a polar aprotic solvent in the presence of an organic base, e.g. at room temperature for e.g. 12 hours, to form the corresponding compound IV-6; the polar aprotic solvent may be: acetonitrile, 1, 4-dioxane, tetrahydrofuran, Dimethylformamide (DMF); organic bases such as sodium methoxide or sodium ethoxide;

(f) reacting compound IV-6 with a fluorinating agent in a polar aprotic solvent, e.g., at room temperature for, e.g., 12 hours, to form the corresponding compound IV-7; the fluorinating agent can be tetrabutylammonium fluoride; the polar aprotic solvent may be: 1, 4-dioxane, tetrahydrofuran, Dimethylformamide (DMF);

(g) hydrolyzing compound IV-7 in polar protic solvent in the presence of strong base, such as at room temperature, to obtain compound IV-8, wherein the polar solvent is ethanol or methanol; the strong base is sodium hydroxide or potassium hydroxide;

(h) reacting the compound IV-8 in the presence of phosphorus oxychloride, for example at 100 ℃ for 5 hours, to obtain the corresponding compound IV-9;

(i) reacting compound IV-9 with compound I-2 obtained in scheme 1 in a polar protic solvent in the presence of an organic base, e.g. at 60-72 ℃ to form compound I-IV; the polar protic solvent is, for example, methanol or ethanol; the organic base is, for example, triethylamine or diisopropylethylamine;

compounds 15-19 of the present invention can be prepared, for example, in scheme 4;

in a preferred embodiment, the compounds of the present invention can be prepared as shown in schemes 5-7 below.

Route 5

R₂、R₆、R₇And R₈As defined above

(a) Reacting compound V-1 with bis (3, 4-dimethylbenzyl) amine in a polar aprotic solvent in the presence of an organic base, e.g. at room temperature for e.g. 5 hours, to give the corresponding compound V-2; the polar aprotic solvent may be: 1, 4-dioxane or tetrahydrofuran; the organic base is, for example: DMAP, imidazole, pyridine, triethylamine or diisopropylethylamine;

(b) reacting compound V-2 with a fluorinating agent or an alkylating agent in a polar aprotic solvent in the presence of a strong base, e.g., at-80 ℃ for, e.g., 6 hours, to form compound V-3; the fluorinating agent may be; n-fluorobisbenzenesulfonamide; the alkylating agent can be methyl iodide, ethyl iodide, propyl iodide or 1,3, 2-dioxolane 2, 2-dioxide; the polar aprotic solvent may be tetrahydrofuran or dichloromethane; strong bases are for example: n-butyl lithium, lithium diisopropylamide or sodium bistrimethylsilyl amide;

(c) reacting compound V-3 with an acid in a polar aprotic solvent, e.g., at room temperature for, e.g., 4 hours, to form compound V-4; the acid is, for example, trifluoroacetic acid or dilute hydrochloric acid (2 mol/L); the polar aprotic solvent may be tetrahydrofuran or dichloromethane;

(d) reaction of the compound III-9 obtained in scheme 3 with piperidinecarboxylic acid in a polar protic solvent in the presence of an organic base, e.g. at 60-70 deg.C, to give the corresponding compound V-5; the polar protic solvent is, for example, methanol or ethanol; the organic base is, for example, triethylamine or diisopropylethylamine;

(e) compounds V-5 and V-4 are reacted in a polar aprotic solvent, e.g. at room temperature for e.g. 18 hours, under the conditions of a condensing agent, e.g.: mixtures of O-benzotriazol-N, N '-tetramethyluronium tetrafluoroborate (TBTU), 2- (7-azobenzotriazol) -N, N' -tetramethyluronium Hexafluorophosphate (HATU), or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI)/1-Hydroxybenzotriazole (HOBT); the organic base is triethylamine or diisopropylethylamine; the inorganic base is, for example, sodium bicarbonate, sodium carbonate or potassium bicarbonate; the polar aprotic solvents are for example: dimethylsulfoxide, N-dimethylformamide, tetrahydrofuran or dichloromethane;

compounds 20-22, 37, 41, 42 of the present application can be prepared, for example, by scheme 5;

route 6

R₂And R₉As defined above

(a) Reaction of compound VI-1 with thiourea in a polar protic solvent, e.g. heated to 60-72 ℃ for e.g. 30 minutes, to give the corresponding compound VI-2; the polar protic solvent is, for example, methanol or ethanol;

(b) reaction of compound VI-2 with a chlorinating reagent in a polar aprotic solvent, e.g., at 0 deg.C for, e.g., 1 hour, to give the corresponding compound VI-3; the polar aprotic solvents are for example: dimethylsulfoxide, N-dimethylformamide, tetrahydrofuran or dichloromethane; the chlorinating agent is, for example, NCS;

(c) reaction of compound VI-3 with aqueous ammonia in a polar aprotic solvent, e.g. at 0 ℃ for e.g. 1.5 hours, gives the corresponding compound VI-4; the polar aprotic solvents are for example: tetrahydrofuran or dichloromethane;

(d) compound VI-4 and

the reaction in a polar aprotic solvent, e.g. at room temperature for e.g. 18 hours, in the presence of a condensing agent, e.g.: mixtures of O-benzotriazol-N, N '-tetramethyluronium tetrafluoroborate (TBTU), 2- (7-azobenzotriazol) -N, N' -tetramethyluronium Hexafluorophosphate (HATU), or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI)/1-Hydroxybenzotriazole (HOBT); the organic base is, for example: triethylamine or diisopropylethylamine; the inorganic base is sodium bicarbonate, sodium carbonate or potassium bicarbonate; the polar aprotic solvents are for example: dimethylsulfoxide, N-dimethylformamide, tetrahydrofuran or dichloromethane;

(e) removing a tert-butoxycarbonyl protecting group from the compound VI-5 in a polar aprotic solvent in the presence of an acid to obtain a compound VI-6; the polar aprotic solvent is, for example, dichloromethane or tetrahydrofuran; the acid is, for example, formic acid or dilute hydrochloric acid (2 mol/L);

(f) reaction of compound VI-6 with compound III-9 obtained in scheme 3 in a polar protic solvent in the presence of an organic base, e.g. at 60-70 ℃ to give the corresponding compounds I-VI; the polar protic solvent is, for example, methanol or ethanol; the organic base is, for example, triethylamine or diisopropylethylamine;

compounds 23-32,40 of the present application can be prepared, for example, in scheme 6;

route 7

R₂And R₉The definition is as before;

(a) reaction of compound III-9 prepared according to scheme 3 with 4-fluoropiperidinecarboxylic acid in a polar protic solvent in the presence of an organic base, e.g. at 60-70 deg.C, to give the corresponding compound VII-1; the polar protic solvent is, for example, methanol or ethanol; the organic base is, for example, triethylamine or diisopropylethylamine;

(b) adding acyl chloride and DMF into a polar aprotic solvent to perform catalytic reaction on the compound VII-1, for example, reacting overnight at 40-70 ℃ to generate a corresponding compound VII-2; the polar solvent is, for example, tetrahydrofuran or dichloromethane; the acid chloride is, for example, acetyl chloride or oxalyl chloride;

(c-1) reaction of Compound VII-2 with Compound VI-4 prepared in scheme 6 in a polar aprotic solvent in the presence of an organic base, e.g., under ice bath conditions, to produce Compound I-VII; the polar aprotic solvent is, for example, tetrahydrofuran or dichloromethane; the organic base is, for example, triethylamine or diisopropylethylamine;

(c-2) reacting compound VII-2 with 5-chlorothiophene-2-sulfonamide in a polar aprotic solvent in the presence of an organic base, e.g., under ice bath conditions, to form compound 36; the polar aprotic solvent is, for example, tetrahydrofuran or dichloromethane; the organic base is, for example, triethylamine or diisopropylethylamine;

compounds 33-36, 38-39 of the present application can be prepared, for example, in scheme 7.

Detailed Description

Examples

The following specific examples are included to provide those skilled in the art with a clear understanding of the invention and are included to provide a further understanding of the invention. They should not be considered as limiting the scope of the invention but merely as being exemplary illustrations and representative of the invention. It will be appreciated by those skilled in the art that there are other synthetic routes to the compounds of the invention and that the following non-limiting examples are provided.

Chemical combinationThe structure of the substance is determined by Nuclear Magnetic Resonance (NMR). NMR is measured by Varian-MERCURYPlus-400 NMR spectrometer or AVANCE III 500 or 600 NMR spectrometer with solvent of deuterated dimethyl sulfoxide (DMSO-d)₆) Or deuterated chloroform (CDCl)₃) Or deuterated deuterium oxide (D)₂O), chemical shifts are expressed in δ (ppm); the mass spectrum is measured by an LTQ linear ion trap mass spectrometer or a Thermo DFS magnetic high resolution mass spectrometer. The silica gel for separation is 200-300 mesh, and the ratio of the eluent is volume ratio.

Example 1: preparation of N- (benzylsulfonyl) -1- (3-cyano-5-oxo-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) piperidine-4-carboxamide (Compound 1)

(a) Preparation of benzylsulfonamides

Benzylsulfonyl chloride (20g,78.95mmol) was dissolved in dry THF, ammonia (150ml) was added dropwise at 0 ℃ in an ice bath, the temperature was maintained at 0-5 ℃ and after the addition was completed, the reaction was carried out at room temperature. TLC (petroleum ether/ethyl acetate 2/1), after the reaction was complete, the ammonia was removed by spin-drying and column chromatography (petroleum ether/ethyl acetate 5/1) gave 12g of white solid in yield: 88.9 percent.¹H NMR(400MHz,DMSO-d₆)δ7.39–7.33(m,5H),6.85(s,2H),4.26(s,2H).MS(ESI)m/z:172.1[M+H]⁺.

(b)4- ((benzylsulfonyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl ester

1- (tert-Butoxycarbonyl) piperidine-4-carboxylic acid (3g,13.10mmol) was dissolved in dry THF, LiCl (0.14g,3.33mmol), TBTU (4.4g,13.76mmol), TEA (5.46ml,39.30mmol) were added, after 45 minutes at room temperature benzylsulfonamide (2.46g,14.41mmol) was added for about 16h, monitored by TLC (petroleum ether/ethyl acetate ═ 2/1). After the reaction was complete, THF was removed by rotary drying, 30ml of water was added, 2X 40ml of ethyl acetate was extracted, the organic phases were combined and washed with saturated brine respectively, anddrying over sodium sulfate, spin-drying the organic phase to give an oil, slurrying with petroleum ether/ethyl acetate 10/1 to precipitate a solid, filtering the precipitated solid, washing with dilute hydrochloric acid, and drying to give 2.7g of a white solid. Yield: and 55 percent.¹HNMR(400MHz,CDCl₃)δ7.42–7.37(m,3H),7.34–7.31(m,2H),4.64(s,2H),4.08(d,J＝11.2Hz,2H),2.76–2.64(m,2H),2.33–2.24(m,1H),1.74–1.70(m,2H),1.65–1.58(m,2H),1.46(s,9H).MS(ESI)m/z:383.0[M+H]⁺.

(c) N- (benzylsulfonyl) piperidine-4-carboxamides

Tert-butyl 4- ((benzylsulfonyl) carbamoyl) piperidine-1-carboxylate (5g,13.09mmol) was dissolved in formic acid (40ml,39.27mmol) at room temperature overnight. TLC monitoring (petroleum ether/ethyl acetate 2/1). After the reaction was complete, the formic acid was removed by spin drying. Adding 20ml water, adjusting pH to 6 with ammonia water, precipitating solid, stirring for about 1 hr, filtering, washing with water, and vacuum drying. Yield 3g of white solid was obtained: 80 percent.¹H NMR(400MHz,DMSO-d₆):δ1.57-1.72(2H,m),1.72-1.84(2H,m),2.08-2.19(1H,m),2.72-2.85(2H,m),3.07-3.17(2H,m),4.24(2H,s),7.19-7.29(5H,m),8.12(1H,br s).MS(ESI)m/z:283[M+H]⁺.

(d)2- (chloromethyl) -5-cyano-6-oxo-1, 6-dihydropyridine-3-carboxylic acid ethyl ester

Ethylchloroacetoacetate (5g, 30.38mmol) is added with acetic anhydride (13.65g, 133.67mmol) and triethyl orthoformate (4.5g, 30.38mmol) and reacted at 120 ℃ for 3h, after the reaction is finished, the solvent is evaporated under reduced pressure, toluene is taken once, 50ml of n-heptane is added, the product is separated out and filtered, and the obtained crude product is used. Cyanoacetamide (2.554g, 30.38mmol) was dissolved in EtOH (50mL), 20% NaOEt/EtOH (2.07g, 30.38mmol) was added dropwise under ice-bath conditions, followed by addition of the resulting crude ethanolic solution dropwise, stirring overnight at room temperature, TLC (DCM/MeOH-20/1) monitoring the reaction,after the reaction was completed, the reaction solution was filtered, and the filter cake was washed with MTBE and dried to obtain 9.1g of a white solid, yield: 62 percent.¹H NMR(400MHz,DMSO-d₆)δ8.00(s,1H),4.73(s,2H),4.15(q,J＝7.1Hz,2H),1.26(t,J＝7.1Hz,3H).MS(ESI)m/z:241.1[M+H]⁺.

(e) 6-chloro-2- (chloromethyl) -5-cyanonicotinic acid ethyl ester

The compound ethyl 2- (chloromethyl) -5-cyano-6-oxo-1, 6-dihydropyridine-3-carboxylate (1.98g,8.25mmol) was added oxalyl chloride (10ml, 117.2mmol), stirred at room temperature, DMF was added, reacted at 70 ℃ overnight, after completion of the reaction, water was added and quenched, EA extracted, the organic phase was washed, and column chromatography (PE/EA ═ 5/1) gave 1.151g of a white solid in 54% yield.¹H NMR(400MHz,CDCl₃)δ8.60(s,1H),5.10(s,2H),4.49(q,J＝7.2Hz,2H),1.47(t,J＝7.1Hz,3H).MS(ESI)m/z:259.0[M+H]⁺.

(f)6- (4- ((benzylsulfonyl) carbamoyl) piperidin-1-yl) -2- (chloromethyl) -5-cyanonicotinic acid ethyl ester

6-chloro-2- (chloromethyl) -5-cyanonicotinic acid ethyl ester (264mg, 1.019mmol) and N- (benzylsulfonyl) piperidine-4-carboxamide (302mg, 1.070mmol) as starting materials were dissolved in 5mL of ethanol, TEA (306mg, 3.03mmol) was added, the reaction was refluxed overnight, TLC (dichloromethane/methanol ═ 20/1) monitored, after completion of the reaction, the solvent was distilled off, and column chromatography (dichloromethane/methanol ═ 20/1) was performed to obtain 431mg of a white solid, yield: 84 percent.¹H NMR(600MHz,DMSO-d₆)δ11.63(s,1H),7.43–7.39(m,3H),7.29(dd,J＝7.3,1.8Hz,2H),4.98(s,2H),4.70(s,2H),4.59(d,J＝13.5Hz,2H),4.28(q,J＝7.1Hz,2H),3.22–3.16(m,2H),2.63–2.58(m,1H),1.86(dd,J＝12.9,2.4Hz,2H),1.65(ddd,J＝15.5,12.8,3.8Hz,2H),1.32(t,J＝7.1Hz,3H).¹³C NMR(126MHz,DMSO-d₆)δ174.63,163.82,160.03,158.34,148.73,131.22,129.57,129.16,129.08,117.77,113.85,90.89,61.56,57.88,46.64,45.97,41.91,27.91,14.46.

(g) Synthesis of N- (benzylsulfonyl) -1- (3-cyano-5-oxo-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) piperidine-4-carboxamide

Ethyl 6- (4- ((benzylsulfonyl) carbamoyl) piperidin-1-yl) -2- (chloromethyl) -5-cyanonicotinate (44mg, 0.087mmol) was partially dissolved in ethanol (5mL), ammonia was added, the reaction was carried out at room temperature for 5h, the reaction was monitored by TLC for completion, the solvent was distilled off, and column chromatography (dichloromethane/methanol ═ 20/1) gave 29mg of a white solid, yield: 75.7 percent.¹H NMR(400MHz,DMSO-d₆)δ11.63(s,1H),8.56(s,1H),8.30(s,1H),7.40(dd,J＝4.9,2.2Hz,3H),7.29(dd,J＝7.2,2.2Hz,2H),4.68(s,2H),4.38(d,J＝13.6Hz,2H),4.33(s,2H),3.13(t,J＝11.6Hz,2H),2.55(dd,J＝19.1,7.6Hz,1H),1.84(d,J＝10.4Hz,2H),1.68(dd,J＝21.2,11.8Hz,2H).¹³C NMR(126MHz,DMSO-d₆)δ168.75,167.63,162.10,140.56,131.17,128.96,128.91,118.34,116.93,93.26,57.87,47.82,47.32,42.30,28.10.MS(ESI)m/z:438.2[M-H]^-.

Example 2: preparation of N- (benzylsulfonyl) -1- (3-cyano-6-methyl-5-oxo-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) piperidine-4-carboxamide (Compound 2)

Ethyl 6- (4- ((benzylsulfonyl) carbamoyl) piperidin-1-yl) -2- (chloromethyl) -5-cyanobenzoate (50mg, 0.10mmol) was used as a starting material according to the preparation method of example 1 to give 31mg of a white solid in a yield of 68.9%.¹HNMR(500MHz,DMSO-d₆)δ11.61(s,1H),8.28(s,1H),7.43–7.38(m,3H),7.30(dd,J＝7.3,1.9Hz,2H),4.69(s,2H),4.41(s,2H),4.38(d,J＝13.4Hz,2H),3.17–3.10(m,2H),3.03(s,3H),2.61–2.55(m,1H),1.85(dd,J＝12.9,2.6Hz,2H),1.73–1.64(m,2H).¹³C NMR(126MHz,DMSO-d₆)δ174.78,166.54,165.28,161.97,140.08,131.19,129.60,129.11,129.06,118.28,116.93,93.22,57.94,53.39,47.76,41.95,29.23,27.95.MS(ESI)m/z:452.2[M-H]^-.

Example 3: n- (benzylsulfonyl) -1- (3-cyano-6-fluoro-5-oxo-5, 6,7, 8-tetrahydroquinolin-2-yl) piperidine-4-carboxamide (Compound 3)

(a)2- ((dimethylamino) methylene) cyclohexane-1, 3-dione

Dissolving 1, 3-cyclohexanedione (5g, 44.59mmol) in 20mL of N, N-dimethylformamide dimethyl acetal, reacting at 80 ℃ overnight, evaporating low-boiling-point substances after the reaction is finished, and pulping by using ethyl acetate/N-hexane to obtain 7.45g of yellow solid, wherein the yield is as follows: 99.89 percent.¹H NMR(400MHz,CDCl₃)δ8.05(s,1H),3.39(s,3H),3.16(s,3H),2.46(t,J＝6.4Hz,4H),1.97–1.90(m,2H).MS(ESI)m/z:166.1[M-H]^-.

(b)2, 5-dioxo-1, 2,5,6,7, 8-hexahydroquinoline-3-carbonitrile

Dissolving 2- ((dimethylamino) methylene) cyclohexane-1, 3-dione (7.23g, 43.2mmol) in 50mL of acetonitrile, adding malononitrile (2.86g, 43.2mmol), ammonium acetate (3.33g, 4.32mmol), refluxing for reaction, after completion of the reaction, distilling off the low boiling solvent, and performing column chromatography (dichloromethane/methanol ═ 50/1) to obtain a yellow solid (4.29 g, yield: 52.7 percent.¹H NMR(400MHz,DMSO-d₆)δ12.98(s,1H),8.36(s,1H),2.87(t,J＝6.1Hz,2H),2.49–2.43(m,2H),2.05–1.98(m,2H).MS(ESI)m/z:189.1[M+H]⁺.

(c) 6-fluoro-2, 5-dioxo-1, 2,5,6,7, 8-hexahydroquinoline-3-carbonitrile

2, 5-dioxo-1, 2,5,6,7, 8-hexahydroquinoline-3-carbonitrile (0.42g, 2.66mmol) was dissolved in 10mL methanol, selective fluorinating reagent (1.0g, 3.19mmol) was added, and concentrated H₂SO₄(26mg,0.266mmol)，N₂The reaction was carried out for 15h under protection at 50 ℃ and monitored by TLC (petroleum ether/ethyl acetate: 1/1), after completion of the reaction, the solvent was distilled off and column chromatography (petroleum ether/ethyl acetate: 1/1) gave 0.45g of a yellow solid in yield: 70 percent.¹H NMR(400MHz,DMSO-d₆)δ13.15(s,1H),8.43(s,1H),5.68–4.78(m,1H),3.18–3.03(m,1H),2.99–2.89(m,1H),2.48–2.41(m,1H),2.31–2.25(m,1H).MS(ESI)m/z:207.1[M+H]⁺.

(f) 2-chloro-6-fluoro-5-oxo-5, 6,7, 8-tetrahydroquinoline-3-carbonitrile

2, 5-dioxo-1, 2,5,6,7, 8-hexahydroquinoline-3-carbonitrile (0.1mg, 0.49mmol) was dissolved in 2ml dry toluene, SOCl was added₂(0.2ml, 1.47mmol) and 1 drop of DMF were heated to 80 ℃ for reaction. TLC monitoring (petroleum ether/ethyl acetate 5/1) and, after completion of the reaction, column chromatography (petroleum ether/ethyl acetate 5/1) gives a pale white solid mg, yield: 51.3 percent.¹H NMR(400MHz,DMSO-d₆)δ8.84(s,1H),5.54(dd,J＝13.1,5.6Hz,1H),3.44–3.36(m,1H),3.26–3.21(m,1H),2.60–2.56(m,1H),2.40–2.33(m,1H).MS(ESI)m/z:225.0[M+H]⁺.

(g) Synthesis of N- (benzylsulfonyl) -1- (3-cyano-6-fluoro-5-oxo-5, 6,7, 8-tetrahydroquinolin-2-yl) piperidine-4-carboxamide

2-chloro-6-fluoro-5-oxo-5, 6,7, 8-tetrahydroquinoline-3-carbonitrile (40mg, 0.176mmol), N- (benzylsulfonyl) piperidine-4-carboxamide (60mg, 0.27mmol) was dissolved in 10mL of ethanol, TEA (53mg, 0.528mmol) was added, the reaction was refluxed overnight, TLC (dichloromethane/methanol ═ 10/1) was monitored for the reaction, and after completion of the reaction, the low-boiling solvent was distilled off, and column chromatography (dichloromethane/methanol ═ 50/1) was performed to give 51mg of a white solid, yield: 61.4 percent.¹H NMR(500MHz,DMSO-d₆)δ11.60(s,1H),8.31(s,1H),7.42–7.35(m,3H),7.32–7.25(m,2H),5.32(dd,J＝12.4,5.3Hz,1H),4.68(s,2H),4.59–4.50(m,2H),3.18(t,J＝12.5Hz,2H),3.14–3.08(m,1H),2.95(ddd,J＝17.7,7.9,4.1Hz,1H),2.63–2.55(m,1H),2.27–2.15(m,2H),2.02–1.94(m,1H),1.85(dd,J＝13.0,2.4Hz,2H),1.63(ddd,J＝15.2,13.1,3.8Hz,2H).¹³C NMR(126MHz,DMSO-d₆)δ189.64,189.51,174.11,166.00,158.58,144.58,130.70,129.07,128.64,128.57,117.46,117.16,90.91,89.44,57.45,46.36,46.32,41.36,30.21,30.12,27.49.MS(ESI)m/z:469.1[M-H]^-.

Example 4: n- (benzylsulfonyl) -1- (6-chloro-3-cyano-5-oxo-5, 6,7, 8-tetrahydroquinolin-2-yl) piperidine-4-carboxamide (Compound 4)

(a) 6-chloro-2, 5-dioxo-1, 2,5,6,7, 8-hexahydroquinoline-3-carbonitrile

2, 5-dioxo-1, 2,5,6,7, 8-hexahydroquinoline-3-carbonitrile (1.5g, 7.96mmol) was dissolved in 15mL of acetonitrile, NCS (1.28g, 9.6mmol), PTSA (0.23g,0.15mmol) was added, the reaction was refluxed for 15h under the protection of Ar, monitored by TLC (petroleum ether/ethyl acetate ═ 2/1), after completion of the reaction, the solvent was distilled off, and column chromatography (petroleum ether/ethyl acetate ═ 1/1) was performed to give 1.15g of a yellow solid, yield: 65 percent.¹H NMR(400MHz,DMSO-d₆)δ13.20(s,1H),8.44(s,1H),4.94(dd,J＝5.8,3.7Hz,1H),2.39–2.29(m,2H),2.03–1.94(m,2H).MS(ESI)m/z:223.0[M+H]⁺.

(b)2, 6-dichloro-5-oxo-5, 6,7, 8-tetrahydroquinoline-3-carbonitrile

Prepared as described in (f) in example 3, starting from 6-chloro-2, 5-dioxo-1, 2,5,6,7, 8-hexahydroquinoline-3-carbonitrile (0.1g, 0.45mmol), to give 65mg as a yellow solid in yield: 62 percent.¹H NMR(400MHz,DMSO-d₆)δ8.84(s,1H),5.54(dd,J＝13.1,5.6Hz,1H),2.39–2.29(m,2H),2.03–1.94(m,2H).MS(ESI)m/z:225.0[M+H]⁺.

(c) Synthesis of N- (benzylsulfonyl) -1- (6-chloro-3-cyano-5-oxo-5, 6,7, 8-tetrahydroquinolin-2-yl) piperidine-4-carboxamide

Prepared as described in example 3 (g) starting from 2, 6-dichloro-5-oxo-5, 6,7, 8-tetrahydroquinoline-3-carbonitrile (50mg, 0.21mmol) and N- (benzylsulfonyl) piperidine-4-carboxamide (65mg, 0.23mmol) to give 61mg of a white solid in yield: 62 percent.¹H NMR(500MHz,DMSO-d₆)δ11.62(s,1H),8.35(s,1H),7.43–7.37(m,3H),7.31–7.27(m,2H),4.97(dd,J＝8.7,4.1Hz,1H),4.69(s,2H),4.61–4.55(m,2H),3.24–3.16(m,2H),3.03(t,J＝6.1Hz,2H),2.65–2.60(m,1H),2.37–2.29(m,1H),1.99(dt,J＝12.6,7.1Hz,1H),1.86(dd,J＝12.9,2.7Hz,2H),1.65(qd,J＝12.5,3.7Hz,2H).¹³C NMR(126MHz,DMSO-d₆)δ187.34,174.15,166.00,158.49,145.18,130.72,128.66,128.59,117.45,116.65,91.11,59.60,57.43,46.37,46.31,41.39,30.27,29.97,27.52.MS(ESI)m/z:485.25[M-H]^-.

Example 5: n- (benzylsulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) piperidine-4-carboxamide (Compound 5)

(a)4- (benzyloxy) -3-oxobutanoic acid ethyl ester

NaH (15g, 366mmol) is suspended in dry THF (300mL), BnOH (26g, 238mmol) is added dropwise under ice-bath cooling under argon protection, after addition is completed, stirring is carried out at room temperature for 30min, a THF solution of ethyl chloroacetoacetate (30g, 183mmol) is added dropwise under ice-bath cooling, stirring is carried out at room temperature overnight, TLC (petroleum ether/ethyl acetate ═ 10/1) monitoring is carried out, after the reaction is completed, water is added for quenching, THF is spin-dried, EA extraction is carried out, column chromatography (petroleum ether/ethyl acetate ═ 10/1) is carried out, 39.7g of a product is obtained, yield: 91.96 percent.¹H NMR(400MHz,CDCl₃)δ7.39–7.29(m,5H),4.59(s,2H),4.17(dd,J＝14.1,7.0Hz,4H),3.54(s,2H),1.25(t,J＝7.1Hz,3H).MS(ESI)m/z:235.08[M-H]^-.

(b) (E) -4- (benzyloxy) -2- ((dimethylamino) methylene) -3-oxobutanoic acid ethyl ester

Ethyl 4- (benzyloxy) -3-oxobutyrate (40g, 169.5mmol) was dissolved in DMF-dimethyl acetal (30g,254mmol) and reacted at 60 ℃ for about 14h, the reaction turned gradually from pale yellow to black. TLC (petroleum ether/ethyl acetate ═ 1/1) monitored the reaction, after completion of the reaction, cooled to room temperature, 100ml of water was added, EA extracted (3 × 200ml), the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent evaporated, and column chromatographed (petroleum ether/ethyl acetate ═ 1/1) to give 46g of a light red oil, yield: 94 percent.¹H NMR(400MHz,CDCl₃)δ7.71(s,1H),7.37–7.22(m,5H),4.57(s,2H),4.43(s,2H),4.13(q,J＝7.1Hz,2H),3.21(s,3H),3.01–2.74(m,3H),1.23(t,J＝7.1Hz,3H).MS(ESI)m/z:290.10[M-H]^-.

(c)2- ((benzyloxy) methyl) -5-cyano-6-oxo-1, 6-dihydropyridine-3-carboxylic acid ethyl ester

Cyanoacetamide (8g, 94.5mmol) was partially dissolved in ethanol, 20% NaOEt/EtOH (32g, 94.5mmol) was added, stirring at room temperature for 1h, and ethyl (E) -4- (benzyloxy) -2- ((dimethylamino) methylene) -3-oxobutanoate (2g, 85.9mmol) was added dropwise. The reaction was stirred at rt for 16h, monitored by TLC (petroleum ether/ethyl acetate 2/1), after completion of the reaction 100ml of water was added, EA extracted (3 × 100ml), the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent evaporated, and column chromatographed (petroleum ether/ethyl acetate 2/1) to give 22g of a white solid, yield: 81.9 percent.¹H NMR(400MHz,CDCl₃)δ10.23(s,1H),8.39(s,1H),7.45–7.30(m,5H),4.96(s,2H),4.74(s,2H),4.29(q,J＝7.1Hz,2H),1.35(t,J＝7.1Hz,3H).MS(ESI)m/z:311.08[M-H]^-.

(d) 5-cyano-2- (hydroxymethyl) -6-oxo-1, 6-dihydropyridine-3-carboxylic acid ethyl ester

2- ((benzyloxy) methyl) -5-cyano-6-oxo-1, 6-dihydropyridine-3-carboxylic acid ethyl ester (15g, 48.2mmol)) was dissolved in 300ml of DCM solution and BCl was added dropwise at-78 ℃ under Ar protection₃(96ml, 96mmol) and after about 6h the reaction was transferred to room temperature for 2 h. TLC (dichloromethane/methanol-20/1) and after completion of the reaction, the reaction was quenched by slowly adding methanol dropwise under ice bath conditions. 100ml of water was added, DCM extraction (3 × 100ml) was carried out, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated, and column chromatography was carried out (dichloromethane/methanol ═ 20/1) to give 5.5g of a white solid, yield: 53 percent.¹HNMR(400MHz,DMSO-d₆)δ11.81(s,1H),8.48(s,1H),6.07(s,1H),4.85(s,2H),4.23(q,J＝7.1Hz,2H),1.30(t,J＝7.2Hz,3H).MS(ESI)m/z:221.05[M-H]^-.

(e) 5-cyano-2- (hydroxymethyl) -6-oxo-1, 6-dihydropyridine-3-carboxylic acid

5-cyano-2- (hydroxymethyl) -6-oxo-1, 6-dihydropyridine-3-carboxylic acid ethyl ester (5g, 22.5mmol)) was dissolved in 50ml of ethanol solution, NaOH (2M, 4.5ml) solution was added dropwise at room temperature, after about 6h of reaction, TLC monitoring (dichloromethane/methanol. RTM. 20/1) was carried out, after completion of the reaction, 1M dilute hydrochloric acid solution was slowly added dropwise to adjust the solution pH. apprxeq.6. Continuously separating out solid, filtering, and drying in vacuum to obtain 4.15g of white solid, wherein the yield is as follows: 95 percent.¹H NMR(400MHz,DMSO-d₆)δ7.98(s,1H),4.33(s,2H).MS(ESI)m/z:193.0[M-H]^-.¹³C NMR(126MHz,DMSO-d₆)δ170.24,164.88,147.15,121.42,114.83,91.33,66.24.MS(ESI)m/z:193.0[M-H]^-.

(f) 2-chloro-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridine-3-carbonitrile

5-cyano-2- (hydroxymethyl) -6-oxo-1, 6-dihydropyridine-3-carboxylic acid (4g, 20.7mmol) was placed in a 200ml reaction flask and POCl was slowly added dropwise under ice-bath conditions₃(15ml), the reaction evolved a lot of heat. Refluxing the mixture for 5h at 100 ℃ under the protection of Ar, monitoring by TLC (petroleum ether/ethyl acetate: 5/1), distilling part of phosphorus oxychloride after the reaction is completed, and adding ice water dropwise to quench the reaction under the condition of ice bath. 50ml of water was added, extraction was performed with ethyl acetate (3X 50ml), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated, and column chromatography was performed (petroleum ether/ethyl acetate: 5/1) to give 2.2g of a pale yellow solid with a yield of 55%.¹H NMR(400MHz,DMSO-d₆)δ8.17(s,1H),5.03(s,2H).¹³C NMR(126MHz,DMSO-d₆)δ170.77,166.58,156.82,141.81,119.00,114.52,110.29,70.47.MS(ESI)m/z:195.2[M+H]⁺.

(g) Synthesis of N- (benzylsulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) piperidine-4-carboxamide

2-chloro-5-oxo-5, 7-dihydrofuro [3,4-b]Pyridine-3-carbonitrile (30mg,0.155mmol) and N- (benzylsulfonyl) piperidine-4-carboxamide (53mg, 0.186mmol) were dissolved in 5mL of ethanol, TEA (47mg, 0.465mmol) was added, the reaction was refluxed overnight, the reaction was monitored by TLC (dichloromethane/methanol ═ 15/1), and after completion of the reaction, the low-boiling solvent was distilled off, and column chromatography (dichloromethane/methanol ═ 30/1) was performed to give 58mg of a white solid in 85.4% yield.¹H NMR(600MHz,DMSO-d₆)δ11.62(s,1H),8.57(s,1H),7.40(d,J＝6.5Hz,3H),7.29(d,J＝6.9Hz,2H),5.26(s,2H),4.70(s,2H),4.51(d,J＝13.5Hz,2H),3.23(t,J＝12.3Hz,2H),2.61(dd,J＝13.2,9.2Hz,1H),1.87(d,J＝11.4Hz,2H),1.67(dt,J＝14.9,7.7Hz,2H).¹³C NMR(126MHz,DMSO-d6)δ174.10,170.74,167.66,161.48,143.28,130.70,129.62,129.06,128.64,128.58,117.39,108.34,93.08,69.90,57.44,46.94,41.24,40.66,27.44.MS(ESI)m/z:454.1[M+H]⁺.

Example 6: n- (benzylsulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) azetidine-3-carboxamide (Compound 6)

(a)3- ((benzylsulfonyl) carbamoyl) azetidine-1-carboxylic acid tert-butyl ester

Prepared as described in example 1 (b) starting from 1- (tert-butoxycarbonyl) azetidine-3-carboxylic acid (0.5g,2.49mmol) and benzylsulfonamide (0.5g,2.6mmol) and dried in vacuo to give 0.45g of a white solid in 45% yield.¹H NMR(400MHz,DMSO-d₆)δ11.73(s,1H),7.42–7.38(m,3H),7.34–7.28(m,2H),4.73(s,2H),3.91(t,J＝8.9Hz,2H),3.85–3.78(m,2H),2.03–1.95(m,1H),1.39(s,9H).MS(ESI)m/z:353.1[M-H]^-.

(b) N- (benzylsulfonyl) azetidine-3-carboxamides

Prepared as described in example 1 (c) starting from tert-butyl 3- ((benzylsulfonyl) carbamoyl) azetidine-1-carboxylate (0.25g,0.70mmol) and dried in vacuo to give 0.165g of a white solid in 93% yield.¹H NMR(400MHz,DMSO-d₆))δ8.46(s,1H),7.31–7.20(m,5H),4.28(s,2H),4.00–3.88(m,4H),3.22(ddd,J＝17.1,9.4,8.0Hz,1H).¹³C NMR(126MHz,DMSO-d₆)δ174.89,133.15,130.43,127.78,126.87,56.93,48.67,38.22.MS(ESI)m/z:253.4[M-H]^-.

(c) N- (benzylsulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl)

Preparation of azetidine-3-carboxamides

With N- (benzylsulfonyl) azetidine-3-carboxamide (72mg, 0.28mmol) and 2-chloro-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (50mg, 0.26mmol) was prepared as in (g) in example 5, and dried under vacuum to give 75mg of a white solid in 70% yield.¹H NMR(500MHz,DMSO-d₆)δ11.84(s,1H),8.50(s,1H),7.41–7.33(m,5H),5.26(s,2H),4.75(s,2H),4.51–4.38(m,2H),3.59(ddd,J＝14.5,8.9,5.7Hz,1H).¹³C NMR(126MHz,DMSO-d₆)δ171.52,171.29,167.92,160.19,141.83,130.73,128.99,128.72,128.60,116.58,107.41,90.11,69.80,57.66,33.96,28.96.MS(ESI)m/z:413.2[M+H]⁺.

EXAMPLE 7N- (benzylsulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) pyrrolidine-3-carboxamide (Compound 7)

(a)3- ((benzylsulfonyl) carbamoyl) pyrrolidine-1-carboxylic acid tert-butyl ester

Prepared as in (b) of example 1 starting from 1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid (0.5g, 2.3mmol) and benzylsulfonamide (0.55g, 2.9mmol) and dried in vacuo to give 0.5g of a white solid in 37% yield.¹H NMR(400MHz,DMSO-d₆)δ11.70(s,1H),7.40(dd,J＝5.0,1.8Hz,3H),7.32–7.26(m,2H),4.70(s,2H),3.46–3.33(m,2H),3.27–3.16(m,2H),3.03–2.92(m,1H),2.06–1.94(m,2H),1.41(s,9H).(ESI)m/z:369.1[M+H]⁺.

(b) N- (benzylsulfonyl) pyrrolidine-3-carboxamides

Prepared by the method of (c) in example 1 using tert-butyl 3- ((benzylsulfonyl) carbamoyl) pyrrolidine-1-carboxylate (0.55g, 1.49mmol) as a starting material and dried in vacuo to give0.36g of a white solid, yield 91%.¹H NMR(400MHz,DMSO-d₆)δ8.57(s,1H),7.30–7.20(m,5H),4.26(s,2H),3.29–3.25(m,2H),3.12–3.05(m,2H),2.82–2.74(m,1H),1.99–1.90(m,2H).(ESI)m/z:269.1[M+H]⁺.

(c) Preparation of N- (benzylsulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) pyrrolidine-3-carboxamide

N- (Benzylsulfonyl) pyrrolidine-3-carboxamide (80mg, 0.30mmol) and 2-chloro-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (58mg, 0.30mmol) was prepared as starting material in example 5 (g) and dried in vacuo to give 90mg of a white solid in 71% yield.¹H NMR(400MHz,DMSO-d₆)δ11.89(s,1H),8.53(s,1H),7.40–7.35(m,3H),7.30(dd,J＝6.3,3.0Hz,2H),5.26(s,2H),4.71(s,2H),3.98–3.80(m,4H),3.22–3.13(m,1H),2.27–2.06(m,2H).¹³C NMR(126MHz,DMSO-d₆)δ172.50,171.16,167.91,157.83,143.04,130.62,129.14,128.62,128.57,128.52,117.96,106.89,90.90,69.83,57.53,51.16,48.70,28.13.MS(ESI)m/z:439.1[M-H]^-.

Example 8: n- ((5-chlorothien-2-yl) sulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) piperidine-4-carboxamide (Compound 8)

(a)4- (((5-chlorothien-2-yl) sulfonyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl ester

1- (tert-Butoxycarbonyl) piperidine-4-carboxylic acid (7.00g,30.5mmol) and 5-chlorothiophene-2-sulfonamide (6.28g,32.02mmol) were prepared as described in example 1 (b) and dried in vacuo to give 11.3g of a white solid in 90% yield.¹HNMR(400MHz,CDCl₃):δ1.45(9H,s),1.55-1.65(2H,m),1.79-1.82(2H,m),2.92-2.37(1H,m),2.73-2.80(2H,m),4.06-4.11(2H,m),6.96(1H,d,J＝4.1Hz),7.69(1H,d,J＝4.1Hz),8.11(1H,br s).MS(ESI)m/z:409.1[M+H]⁺

(b) N- ((5-chlorothien-2-yl) sulfonyl) piperidine-4-carboxamide

Tert-butyl 4- (((5-chlorothien-2-yl) sulfonyl) carbamoyl) piperidine-1-carboxylate (10g,24.50mmol) was prepared according to the method of (c) in example 1 to give 5.89g of a white solid in 78% yield.¹H NMR(400MHz,DMSO-d₆):δ1.58-1.68(2H,m),1.87-1.90(2H,m),2.52-2.59(1H,m),2.80-2.88(2H,m),3.22-3.25(2H,m),7.29(1H,d,J＝4.1Hz),7.67(1H,d,J＝4.1Hz),8.51(1H,br s),8.82(1H,br s).MS(ESI)m/z:309.01[M+H]⁺.

(c) Preparation of N- ((5-chlorothien-2-yl) sulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) piperidine-4-carboxamide

2-chloro-7-methyl-5-oxo-5, 7-dihydrofuro [3,4-b]Pyridine-3-carbonitrile (50mg,0.24mmol) and N- ((5-chlorothien-2-yl) sulfonyl) piperidine-4-carboxamide (89mg,0.288mmol) were prepared as described in (c) of example 7, and dried in vacuo to give 75mg of a white solid in 67% yield.¹H NMR(400MHz,DMSO-d₆)δ12.58(s,1H),8.57(s,1H),7.68(d,J＝4.1Hz,1H),7.29(d,J＝4.1Hz,1H),5.26(s,2H),4.47(d,J＝13.6Hz,2H),3.25(t,J＝11.4Hz,2H),2.68(s,1H),1.90(d,J＝9.1Hz,2H),1.59(dd,J＝20.9,11.6Hz,2H).¹³C NMR(126MHz,DMSO-d₆)δ173.35,170.71,167.65,161.51,143.22,137.77,136.60,133.88,127.72,117.34,108.35,93.14,69.88,46.91,41.24,27.23.MS(ESI)m/z:465.1[M-H]^-.

EXAMPLE 9N- ((5-chlorothien-2-yl) sulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -4-methylpiperidine-4-carboxamide (Compound 9)

(a)4- (((5-chlorothien-2-yl) sulfonyl) carbamoyl) -4-methylpiperidine-1-carboxylic acid tert-butyl ester

Prepared according to the method of (b) in example 1 using 1- (tert-butoxycarbonyl) -4-methylpiperidine-4-carboxylic acid (0.6g,2.45mmol) and 5-chlorothiophene-2-sulfonamide (0.53g,2.36mmol) as starting materials to give 0.43g of a white solid in a yield of 43%.¹H NMR(400MHz,DMSO-d₆)δ7.67(d,J＝4.1Hz,1H),7.28(d,J＝4.1Hz,1H),3.53–3.45(m,2H),2.95–2.85(m,2H),1.92–1.84(m,2H),1.37(s,9H),1.34–1.26(m,2H),1.11(s,3H).MS(ESI)M/Z:423.1[M+H]⁺.

(b) N- ((5-chlorothien-2-yl) sulfonyl) -4-methylpiperidine-4-carboxamide

Prepared by the method of (c) in example 1 using tert-butyl 4- (((5-chlorothien-2-yl) sulfonyl) carbamoyl) -4-methylpiperidine-1-carboxylate (0.4g,1.0mmol) as a starting material, 0.30g of a white solid was obtained in a yield of 95%.¹H NMR(400MHz,DMSO-d₆)δ7.22(d,J＝3.9Hz,1H),6.98(d,J＝3.9Hz,1H),3.10(dt,J＝6.5,3.6Hz,2H),2.73(td,J＝12.4,2.8Hz,2H),2.10(d,J＝14.1Hz,2H),1.33(td,J＝14.1,4.1Hz,2H),0.99(s,3H).MS(ESI)M/Z:323.0[M+H]⁺.

(c) Preparation of N- ((5-chlorothien-2-yl) sulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -4-methylpiperidine-4-carboxamide

With 1- (3-cyano-5-oxo-5, 7-dihydrofuran [3,4-b ]]Pyridin-2-yl) -4-methylpiperidine-4-carboxylic acid (80mg,0.26mmol) and 2-chlorothiophene-5-sulfonamide (51mg,0.26mmol) were prepared according to the method described in (c) in example 8 to give 83mg of a white solid in a yield of 68%.¹H NMR(500MHz,DMSO-d₆)δ12.31(s,1H),8.53(s,1H),7.68(d,J＝3.9Hz,1H),7.27(d,J＝4.1Hz,1H),5.24(s,2H),4.04(dd,J＝9.8,5.6Hz,2H),3.52–3.46(m,2H),2.13–2.08(m,2H),1.60–1.53(m,2H),1.20(s,3H).¹³C NMR(126MHz,DMSO-d₆)δ175.83,170.69,167.65,161.34,143.22,133.85,129.62,127.63,117.41,108.16,92.93,69.86,44.74,42.22,33.14,23.04.MS(ESI)m/z:479.1[M-H]^-.

EXAMPLE 10N- ((5-chlorothien-2-yl) sulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) azetidine-3-carboxamide (Compound 10)

(a)3- (((5-chlorothien-2-yl) sulfonyl) carbamoyl) azetidine-1-carboxylic acid tert-butyl ester

Prepared by the method of (b) in example 1 starting from 1- (tert-butoxycarbonyl) azetidine-3-carboxylic acid (0.5g,2.49mmol) and 5-chlorothiophene-2-sulfonamide (0.51g,2.6mmol) and dried in vacuo to give 0.25g of a white solid in 26% yield.¹H NMR(400MHz,DMSO-d₆)δ12.61(s,1H),7.70(d,J＝4.2Hz,1H),7.30(d,J＝4.2Hz,1H),3.91(t,J＝8.5Hz,2H),3.79–3.72(m,2H),3.37–3.34(m,1H),1.36(s,9H).MS(ESI)m/z:381.0[M+H]⁺.

(b) N- ((5-chlorothien-2-yl) sulfonyl) azetidine-3-carboxamide

Prepared by the method of (c) in example 1 using tert-butyl 3- (((5-chlorothien-2-yl) sulfonyl) carbamoyl) azetidine-1-carboxylate (0.25g,0.66mmol) as a starting material and dried in vacuo to give 0.18g of a white solid in 96% yield.¹H NMR(400MHz,DMSO-d₆)δ8.47(s,2H),7.27(d,J＝3.9Hz,1H),7.00(d,J＝3.9Hz,1H),3.97(t,J＝10.1Hz,2H),3.93–3.87(m,2H),3.29–3.22(m,1H).MS(ESI)m/z:281.0[M+H]⁺.

(c) Preparation of N- ((5-chlorothien-2-yl) sulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) azetidine-3-carboxamide

With 2-chloro-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (0.04g, 0.206mmol) and N- ((5-chlorothien-2-yl) sulfonyl) azetidine-3-carboxamide (0.07g,0.247mmol as starting materials were prepared according to the method of (c) in example 8 and dried in vacuo to give 56mg of a white solid in 62% yield.¹H NMR(500MHz,DMSO-d₆)δ8.47(s,1H),7.70(d,J＝4.1Hz,1H),7.29(d,J＝4.1Hz,1H),5.22(s,2H),4.56–4.44(m,2H),4.39–4.28(m,2H),3.64(ddd,J＝11.3,9.0,5.8Hz,1H).¹³C NMR(126MHz,DMSO-d₆)δ171.46,170.81,167.90,160.22,141.77,137.74,136.65,133.98,127.75,116.55,107.40,90.15,69.77,34.10.MS(ESI)m/z:436.9[M-H]^-.

Example 11: n- (benzylsulfonyl) -1- (3-cyano-7-methyl-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) azetidine-3-carboxamide (Compound 11)

(a) 4-chloro-3-oxopentanoic acid methyl ester

Dissolving methyl 3-oxopentanoate (20g,144mmol) in 200ml dichloromethane, adding benzyltrimethyl ammonium dichloroiodate (50g, 144mmol) under the protection of Ar, monitoring by TLC (petroleum ether/ethyl acetate ═ 10/1), after the reaction is completed, adding 50ml water for quenching, extracting, washing the organic phase with saturated brine respectively, drying with anhydrous ammonium sulfate, and performing column chromatography (petroleum ether/ethyl acetate ═ 10/1) to obtain 16g product, light yellow liquid, yield: 43.2 percent.¹H NMR(400MHz,CDCl₃)δ4.52(q,J＝6.8Hz,1H),3.80(d,J＝16.3Hz,1H),3.74(s,3H),3.68(d,J＝16.3Hz,1H),1.62(d,J＝6.8Hz,3H).MS(ESI)m/z:165.01[M+H]⁺.

(b)4- (benzyloxy) -3-oxopentanoic acid methyl ester

Prepared by the method of example 5(a) using methyl 4-chloro-3-oxopentanoate (16g,97.6mmol) as a starting material, 21g of oil was obtained in 91% yield.¹H NMR(400MHz,CDCl₃)δ7.39–7.29(m,5H),4.63(s,2H),4.32(q,J＝6.8Hz,1H),3.84(d,J＝16.3Hz,1H),3.74(s,3H),3.62(d,J＝16.3Hz,1H),1.74(d,J＝6.8Hz,3H).MS(ESI)m/z:237.1[M+H]⁺.

(c) 4-hydroxy-3-oxopentanoic acid methyl ester

Methyl 4- (benzyloxy) -3-oxopentanoate (18g, 76.27mmol) was dissolved in 180ml methanol, Pd/C (1g) was added and the reaction was carried out at room temperature for 7h, after completion of the reaction, Pd/C was removed by filtration and the solvent was evaporated to dryness to give 9.5g of an oily liquid with a yield of 86%.¹HNMR(400MHz,CDCl₃)δ4.28(q,J＝6.8Hz,1H),3.68(s,3H),3.45(s,2H).1.28(d,J＝6.8Hz,3H).MS(ESI)m/z:147.1[M+H]⁺.

(d)4- ((tert-butyldimethylsilyl) oxy) -3-oxopentanoic acid methyl ester

Methyl 4-hydroxy-3-oxopentanoate (9.5g, 65.07mmol) as starting material was dissolved in THF (70ml), imidazole (4.4g, 65.07mmol) and a catalytic amount of DMAP were added, a THF solution of TBSCl (9.7g, 65.07mmol) was added dropwise with stirring, the reaction was monitored by TLC (petroleum ether/ethyl acetate: 5/1) for slight exotherm with the appearance of white insoluble material, after completion of the reaction, water was added for dilution, EA extraction was performed, and column chromatography (petroleum ether/ethyl acetate: 20/1) gave 12g of a pale yellow oil in 70% yield.¹H NMR(400MHz,CDCl₃)δ4.25(q,J＝6.8Hz,1H),3.75(s,3H),3.65(s,2H),1.34(d,J＝6.8Hz,3H),0.93(s,9H),0.11(d,J＝2.8Hz,6H).MS(ESI)m/z:260.1[M+H]⁺.

(e) (E) -4- ((tert-butyldimethylsilyl) oxy) -2- ((dimethylamino) methylene) -3-oxopentanoic acid methyl ester

Methyl 4- ((tert-butyldimethylsilyl) oxy) -3-oxopentanoate (12g,46.15mmol) was dissolved in N, N-dimethylformamide dimethyl acetal (5.5g, 46.15mmol) and reacted at 80 ℃ for 1h, after completion of the reaction, the solvent was distilled off and column chromatography (petroleum ether/ethyl acetate 5/1) gave 10.5g of a pale yellow oil in 72% yield.¹H NMR(400MHz,CDCl₃)δ7.64(s,1H),5.04–4.85(m,1H),3.71(s,3H),3.00(s,6H),1.34(d,J＝6.7Hz,3H),0.88(s,9H),0.08–0.04(m,6H).MS(ESI)m/z:316.4[M+H]⁺.

(f)2- (1- ((tert-butyldimethylsilyl) oxy) ethyl) -5-cyano-6-oxo-1, 6-dihydropyridine-3-carboxylic acid methyl ester

Cyanoacetamide (2.80g, 33.33mmol) was partially dissolved in ethanol, 20% NaOEt/EtOH (11.32g,33.33mmol) was added dropwise (E) -4- ((tert-butyldimethylsilyl) oxy) -2- ((dimethylamino) methylene) -3-oxopentanoic acid methyl ester (10.5g,33.33mmol), stirred at room temperature for 12h, monitored by TLC (petroleum ether/ethyl acetate ═ 2/1), after completion of the reaction, the solvent was distilled off, and column chromatography (petroleum ether/ethyl acetate ═ 5/1) afforded 9g of a pale yellow solid in 81% yield.¹H NMR(400MHz,CDCl₃)δ10.04(s,1H),8.44(s,1H),4.33(q,J＝7.3Hz,3H),1.45(d,J＝6.2Hz,4H),1.39(t,J＝7.1Hz,4H),0.92(s,9H),0.17(s,3H),0.12(s,3H).MS(ESI)m/z:337.2[M+H]⁺.

(g) 5-cyano-2- (1-hydroxyethyl) -6-oxo-1, 6-dihydropyridine-3-carboxylic acid methyl ester

2- (1- ((tert-butyldimethylsilyl) oxy) ethyl) -5-cyano-6-oxo-1, 6-dihydroPyridine-3-carboxylic acid methyl ester (9g,26.79mmol) was dissolved in THF (100mL), TBAF (7g, 26.79mmol) was added dropwise and reacted at room temperature for 18h, and after TLC monitoring (dichloromethane/methanol ═ 50/1) the reaction was completed, column chromatography (dichloromethane/methanol ═ 50/1) gave 8.2g of a pale yellow solid in 91% yield.¹H NMR(400MHz,CDCl₃)δ8.44(s,1H),5.83–5.80(m,1H),3.88(s,3H),1.55(d,J＝6.4Hz,3H)MS(ESI)m/z:223.1[M+H]⁺.

(h) 5-cyano-2- (1-hydroxyethyl) -6-oxo-1, 6-dihydropyridine-3-carboxylic acid

Prepared by the method of example 5(e) starting from methyl 5-cyano-2- (1-hydroxyethyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate (2g,9mmol) to give 1.8g of a white solid in 96% yield.¹H NMR(400MHz,DMSO-d₆)δ11.82(s,1H),8.34(s,1H),4.78(dd,J＝13.0,6.5Hz,3H),1.32(d,J＝6.6Hz,3H).MS(ESI)m/z:209.2[M+H]⁺.

(i) 2-chloro-7-methyl-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridine-3-carbonitrile

Prepared as in example 5(f) starting from 5-cyano-2- (1-hydroxyethyl) -6-oxo-1, 6-dihydropyridine-3-carboxylic acid (0.25g,1.2mmol) in 56% yield as a pale yellow solid 0.14 g.¹H NMR(400MHz,DMSO-d₆)δ8.34(s,1H),4.78(dd,J＝13.0,6.5Hz,3H),1.32(d,J＝6.6Hz,3H).¹³C NMR(126MHz,DMSO)δ173.16,165.65,156.98,142.06,118.89,114.49,110.56,78.28,17.59.MS(ESI)m/z:209.0[M+H]⁺.

(j) N- (benzylsulfonyl) azetidine-3-carboxamides

With 3- ((benzylsulfonyl) carbamoyl) azetidine-1-carboxylic acidTert-butyl ester (0.25g,0.70mmol) was used as a starting material, prepared as described in example 1 (c), and dried under vacuum to give 0.165g of a white solid in 93% yield.¹H NMR(400MHz,DMSO-d₆))δ8.46(s,1H),7.31–7.20(m,5H),4.28(s,2H),4.00–3.88(m,4H),3.22(ddd,J＝17.1,9.4,8.0Hz,1H).¹³C NMR(126MHz,DMSO)δ174.89,133.15,130.43,127.78,126.87,56.93,48.67,38.22.MS(ESI)m/z:253.4[M-H]^-.

(k) Preparation of N- (benzylsulfonyl) -1- (3-cyano-7-methyl-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) azetidine-3-carboxamide

With N- (benzylsulfonyl) azetidine-3-carboxamide (98mg, 0.38mmol)) and 2-chloro-7-methyl-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (80mg, 0.38mmol) was prepared as in example 5 (g) and dried under vacuum to give 0.123g of a white solid with a yield of 76%.¹H NMR(400MHz,DMSO-d₆)δ11.86(s,1H),8.50(s,1H),7.41–7.32(m,5H),5.50(q,J＝6.8Hz,1H),4.76(s,2H),4.62–4.28(m,4H),3.64–3.53(m,1H),1.51(d,J＝6.8Hz,3H).¹³C NMR(126MHz,DMSO-d₆)δ174.09,171.28,166.98,160.26,142.00,130.74,129.00,128.70,128.59,116.56,107.04,90.25,77.25,57.67,33.95,18.22.MS(ESI)m/z:425.1[M-H]^-.

EXAMPLE 12N- (benzylsulfonyl) -1- (3-cyano-7-methyl-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) pyrrolidine-3-carboxamide (Compound 12)

Using N- (benzylsulfonyl) pyrrolidine-3-carboxamide (80mg, 0.30mmol) and 2-chloro-7-methyl-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (62mg, 0.30mmol) was prepared as in (g) in example 5 and dried in vacuo to give 91mg of a white solid in 69% yield.¹H NMR(400MHz,DMSO-d₆)δ11.89(s,1H),8.51(d,J＝1.8Hz,1H),7.42–7.33(m,3H),7.33–7.26(m,2H),5.50(qd,J＝6.8,2.6Hz,1H),4.72(s,2H),4.00–3.79(m,4H),3.22–3.12(m,1H),2.27–2.06(m,2H),1.52(dd,J＝6.8,2.4Hz,3H).¹³C NMR(126MHz,DMSO-d₆)δ173.72,172.44,166.97,157.87,157.81,143.23,130.63,129.13,128.62,128.56,117.95,106.52,91.03,90.99,77.28,57.52,51.13,48.70,18.25,18.22.MS(ESI)m/z:439.1[M-H]^-.

Example 13: n- ((5-chlorothien-2-yl) sulfonyl) -1- (3-cyano-7-methyl-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) piperidinazole-4-carboxamide (Compound 13)

With 2-chloro-7-methyl-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (100mg, 0.48mmol) and N- ((5-chlorothien-2-yl) sulfonyl) piperidine-4-carboxamide (148mg, 0.48mmol) were prepared as in (g) in example 5, and dried in vacuo to give 140mg of a white solid in 62% yield.¹H NMR(400MHz,DMSO-d₆)δ12.58(s,1H),8.54(s,1H),7.68(d,J＝4.1Hz,1H),7.29(d,J＝4.1Hz,1H),5.49(q,J＝6.8Hz,1H),4.54–4.44(m,2H),3.28–3.19(m,2H),2.71–2.63(m,1H),1.91(dd,J＝13.1,2.8Hz,2H),1.64–1.53(m,2H),1.50(d,J＝6.8Hz,3H).¹³C NMR(126MHz,DMSO-d₆)δ173.73,167.21,162.02,143.91,138.23,137.12,134.41,128.23,117.83,108.45,93.66,77.88,47.33,41.74,27.71,18.58.MS(ESI)m/z:479.0[M-H]^-.

Example 14: n- ((5-chlorothien-2-yl) sulfonyl) -1- (3-cyano-7-methyl-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) azetidine-3-carboxamide (Compound 14)

With 2-chloro-7-methyl-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (60mg, 0.28mmol) and N- ((5-chlorothien-2-yl) sulfonyl) azetidine-3-carboxamide (81mg, 0.32mmol) as starting materialsPrepared according to the method of example 5 (g) and dried in vacuo to give 82mg of a white solid in 65% yield.¹H NMR(400MHz,DMSO-d₆)δ8.45(s,1H),7.54(d,J＝4.0Hz,1H),7.18(d,J＝4.0Hz,1H),5.47(q,J＝6.7Hz,1H),4.64–4.18(m,4H),3.56–3.46(m,1H),1.48(d,J＝6.8Hz,3H).¹³C NMR(126MHz,DMSO-d₆)δ174.11,167.00,160.22,141.96,126.99,116.60,106.79,90.08,77.22,45.76,34.87,18.21.MS(ESI)m/z:451.0[M-H]^-.

Example 15: n- ((5-chlorothien-2-yl) sulfonyl) -1- (3-cyano-5-oxo-7, 8-dihydro-5H-pyrano [4,3-b ] pyridin-2-yl) piperidinazole-4-carboxamide (Compound 15)

(a)5- (benzyloxy) -3-oxopentanoic acid ethyl ester

NaH (3.23g, 80.17mmol) is suspended in dry THF (150mL), under argon protection, ethyl acetoacetate (10g, 76.84mmol) is added dropwise under ice-water cooling, after addition is complete, stirring is carried out at room temperature for 10min, n-butyl lithium (2.5M, 33.8mL) is added dropwise under ice-water cooling, the reaction solution is stirred at room temperature for 10min, ice-water cooling is carried out, benzyloxychloromethane (9.63g, 61.47mmol) is added dropwise, stirring is carried out at room temperature overnight, TLC (petroleum ether/ethyl acetate ═ 5/1) monitoring is carried out, after the reaction is complete, water is added for quenching, EA extraction is carried out, and column chromatography (petroleum ether/ethyl acetate ═ 10/1) is carried out to obtain 8.3g of a product, yield: 43.2 percent.¹H NMR(400MHz,CDCl₃)δ7.37–7.28(m,5H),4.51(s,2H),4.18(q,J＝7.1Hz,2H),3.75(t,J＝6.2Hz,2H),3.18(t,J＝6.2Hz,2H),3.49(s,2H),2.83(t,J＝6.2Hz,2H),1.27(t,J＝7.1Hz,3H).MS(ESI)m/z:251.02[M+H]⁺

(b) 5-hydroxy-3-oxopentanoic acid ethyl ester

Prepared by the method of (c) in example 11 starting from ethyl 5- (benzyloxy) -3-oxopentanoate (8g, 31.96mmol) to give 5.02g of a colorless oily liquid, yield: 98 percent.¹H NMR(400MHz,CDCl₃)δ6.97(s,1H),4.19(q,J＝14.4,7.2Hz,2H),3.83(t,J＝6.2Hz,2H),3.48(s,2H),2.80(t,J＝5.4Hz,2H),1.23(t,J＝7.0Hz,3H).MS(ESI)m/z:159.1[M-H]^-.

(c)5- ((tert-butyldimethylsilyl) oxy) -3-oxopentanoic acid ethyl ester

Prepared by the method of (d) in example 11 starting from ethyl 5-hydroxy-3-oxopentanoate (5.53g, 28.245mmol), imidazole (2.89g, 42.37mmol) and TBSCl (5.108g, 33.894mmol) to give 6.3g of a colorless oily liquid, yield: 81.3 percent.¹H NMR(400MHz,CDCl₃)δ4.18(q,J＝7.0,2.3Hz,2H),3.89(t,J＝6.2Hz,2H),3.48(s,2H),2.71(t,J＝6.2Hz,2H),1.27(td,J＝7.1,2.6Hz,4H),0.86(s,9H),0.04(s,6H).MS(ESI)m/z:275.2[M+H]⁺.

(d) (E) -5- ((tert-butyldimethylsilyl) oxy) -2- ((dimethylamino) methylene) -3-oxopentanoic acid ethyl ester

Prepared by the method of (e) in example 11 starting from ethyl 5- ((tert-butyldimethylsilyl) oxy) -3-oxopentanoate (6.86g, 25.0mmol) and N, N-dimethylformamide dimethyl acetal (3.57g, 30.0mmol), 7.89g of a pale yellow oily liquid was obtained, yield: 95.8 percent.¹H NMR(400MHz,CDCl₃)δ7.70(s,1H),4.19(q,J＝7.1Hz,2H),3.90(t,J＝6.3Hz,2H),3.16(t,J＝6.3Hz,2H),2.96(s,6H),1.30(t,J＝7.1Hz,3H),0.90(s,9H),0.08(s,6H).MS(ESI)m/z:330.1[M+H]⁺.

(e)2- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -5-cyano-6-oxo-1, 6-dihydropyridine-3-carboxylic acid ethyl ester

With cyanoacetamide (2.29g, 27)31mmol) and ethyl (E) -5- ((tert-butyldimethylsilyl) oxy) -2- ((dimethylamino) methylene) -3-oxopentanoate (7.5g, 22.761mmol), prepared according to the method of (f) in example 11, 6.44g of a light yellow solid, yield: 80.7 percent.¹H NMR(400MHz,DMSO-d₆)δ7.71(s,1H),4.07(q,J＝7.1Hz,2H),3.52(t,J＝6.3Hz,2H),3.16(t,J＝6.3Hz,2H),1.28(t,J＝7.1Hz,3H).MS(ESI)m/z:351.23[M+H]⁺.

(f) 5-cyano-2- (2-hydroxyethyl) -6-oxo-1, 6-dihydropyridine-3-carboxylic acid ethyl ester

Prepared from ethyl 2- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -5-cyano-6-oxo-1, 6-dihydropyridine-3-carboxylate (6.4g, 27.02mmol) according to the method of example 11 (g) to give 4.23g of a pale yellow solid in yield: 98.3 percent.¹H NMR(400MHz,DMSO-d₆)δ8.45(s,1H),4.22(q,J＝7.1Hz,2H),3.66(t,J＝6.3Hz,2H),3.16(t,J＝6.3Hz,2H),1.28(t,J＝7.1Hz,3H),0.86(s,9H),0.02(s,6H).MS(ESI)m/z:235.1[M-H]^-.

(g) 5-cyano-2- (2-hydroxyethyl) -6-oxo-1, 6-dihydropyridine-3-carboxylic acid

Prepared by the method of (h) in example 11 starting from ethyl 5-cyano-2- (2-hydroxyethyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate (2g, 8.47mmol) to give 1.67g of a white solid in 94% yield.¹H NMR(400MHz,DMSO-d₆)δ8.90(s,1H),4.64(t,J＝6.1Hz,2H),3.30(t,J＝6.1Hz,2H).MS(ESI)m/z:209.16[M+H]⁺.

(h) 2-chloro-5-oxo-7, 8-dihydro-5H-pyrano [4,3-b ] pyridine-3-carbonitrile

With 5-cyano-2- (2-hydroxyethyl) -6-oxo-1, 6-dihydropyridine-3-carboxylic acid (1.5g, 7.2mmol) was prepared according to the procedure in example 11 (i) to give 523mg of a light yellow solid in yield: 34.8 percent.¹H NMR(400MHz,DMSO-d₆)δ8.90(s,1H),4.64(t,J＝6.1Hz,2H),3.30(t,J＝6.1Hz,2H).¹³C NMR(126MHz,DMSO-d₆)δ164.22,162.01,154.44,144.72,120.95,114.26,109.17,66.22,30.03.MS(ESI)m/z:209.10[M+H]⁺.

(i) Preparation of N- ((5-chlorothien-2-yl) sulfonyl) -1- (3-cyano-5-oxo-7, 8-dihydro-5H-pyrano [4,3-b ] pyridin-2-yl) piperidinazole-4-carboxamide

With 2-chloro-5-oxo-7, 8-dihydro-5H-pyrano [4,3-b ]]Pyridine-3-carbonitrile (50mg,0.24mmol) and N- ((5-chlorothien-2-yl) sulfonyl) piperidine-4-carboxamide (89mg,0.288mmol) were prepared according to the method of example 5 (g) to give 91mg, 78.9% yield.¹H NMR(400MHz,DMSO-d₆)δ12.57(s,1H),8.34(s,1H),7.67(d,J＝4.1Hz,1H),7.29(d,J＝4.1Hz,1H),4.54–4.48(m,4H),3.24–3.15(m,2H),3.02(t,J＝6.1Hz,2H),2.66(tt,J＝11.4,4.0Hz,1H),1.89(dd,J＝13.2,2.6Hz,2H),1.61–1.49(m,2H).¹³C NMR(126MHz,DMSO-d₆)δ173.36,163.05,162.93,159.06,146.35,133.87,127.72,117.32,110.54,90.97,65.71,46.35,41.35,30.58,27.26.MS(ESI)m/z:479.0[M-H]^-.

EXAMPLE 16N- ((5-chlorothien-2-yl) sulfonyl) -1- (3-cyano-5-oxo-7, 8-dihydro-5H-pyrano [4,3-b ] pyridin-2-yl) azetidine-3-carboxamide (Compound 16)

With 2-chloro-5-oxo-7, 8-dihydro-5H-pyrano [4,3-b ]]Pyridine-3-carbonitrile (80mg, 0.38mmol) and N- ((5-chlorothien-2-yl) sulfonyl) azetidine-3-carboxamide (108mg, 0.38mmol) were prepared as in (g) in example 5, and dried in vacuo to give 140mg of a white solid in 82% yield.¹H NMR(400MHz,DMSO-d₆)δ8.28(s,1H),7.59(d,J＝4.0Hz,1H),7.22(d,J＝4.1Hz,1H),4.47(t,J＝6.0Hz,2H),4.45–4.22(m,4H),3.10(td,J＝11.9,7.1Hz,1H),2.99(t,J＝6.0Hz,2H).¹³C NMR(126MHz,DMSO-d₆)δ172.21,163.87,163.13,158.43,144.86,139.86,135.19,132.51,127.24,116.47,109.74,88.39,65.56,45.74,34.64,30.52.MS(ESI)m/z:451.0[M-H]^-.

Example 17: n- (benzylsulfonyl) -1- (3-cyano-5-oxo-7, 8-dihydro-5H-pyrano [4,3-b ] pyridin-2-yl) azetidine-3-carboxamide (Compound 17)

With N- (benzylsulfonyl) azetidine-3-carboxamide (67mg, 0.26mmol) and 2-chloro-5-oxo-7, 8-dihydro-5H-pyrano [4,3-b ]]Pyridine-3-carbonitrile (50mg,0.24mmol) was prepared as in (i) in example 15, and dried under vacuum to give 123mg of a white solid in 76% yield.¹H NMR(400MHz,DMSO-d₆)δ11.85(s,1H),8.33(s,1H),7.42–7.37(m,3H),7.36–7.31(m,2H),4.75(s,2H),4.50(t,J＝6.0Hz,2H),4.48–4.28(m,4H),3.62–3.52(m,1H),3.03(t,J＝6.0Hz,2H).¹³C NMR(126MHz,DMSO-d₆)δ171.37,163.90,163.14,158.44,144.91,130.72,129.01,128.71,128.59,116.45,109.91,88.50,65.59,57.66,33.99,30.54.MS(ESI)m/z:425.1[M-H]^-.

EXAMPLE 18N- (benzylsulfonyl) -1- (3-cyano-5-oxo-7, 8-dihydro-5H-pyrano [4,3-b ] pyridin-2-yl) pyrrolidine-3-carboxamide (Compound 18)

With N- (benzylsulfonyl) pyrrolidine-3-carboxamide (100mg, 0.37mmol) and 2-chloro-5-oxo-7, 8-dihydro-5H-pyrano [4,3-b ]]Pyridine-3-carbonitrile (78mg, 0.37mmol) was prepared as in (g) in example 5, and dried under vacuum to give 118mg of a white solid in 73% yield.¹H NMR(400MHz,DMSO-d₆)δ11.87(s,1H),8.32(s,1H),7.42–7.35(m,3H),7.30(dd,J＝6.5,2.8Hz,2H),4.73(s,2H),4.51(t,J＝6.0Hz,2H),3.98–3.78(m,4H),3.03(t,J＝6.0Hz,2H),2.25–2.05(m,2H),2.03–1.95(m,1H).¹³CNMR(126MHz,DMSO-d₆)δ172.91,163.92,163.67,156.41,146.62,131.13,129.51,129.17,129.09,118.37,109.85,89.67,66.15,58.03,51.32,48.77,31.15.MS(ESI)m/z:439.1[M-H]^-.

Example 19: n- (benzylsulfonyl) -1- (3-cyano-5-oxo-7, 8-dihydro-5H-pyrano [4,3-b ] pyridin-2-yl) piperidine-4-carboxamide (Compound 19)

With-chloro-5-oxo-7, 8-dihydro-5H-pyrano [4,3-b ]]Pyridine-3-carbonitrile (78mg, 0.37mmol) and N- (benzylsulfonyl) piperidine-4-carboxamide (29mg, 0.104mmol) were prepared as in (g) of example 5 to give 29mg of a white solid in 73.9% yield.¹H NMR(500MHz,DMSO-d₆)δ11.61(s,1H),8.35(s,1H),7.44–7.37(m,3H),7.32–7.27(m,2H),4.70(s,2H),4.58–4.53(m,2H),4.52(t,J＝6.1Hz,2H),3.20(dd,J＝18.5,6.7Hz,2H),3.04(t,J＝6.1Hz,2H),2.61(ddd,J＝11.1,9.4,3.7Hz,1H),1.86(dd,J＝12.8,2.5Hz,2H),1.71–1.61(m,2H).¹³C NMR(126MHz,DMSO-d₆)δ174.11,163.08,162.95,159.05,146.39,130.70,129.06,128.64,128.57,117.36,110.54,90.93,65.73,57.44,46.40,41.35,30.61,27.47.MS(ESI)m/z:453.2[M-H]^-.

EXAMPLE 20 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((difluoro (phenyl) methyl) sulfonyl) piperidine-4-carboxamide (Compound 20)

(a) N, N-bis (2, 4-dimethoxybenzyl) -1-phenylmethanesulfonamide

Benzylsulfonyl chloride (8.4g,44.16mmol) was dissolved in dry tetrahydrofuran (150mL), DMAP (6g,48.57mmol) was added, and bis (3, 4-dimethylbenzyl) was added dropwise under ice-bath conditionsYl) amine (14g,44.16 mmol). The reaction was monitored by TLC (petroleum ether/ethyl acetate ═ 5:1), after completion of the reaction, the solvent was evaporated, 50ml of water was added, ethyl acetate was extracted, the organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate ═ 5/1) to give 10g of a white solid in 50% yield.¹H NMR(400MHz,DMSO-d₆)δ7.37–7.32(m,3H),7.21(dd,J＝6.5,3.0Hz,2H),7.08(d,J＝8.3Hz,2H),6.53–6.46(m,4H),4.27(s,2H),4.11(s,4H),3.74(s,6H),3.72(s,6H).¹³C NMR(126MHz,DMSO)δ160.3,158.2,131.1,130.6,129.3,128.3,128.1,117.1,103.8,98.1,58.9,55.2,54.9,45.3.MS(ESI)m/z:470.2[M-H]^-.

(b) N, N-bis (2, 4-dimethoxyphenyl) -1, 1-difluoro-1-phenylmethanesulfonamide

Dissolving N, N-bis (2, 4-dimethoxybenzyl) -1-phenylmethanesulfonamide (3g,6.37mmol) and N-fluorobisbenzenesulfonamide (4.4g,14mmol) in dry tetrahydrofuran (40ml), cooling to-80 deg.C, adding sodium bis (trimethylsilyl) amide (9ml,2M) dropwise under Ar gas protection, stirring for about 30 minutes after the addition, transferring to room temperature, monitoring the reaction by TLC (petroleum ether/ethyl acetate ═ 5/1), adding saturated ammonium chloride solution dropwise after the reaction of the raw materials is completed, quenching the reaction, extracting with ethyl acetate (2 × 50ml), combining the organic phases, washing with water and saturated common salt solution in sequence, drying over anhydrous sodium sulfate, filtering, evaporating off the solvent, purifying the crude product by column chromatography (petroleum ether/ethyl acetate ═ 10/1) to obtain 2.1g of white solid, the yield thereof was found to be 66%.¹H NMR(400MHz,DMSO-d₆)δ7.70–7.57(m,5H),7.02(d,J＝8.2Hz,2H),6.43(d,J＝2.4Hz,1H),6.41(dd,J＝4.3,2.3Hz,3H),4.28(s,4H),3.71(s,6H),3.63(s,6H).MS(ESI)m/z:506.1[M-H]^-.

(c) Difluoro (phenyl) methanesulfonamides

N, N-bis (2, 4-dimethoxyphenyl) -1, 1-difluoro-1-phenylmethanesulfonamide (0.5g,0.986mmol) was dissolved in 10ml of dichloromethane, 5ml of trifluoroacetic acid was added, the reaction was stirred for 4 hours, the reaction was monitored by TLC (petroleum ether/ethyl acetate ═ 5/1), after completion of the reaction of the raw materials, water was added to dilute, extraction was performed 2 times with dichloromethane, the organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate ═ 10/1) to give 0.14g of a white solid in 70% yield.¹H NMR(400MHz,CD₃OD)δ8.12(s,2H),7.66–7.54(m,5H).¹⁹F NMR(471MHz,DMSO-d₆)δ-102.42.MS(ESI)m/z:206.0[M-H]^-.

(d)1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) piperidine-4-carboxylic acid

2-chloro-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (0.2g,1.0mmol) and pipecolic acid (0.15g,1.13mmol) were dissolved in 5ml of ethanol, DIPEA (0.5ml,3mmol) was added to the mixture and the mixture was refluxed overnight, the reaction was monitored by TLC (oil ether/ethyl acetate ═ 5/1), after completion of the reaction, low-boiling ethanol was distilled off, 5ml of water was added, dichloromethane was extracted (2 × 10ml), the organic phases were combined, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate ═ 2/1) to give 0.2g of a white solid in 70% yield.¹H NMR(400MHz,CDCl₃)δ8.21(s,1H),5.12(s,2H),4.56(d,J＝13.8Hz,2H),3.42(dd,J＝17.8,6.8Hz,2H),2.79–2.69(m,1H),2.13(d,J＝11.2Hz,2H),1.95–1.89(m,2H).MS(ESI)m/z:288.1[M+H]⁺.

(e) Preparation of 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((difluoro (phenyl) methyl) sulfonyl) piperidine-4-carboxamide

1- (3-cyano-5-oxo-5, 7-dihydrofuro [3, 4-b)]Pyridin-2-yl) piperidine-4-carboxylic acid (100mg,0.35mmol) was dissolved in 5ml dichloromethane and EDCI (87mg,0.46mmol), DIPEA (225mg,1.75mmol) and HOBt (62mg,0.46mmol) were added with stirring at room temperature under Ar gas and after stirring for about 45 minutes difluoro (phenyl) methanesulfonamide (72mg,0.35mmol) was added and stirring at room temperature. The reaction was monitored by TLC (petroleum ether/ethyl acetate 5/1) and, after completion of the reaction, the solvent was distilled off. Column chromatography (dichloromethane/methanol-30/1) afforded 96mg of a white solid in 58% yield.¹H NMR(500MHz,DMSO-d₆)δ8.53(s,1H),7.61(d,J＝7.2Hz,3H),7.52(d,J＝6.8Hz,2H),5.25(s,2H),4.45–4.38(m,2H),3.18–3.10(m,2H),2.01(m,1H),1.88–1.83(m,2H),1.62–1.55(m,2H).¹³C NMR(126MHz,DMSO-d₆)δ170.78,167.71,161.39,143.27,131.54,129.63,128.27,127.04,126.99,126.95,117.44,108.09,92.86,69.89,53.57,47.23,41.81,28.11.MS(ESI)m/z:475.2[M-H]^-.

EXAMPLE 21- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((1-phenylcyclopropyl) sulfonyl) piperidine-4-carboxamide (Compound 21)

(a) N, N-bis (2, 4-dimethoxy) -1-phenylcyclopropane-1-sulfonamide

Prepared as in (b) of example 20 starting from N, N-bis (2, 4-dimethoxybenzyl) -1-phenylmethanesulfonamide (3.4g,7.2mmol) and 1,3, 2-dioxazole thiophene-2, 2-dioxide (1.16g,9.4mmol) and dried in vacuo to give 2.65g of a white solid in 74% yield.¹H NMR(500MHz,DMSO-d₆)δ7.44–7.36(m,5H),6.96–6.92(m,2H),6.39–6.35(m,4H),3.88(s,4H),3.70(s,6H),3.61(s,6H),1.57–1.52(m,2H),1.19–1.14(m,2H).MS(ESI)m/z:298.2[M+H]⁺.

(b) 1-phenylcyclopropane-1-sulfonamides

Prepared as in (c) of example 20 starting from N, N-bis (2, 4-dimethoxy) -1-phenylcyclopropane-1-sulfonamide (2.5g,5.77mmol) and dried in vacuo to give 1.13g of a white solid in 78% yield.¹H NMR(500MHz,DMSO-d₆)δ7.50(dd,J＝7.9,1.6Hz,2H),7.38–7.33(m,3H),6.81(s,2H),1.54(q,J＝4.6Hz,2H),1.14(q,J＝4.9Hz,2H).MS(ESI)m/z:198.1[M+H]⁺.

(c) Preparation of 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((1-phenylcyclopropyl) sulfonyl) piperidine-4-carboxamide

1- (3-cyano-5-oxo-5, 7-dihydrofuro [3, 4-b)]Pyridin-2-yl) piperidine-4-carboxylic acid (100mg,0.35mmol) and 1-phenylcyclopropane-1-sulfonamide (70mg,0.35mmol) were prepared according to the method of (e) in example 20 to give 106mg of a white solid in a yield of 63%.¹H NMR(500MHz,CDCl₃)δ8.21–8.17(m,1H),7.49(d,J＝4.2Hz,2H),7.41–7.34(m,3H),5.11(s,2H),4.67–4.56(m,2H),3.29–3.19(m,2H),2.45(m,1H),2.10–2.00(m,4H),1.92–1.79(m,4H).¹³C NMR(126MHz,CDCl₃)δ172.13,170.29,167.78,161.82,143.15,133.86,131.89,129.59,128.73,117.15,109.11,93.89,70.00,47.26,45.59,42.03,27.88,13.64.MS(ESI)m/z:465.3[M-H]^-.

Example 22: 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((1-phenylethyl) sulfonyl) piperidine-4-carboxamide (Compound 22)

(a) N, N-bis (2, 4-dimethoxybenzyl) -1-phenyl-1-sulfonamide

Prepared by the method of (b) in example 20 using N, N-bis (2, 4-dimethoxybenzyl) -1-phenylmethanesulfonamide (3g,6.37mmol) and iodomethane (2.17g,15.3mmol) as starting materials, 2.3g of a white solid was obtained in 77% yield.¹H NMR(400MHz,DMSO-d₆)δ7.36–7.32(m,3H),7.24–7.19(m,2H),7.03(d,J＝8.3Hz,2H),6.48(dd,J＝6.1,2.4Hz,3H),6.46(d,J＝2.4Hz,1H),4.20(q,J＝7.0Hz,1H),3.74(s,6H),3.70(s,6H).MS(ESI)m/z:484.2[M-H]^-.

(b) 1-phenylethane-1-sulfonamides

Prepared as in (c) in example 20 starting from N, N-bis (2, 4-dimethoxybenzyl) -1-phenyl-1-sulfonamide (1g,2.06mmol) and dried in vacuo to give 0.25g of a white solid in 65% yield.¹H NMR(400MHz,DMSO-d₆)δ7.40–7.31(m,5H),6.79(s,2H),4.22(q,J＝7.1Hz,1H),1.62(d,J＝7.1Hz,3H).MS(ESI)m/z:184.1[M-H]^-.

(c) Preparation of 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((1-phenylethyl) sulfonyl) piperidine-4-carboxamide

1- (3-cyano-5-oxo-5, 7-dihydrofuro [3, 4-b)]Pyridin-2-yl) piperidine-4-carboxylic acid (70.5mg,0.246mmol) and p-1-phenylethane-1-sulfonamide (50mg,0.27mmol) were prepared as in (e) of example 20 by drying in vacuo to give 81mg of a white solid in 73% yield.¹H NMR(500MHz,DMSO-d₆)δ11.57(s,1H),8.56(s,1H),7.41–7.38(m,3H),7.38–7.34(m,2H),5.26(s,2H),4.80(q,J＝7.2Hz,1H),4.51–4.45(m,2H),3.25–3.18(m,2H),2.58(ddd,J＝11.2,7.0,4.2Hz,1H),1.93–1.85(m,2H),1.78–1.70(m,2H),1.67(d,J＝7.2Hz,3H).¹³C NMR(126MHz,DMSO-d₆)δ173.94,170.74,167.66,161.47,143.27,134.23,129.10,128.78,128.50,117.37,108.33,93.07,69.89,61.66,46.94,46.90,41.21,27.58,27.22,14.68.MS(ESI)m/z:453.3[M-H]^-.

Example 23: 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((4-methylbenzyl) sulfonyl) piperidine-4-carboxamide (Compound 23)

(a)2- (4-methylbenzyl) isothiourea chloride

4-methylbenzyl chloride (5g,35.7mmol) and thiourea (2.85g,37.4mmol) were charged to a 100ml reaction flask, and about 50ml of ethanol was added to conduct a reaction under reflux. The reaction was monitored by TLC (5: 1 petroleum ether/ethyl acetate) and after completion the reaction was carried out the solvent was dried and directly put into the next reaction.

(b) P-tolyl methanesulfonyl chloride

The crude 2- (4-methylbenzyl) isothiouronium chloride from the previous step was dissolved in 100ml acetonitrile and N-chlorosuccinimide (19g,142.8mmol) and dilute hydrochloric acid (9ml,2M) were added under ice-bath conditions and the reaction was monitored by TLC (petroleum ether/ethyl acetate ═ 5: 1). After the reaction was completed, low-boiling ethanol was distilled off, 50ml of water was added, dichloromethane was extracted (2 × 50ml), the organic phases were combined, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off, and the crude product was directly subjected to the next reaction without purification.

(c) Para-methylbenzenesulfonamide

The crude p-tolylmethanesulfonyl chloride was dissolved in tetrahydrofuran, and aqueous ammonia (6ml) was added dropwise under ice-bath conditions. The reaction was monitored by TLC (oil ether/ethyl acetate-5/1), after completion of the reaction, the solvent was distilled off, 10ml of water was added, dichloromethane was extracted (2 × 50ml), the organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate-5/1) to give 2.5g of a white solid in 25% overall yield over three steps.¹H NMR(400MHz,DMSO-d₆)δ7.25(d,J＝8.0Hz,2H),7.18(d,J＝7.9Hz,2H),6.80(s,2H),4.21(s,2H),2.31(s,3H).MS(ESI)m/z:186.1[M+H]⁺.

(d) Preparation of 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((4-methylbenzyl) sulfonyl) piperidine-4-carboxamide

Prepared as in example 1 starting with p-methylbenzenesulfonamide (0.2g,1.0mmol), and dried in vacuo to yield 87mg of a white solid in 78% yield.¹H NMR(500MHz,DMSO-d₆)δ11.57(s,1H),8.57(s,1H),7.21(d,J＝7.9Hz,2H),7.17(d,J＝8.0Hz,2H),5.27(s,2H),4.64(s,2H),4.54–4.49(m,2H),3.27–3.21(m,2H),2.62(ddd,J＝11.1,9.5,3.9Hz,1H),2.31(s,3H),1.91–1.86(m,2H),1.72–1.66(m,2H).¹³C NMR(126MHz,DMSO-d₆)δ174.09,170.74,167.67,161.48,143.28,138.11,130.58,129.13,125.98,117.39,108.34,93.08,69.90,57.14,46.95,41.22,39.52,27.45,20.73.MS(ESI)m/z:453.3[M-H]^-.

Example 24: 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((4-fluorobenzyl) sulfonyl) piperidine-4-carboxamide (Compound 24)

(a) 4-fluorobenzylsulfonamides

Prepared by the method of (a), (b) and (c) in example 23 using 4-fluorobenzyl chloride (3g,20.8mmol) as a starting material, and dried in vacuo to give 1.9g of a white solid in 50% yield in three steps.¹H NMR(400MHz,DMSO-d₆)δ7.44–7.38(m,2H),7.25–7.18(m,2H),6.85(s,2H),4.27(s,2H).MS(ESI)m/z：190.1[M+H]⁺.

(b)4- (((4-fluorobenzyl) sulfonyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl ester

4-fluorobenzylsulfonamide (0.22g,1.20mmol) and 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (0.2g, 0).87mmol) was used as starting material, prepared according to the method of example 1 (b), and dried under vacuum to give 0.26g of a white solid, 75%.¹H NMR(400MHz,DMSO-d₆)δ11.57(s,1H),7.35–7.29(m,2H),7.25(m,2H),4.69(s,2H),3.93(d,J＝13.0Hz,2H),2.75–2.59(m,2H),2.43–2.31(m,2H),2.03–1.92(m,2H),1.67(d,J＝11.0Hz,2H),1.40(s,9H).MS(ESI)m/z:401.2[M+H]⁺.

(c) N- ((4-fluorobenzyl) sulfonyl) piperidine-4-carboxamide

Prepared by the method of (c) in example 1 using tert-butyl 4- (((4-fluorobenzyl) sulfonyl) carbamoyl) piperidine-1-carboxylate (0.21g,0.525mmol) as a starting material, and dried in vacuo to give 0.143g of a white solid in 91% yield in three steps.¹HNMR(400MHz,DMSO-d₆)δ8.16(s,1H),7.24(dd,J＝8.7,5.7Hz,2H),7.11–7.05(m,2H),4.23(s,2H),3.15(dt,J＝12.4,4.1Hz,2H),2.83(td,J＝12.2,3.1Hz,2H),2.18–2.09(m,1H),1.84–1.75(m,2H),1.70–1.57(m,2H).MS(ESI)m/z:301.1[M+H]⁺.

(d) Preparation of 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((4-fluorobenzyl) sulfonyl) piperidine-4-carboxamide

With 2-chloro-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (30mg,0.155mmol) and N- (benzylsulfonyl) piperidine-4-carboxamide (50mg, 0.167mmol) were prepared as in (g) of example 5, and dried in vacuo to give 52mg of a white solid in 74% yield.¹H NMR(400MHz,DMSO-d₆)δ11.66(s,1H),8.59(s,1H),7.36–7.30(m,2H),7.25(t,J＝8.7Hz,2H),5.27(s,2H),4.71(s,2H),4.52(d,J＝11.6Hz,2H),3.23(t,J＝12.3Hz,2H),2.03–1.96(m,1H),1.91–1.84(m,2H),1.73–1.62(m,2H).¹³CNMR(126MHz,DMSO-d₆)δ174.63,171.23,168.16,163.78,161.97,143.76,133.33,133.26,125.92,117.88,116.08,115.91,108.82,93.57,70.39,57.07,47.44,41.76,27.94.MS(ESI)m/z:457.2[M-H]^-.

Example 25: n- ((4-chlorobenzyl) sulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) piperidine-4-carboxamide (Compound 25)

(a) 4-chlorobenzylsulfonamides

Prepared by the method of (a) in example 1 starting with 4-chlorobenzyl chloride (1g,44.6mmol), and dried under vacuum to give 0.8g of a white solid with a yield of 88%.¹H NMR(400MHz,DMSO-d₆)δ7.44–7.40(m,3H),7.35–7.31(m,2H),6.91(s,2H),4.30(s,2H).MS(ESI)M/Z:206.1[M+H]⁺.

(b)4- (((4-chlorobenzyl) sulfonyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl ester

Prepared by the method of (b) in example 1 starting from 4-chlorobenzylsulfonamide (0.3g,1.45mmol) and 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (0.44g,1.9mmol) and dried in vacuo to give 0.44g of a white solid in 73% yield.¹H NMR(400MHz,DMSO-d₆)δ11.67(s,1H),7.91(d,J＝8.1Hz,2H),7.49(d,J＝8.0Hz,2H),4.84(s,2H),3.93(d,J＝11.2Hz,2H),2.76–2.61(m,2H),2.43–2.34(m,2H),2.05–1.92(m,1H),1.71–1.63(m,2H),1.41(s,9H).MS(ESI)m/z:415.1[M-H]^-.

(c) N- ((4-chlorobenzyl) sulfonyl) piperidine-4-carboxamide

Prepared by the method of (c) in example 1 starting from tert-butyl 4- (((4-chlorobenzyl) sulfonyl) carbamoyl) piperidine-1-carboxylate (0.4g,1.0mmol) and dried in vacuo to give 0.28g of a white solid in 92% yield.¹H NMR(400MHz,DMSO-d₆)δ8.20(s,1H),7.82(d,J＝8.1Hz,2H),7.39(d,J＝8.0Hz,2H),3.17(dt,J＝12.7,4.0Hz,1H),2.89–2.79(m,1H),2.15(ddd,J＝14.4,10.3,3.9Hz,1H),1.80(dd,J＝14.5,3.4Hz,2H),1.72–1.60(m,2H).MS(ESI)m/z:315.0[M-H]^-.

(d) Preparation of N- ((4-chlorobenzyl) sulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) piperidine-4-carboxamide

With N- ((4-chlorobenzyl) sulfonyl) piperidine-4-carboxamide (60mg,0.19mmol) and 2-chloro-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (33mg,0.173mmol) was prepared as in (g) in example 5, and dried under vacuum to give 53mg of a white solid in 64% yield.¹H NMR(400MHz,DMSO-d₆)δ11.71(s,1H),8.59(s,1H),7.50–7.42(m,1H),7.35(d,J＝1.6Hz,1H),7.27–7.23(m,1H),5.27(s,2H),4.75(s,2H),4.51(d,J＝13.1Hz,2H),3.27–3.19(m,2H),2.03–1.95(m,1H),1.89–1.82(m,2H),1.73–1.62(m,2H).¹³C NMR(126MHz,DMSO-d₆)δ174.09,170.74,167.65,161.48,143.27,133.00,131.49,130.48,130.38,129.39,128.64,117.36,108.37,93.11,69.90,56.76,46.91,41.25,27.44.MS(ESI)m/z:473.1[M-H]^-.

Example 26: 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((2, 4-difluorobenzyl) sulfonyl) piperidine-4-carboxamide (Compound 26)

(a) (2, 4-difluorophenyl) methanesulfonamide

Prepared as in (a), (b) and (c) in example 23 starting from 1- (chloromethyl) -2, 4-difluorobenzene (3g,18.52mmol) and dried in vacuo to give 1.6g of a white solid in 40% three-step yield.¹H NMR(400MHz,DMSO-d₆)δ7.48(td,J＝8.6,6.7Hz,1H),7.33–7.25(m,1H),7.17–7.10(m,1H),7.01(s,2H).MS(ESI)m/z:208.1[M+H]⁺.

(b)4- (((2, 4-difluorobenzyl) sulfonyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl ester

Prepared as in (b) of example 1 starting from (2, 4-difluorophenyl) methanesulfonamide (0.59g,2.84mmol) and 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (0.5g,2.18mmol) and dried in vacuo to give 0.75g of a white solid in 83% yield.¹H NMR(400MHz,DMSO-d₆)δ7.22(dt,J＝10.0,5.5Hz,1H),7.14–7.09(m,1H),7.02(td,J＝8.7,2.7Hz,1H),3.21(dt,J＝12.4,3.8Hz,2H),2.95(dt,J＝12.0,3.3Hz,2H),1.84–1.77(m,2H),1.75–1.59(m,2H),1.36(s,9H).MS(ESI)m/z:419.2[M+H]⁺.

(c) N- ((2, 4-difluorobenzyl) sulfonyl) piperidine-4-carboxamide

Prepared as in (c) in example 1 from tert-butyl 4- (((2, 4-difluorobenzyl) sulfonyl) carbamoyl) piperidine-1-carboxylate (0.74g,1.78mmol) and dried in vacuo to give 0.43g of a white solid in 75% yield.¹HNMR(400MHz,DMSO-d₆)δ8.20(s,1H),7.32(dt,J＝10.0,5.5Hz,1H),7.18–7.11(m,1H),7.01(td,J＝8.7,2.7Hz,1H),3.18(dt,J＝12.4,3.8Hz,2H),2.86(dt,J＝12.0,3.3Hz,2H),1.87–1.79(m,2H),1.73–1.61(m,2H).MS(ESI)m/z:319.1[M+H]⁺.

(d) Preparation of 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((2, 4-difluorobenzyl) sulfonyl) piperidine-4-carboxamide

With N- ((2, 4-difluorobenzyl) sulfonyl) piperidine-4-carboxamide (100mg,0.31mmol) and 2-chloro-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (50mg,0.257mmol) as a starting material was prepared according to the method of example 5 (g)Preparation, vacuum drying gave 83mg of a white solid in 68% yield.¹H NMR(500MHz,DMSO-d₆)δ11.77(s,1H),8.57(s,1H),7.47(dd,J＝15.2,8.5Hz,1H),7.37–7.32(m,1H),7.20–7.15(m,1H),5.27(s,2H),4.74(s,2H),4.58–4.45(m,2H),3.29–3.20(m,2H),2.65(ddd,J＝10.4,9.0,3.8Hz,1H),1.96–1.86(m,2H),1.75–1.64(m,2H).¹³C NMR(126MHz,DMSO-d₆)δ188.64,173.99,170.74,167.66,161.49,143.28,134.52,129.62,127.87,117.38,112.92,112.04,108.35,105.51,104.14,93.09,69.89,50.69,46.95,41.35,27.37.MS(ESI)m/z:475.2[M-H]^-.

EXAMPLE 27- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((4- (trifluoromethyl) benzyl) sulfonyl) piperidine-4-carboxamide (Compound 27)

(a) (4- (trifluoromethyl) phenyl) methanesulfonamide

Prepared as in (a), (b) and (c) in example 23 starting from 1- (chloromethyl) -4- (trifluoromethyl) benzene (1g,5.15mmol) and dried in vacuo to give 0.8g of a white solid in 66.7% three-step yield.¹H NMR(400MHz,DMSO-d₆)δ7.76(d,J＝8.0Hz,2H),7.59(d,J＝8.0Hz,2H),6.94(s,2H),4.39(s,2H).MS(ESI)m/z:238.1[M-H]^-.

(b)4- (((4- (trifluoromethyl) benzyl) sulfonyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl ester

Prepared as in (b) of example 1 starting from (4- (trifluoromethyl) phenyl) methanesulfonamide (0.8g,3.36mmol) and 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (0.7g,3.06mmol) and dried in vacuo to give 0.87g of a white solid in 62% yield.¹H NMR(400MHz,DMSO-d₆)δ11.64(s,1H),7.76(d,J＝8.0Hz,2H),7.59(d,J＝8.0Hz,2H),4.39(s,2H),3.99–3.83(m,2H),2.79–2.57(m,2H),2.46–2.27(m,2H),2.05–1.87(m,1H),1.73–1.61(m,2H),1.39(s,9H).MS(ESI)m/z:449.1[M-H]^-.

(c) N- ((4- (trifluoromethyl) benzyl) sulfonyl) piperidine-4-carboxamide

Prepared by the method of (c) in example 1 using tert-butyl 4- (((4- (trifluoromethyl) benzyl) sulfonyl) carbamoyl) piperidine-1-carboxylate (0.7g,1.56mmol) as a starting material, and dried in vacuo to give 0.47g of a white solid in 87% yield.¹H NMR(400MHz,DMSO-d₆)δ8.20(s,1H),7.63(d,J＝8.0Hz,2H),7.43(d,J＝7.7Hz,2H),4.36(s,2H),3.22–3.10(m,2H),2.89–2.78(m,2H),2.21–2.10(m,1H),1.87–1.75(m,2H),1.71–1.57(m,2H).MS(ESI)m/z:351.1[M+H]⁺.

(d) Preparation of 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((4- (trifluoromethyl) benzyl) sulfonyl) piperidine-4-carboxamide

With N- ((4- (trifluoromethyl) benzyl) sulfonyl) piperidine-4-carboxamide (80mg,0.228mmol) and 2-chloro-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (44mg,0.228mmol) was prepared as in (g) in example 5, and dried under vacuum to give 87mg of a white solid in 75% yield.¹H NMR(500MHz,DMSO-d₆)δ11.69(s,1H),8.57(s,1H),7.80(d,J＝8.1Hz,2H),7.53(d,J＝8.0Hz,2H),5.26(s,2H),4.85(s,2H),4.52(d,J＝13.5Hz,2H),3.27–3.21(m,2H),2.67–2.60(m,1H),1.91–1.86(m,2H),1.69(ddd,J＝15.0,12.8,3.5Hz,2H).¹³C NMR(126MHz,DMSO-d₆)δ174.16,170.74,167.66,161.50,143.27,133.85,131.62,125.48,125.45,117.38,108.35,93.10,69.89,56.93,46.94,41.26,27.42.MS(ESI)m/z:507.1[M-H]^-.

EXAMPLE 28 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((4-cyanobenzyl) sulfonyl) piperidine-4-carboxamide (Compound 28)

(a) (4-cyanophenyl) methanesulfonamide

Prepared by the method of (a), (b) and (c) in example 24 using 4- (chloromethyl) benzonitrile (3g,19.86mmol) as a starting material, and dried in vacuo to give 0.8g of a white solid in 68% yield in three steps.¹H NMR(500MHz,DMSO-d₆)δ7.88–7.83(m,2H),7.58–7.55(m,2H),6.93(s,2H),4.39(s,2H).MS(ESI)m/z:195.0[M-H]^-.

(b)4- (chloromethyl) benzonitrile 4- (((4-cyanobenzyl) sulfonyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl ester

Prepared by the method of (b) in example 1 starting from (4-cyanophenyl) methanesulfonamide (0.6g,3.06mmol) and 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (0.77g,3.37mmol) and dried in vacuo to give 0.78g of a white solid in 63% yield.¹H NMR(400MHz,DMSO-d₆)δ11.66(s,1H),7.91(d,J＝8.2Hz,2H),7.49(d,J＝8.1Hz,2H),4.84(s,2H),3.99–3.88(m,2H),2.76–2.62(m,2H),2.43–2.31(m,1H),2.05–1.93(m,1H),1.72–1.62(m,2H),1.40(s,9H).MS(ESI)m/z:460.1[M-H]^-.

(c) N- ((4-cyanobenzyl) sulfonyl) piperidine-4-carboxamide

Prepared as in (c) of example 1 starting from 4- (chloromethyl) benzonitrile 4- (((4-cyanobenzyl) sulfonyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl ester (0.4g,0.98mmol) and dried in vacuo to give 0.26g of a white solid in 88% yield.¹H NMR(400MHz,D₂O)δ7.69(d,J＝7.6Hz,2H),7.42(d,J＝7.8Hz,2H),4.51(s,2H),3.38–3.29(m,2H),2.91(t,J＝12.7Hz,2H),2.33(d,J＝11.4Hz,1H),1.95–1.85(m,2H),1.73–1.61(m,2H).MS(ESI)m/z:306.1[M-H]^-.

(d) Preparation of 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((4-cyanobenzyl) sulfonyl) piperidine-4-carboxamide

With N- ((4-cyanobenzyl) sulfonyl) piperidine-4-carboxamide (95mg,0.3mmol) and 2-chloro-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (50mg,0.257mmol) was prepared as in (g) in example 5, and dried under vacuum to give 50mg of a white solid in 42% yield.¹H NMR(500MHz,DMSO-d₆)δ11.72(s,1H),8.57(s,1H),7.90(d,J＝8.2Hz,2H),7.50(d,J＝8.3Hz,2H),5.27(s,2H),4.51(d,J＝13.5Hz,2H),3.24(t,J＝11.5Hz,2H),2.62(tt,J＝11.1,4.0Hz,1H),1.88(dd,J＝13.0,2.7Hz,2H),1.68(ddd,J＝15.4,13.0,3.8Hz,2H).¹³C NMR(126MHz,DMSO-d₆)δ174.13,170.74,167.66,161.50,143.27,134.64,132.46,131.71,118.46,117.38,111.45,108.35,93.11,69.89,57.16,46.94,41.28,27.42.MS(ESI)m/z:464.1[M-H]^-.

EXAMPLE 29N- ((4-chlorobenzyl) sulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -4-methylpiperidine-4-carboxamide (Compound 29)

(a)4- (((4-chlorobenzyl) sulfonyl) carbamoyl) -4-methylpiperidine-1-carboxylic acid tert-butyl ester

Prepared by the method of (b) in example 1 starting from 4-chlorobenzylsulfonamide (0.33g,1.58mmol) and 1- (tert-butoxycarbonyl) -4-methylpiperidine-4-carboxylic acid (0.5g,2.05mmol) and dried in vacuo to give 0.44g of a white solid in 64% yield.¹H NMR(400MHz,DMSO-d₆)δ7.51–7.42(m,2H),7.41–7.30(m,2H),4.27(s,2H),3.52–3.43(m,2H),3.02–2.91(m,2H),2.04–1.98(m,2H),1.95–1.84(m,2H),1.39(s,3H).MS(ESI)m/z:431.1[M+H]⁺.

(b) N- ((4-chlorobenzyl) sulfonyl) -4-methylpiperidine-4-carboxamide

Prepared by the method of (c) in example 1 using tert-butyl 4- (((4-chlorobenzyl) sulfonyl) carbamoyl) -4-methylpiperidine-1-carboxylate (0.3g,0.70mmol) as a starting material, and dried under vacuum to give 0.18g of a white solid in 79% yield.¹H NMR(400MHz,D₂O)δ7.25(d,J＝2.7Hz,2H),7.19(d,J＝2.6Hz,2H),4.34(s,2H),3.12–3.04(m,2H),2.81–2.71(m,2H),2.06–1.98(m,2H),1.45–1.34(m,2H),0.95(s,3H).MS(ESI)m/z:331.1[M+H]⁺.

(c) Preparation of N- ((4-chlorobenzyl) sulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -4-methylpiperidine-4-carboxamide

With N- ((4-chlorobenzyl) sulfonyl) -4-methylpiperidine-4-carboxamide (40mg,0.21mmol) and 2-chloro-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (68mg,0.21mmol) was prepared as in (g) in example 5, and dried under vacuum to give 64mg of a white solid in 63% yield.¹H NMR(500MHz,DMSO-d₆)δ11.39(s,1H),8.56(s,1H),7.47(d,J＝8.3Hz,2H),7.35(d,J＝8.4Hz,2H),5.26(s,2H),4.79(s,2H),4.08–4.00(m,2H),3.60–3.52(m,2H),2.17–2.09(m,2H),1.60–1.54(m,2H),1.19(s,3H).¹³CNMR(126MHz,DMSO-d₆)δ171.21,168.16,161.91,143.74,133.05,129.04,117.95,108.66,93.45,70.37,57.58,45.21,42.72,33.64,23.59.MS(ESI)m/z:467.2[M-H]^-.

EXAMPLE 30 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((2, 4-difluorobenzyl) sulfonyl) -4-methylpiperidine-4-carboxamide (Compound 30)

(a)4- (((2, 4-difluorobenzyl) sulfonyl) carbamoyl) -4-methylpiperidine-1-carboxylic acid tert-butyl ester

Prepared as in (b) of example 1 starting from (2, 4-difluorophenyl) methanesulfonamide (0.2g,1.0mmol) and 1- (tert-butoxycarbonyl) -4-methylpiperidine-4-carboxylic acid (0.3g,1.25mmol) and dried in vacuo to give 0.25g of a white solid in 60% yield.¹H NMR(400MHz,DMSO-d₆)δ11.22(s,1H),7.55(t,J＝8.1Hz,1H),7.27(d,J＝7.9Hz,1H),7.13(d,J＝8.2Hz,1H),4.69(s,2H),3.72–3.55(m,2H),2.98–2.92(m,2H),1.94–1.89(m,2H),1.39(s,9H),1.31–1.28(m,2H),1.10(s,3H).MS(ESI)m/z:433.1[M+H]⁺.

(b) N- ((2, 4-difluorobenzyl) sulfonyl) -4-methylpiperidine-4-carboxamide

Prepared by the method of (c) in example 1 using tert-butyl 4- (((2, 4-difluorobenzyl) sulfonyl) carbamoyl) -4-methylpiperidine-1-carboxylate (0.25g,0.43mmol) as a starting material, and dried in vacuo to give 0.13g of a white solid in 90% yield.¹H NMR(400MHz,D2O)δ8.31(s,1H),7.65(dd,J＝16.0,8.0Hz,1H),7.44–7.34(m,1H),6.89(t,J＝8.9Hz,1H),3.22–3.12(m,2H),2.93–2.83(m,2H),2.09(t,J＝14.3Hz,2H),1.53–1.41(m,2H),1.06(d,J＝12.3Hz,3H).MS(ESI)m/z:333.1[M+H]⁺.

(c) Preparation of 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((2, 4-difluorobenzyl) sulfonyl) -4-methylpiperidine-4-carboxamide

With N- ((2, 4-difluorobenzyl) sulfonyl) -4-methylpiperidine-4-carboxamide (75mg,0.234mmol) and 2-chloro-5-oxo-5, 7-dihydrofuro [3, 4-b)]Pyridine-3-carbonitrile (50mg,0.257mmol) was prepared as in (g) in example 5, and dried under vacuum to give 63mg of a white solid in 55% yield.¹H NMR(500MHz,DMSO-d₆)δ11.50(s,1H),7.48(dd,J＝15.2,8.4Hz,1H),7.34–7.27(m,1H),7.19–7.14(m,1H),5.24(s,2H),4.79(s,2H),4.08–4.02(m,2H),3.64–3.57(m,2H),2.16–2.10(m,2H),1.59–1.54(m,2H),1.21(s,3H).¹³C NMR(126MHz,DMSO-d₆)δ177.57,170.72,167.66,161.38,161.34,143.29,143.25,117.45,108.05,92.77,69.86,45.32,42.25,34.07,24.96.MS(ESI)m/z:489.1[M-H]^-.

EXAMPLE 31- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((4-fluorobenzyl) sulfonyl) -4-methylpiperidine-4-carboxamide (Compound 31)

(a)4- (((4-Fluorobenzyl) sulfonyl) carbamoyl) -4-methylpiperidine-1-carboxylic acid tert-butyl ester

Prepared by the method of (b) in example 1 starting from 4-fluorophenylmethanesulfonamide (0.21g,1.1mmol) and 1- (tert-butoxycarbonyl) -4-methylpiperidine-4-carboxylic acid (0.35g,1.44mmol), and dried in vacuo to give 0.28g of a white solid in 62% yield¹H NMR(400MHz,DMSO-d₆)δ11.29(s,1H),7.38–7.33(m,1H),7.27–7.21(m,1H),4.76(s,2H),3.52–3.44(m,2H),3.02–2.92(m,2H),1.94–1.88(m,2H),1.39(s,9H),1.32–1.28(m,2H),1.10(s,3H).MS(ESI)m/z:415.1[M+H]⁺.

(b) N- ((4-fluorobenzyl) sulfonyl) -4-methylpiperidine-4-carboxamide

Prepared as in (c) in example 1 with tert-butyl 4- (((4-fluorobenzyl) sulfonyl) carbamoyl) -4-methylpiperidine-1-carboxylate (0.25g,0.60mmol) and dried in vacuo to give 0.14g of a white solid in 74% yield.¹HNMR(400MHz,DMSO-d₆)δ8.13(s,1H),7.27(dd,J＝8.4,5.8Hz,2H),7.10(t,J＝8.9Hz,2H),4.27(s,2H),3.12–3.05(m,2H),2.79–2.70(m,2H),2.12(d,J＝14.6Hz,2H),1.34–1.27(m,2H),0.99(s,3H).MS(ESI)M/Z:315.1[M+H]⁺.

(c) Preparation of 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((4-fluorobenzyl) sulfonyl) -4-methylpiperidine-4-carboxamide

With N- ((4-fluorobenzyl) sulfonyl) -4-methylpiperidine-4-carboxamide (60mg,0.2mmol) and 2-chloro-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (43mg,0.22mmol) was prepared as in (g) in example 5, and dried under vacuum to give 40mg of a white solid with a yield of 41%.¹H NMR(500MHz,DMSO-d₆)δ11.36(s,1H),8.55(s,1H),7.39–7.34(m,2H),7.23(t,J＝8.8Hz,2H),5.25(s,2H),4.77(s,2H),4.04(ddd,J＝13.4,6.0,3.4Hz,2H),3.60–3.53(m,2H),2.16–2.10(m,2H),1.60–1.53(m,2H),1.19(s,3H).¹³C NMR(126MHz,DMSO-d₆)δ176.46,170.70,167.66,163.31,161.39,143.24,132.88,132.81,125.39,117.45,115.53,115.36,108.15,92.93,69.87,56.99,44.71,42.20,33.15,23.09.MS(ESI)m/z:471.2[M-H]^-.

EXAMPLE 32 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -4-methyl-N- ((4-methylbenzyl) sulfonyl) piperidine-4-carboxamide (Compound 32)

(a) 4-methyl-4- (((4-methylbenzyl) sulfonyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl ester

Prepared by the method of (b) in example 1 using 4-methylphenylmethanesulfonamide (0.21g,1.1mmol) and 1- (tert-butoxycarbonyl) -4-methylpiperidine-4-carboxylic acid (0.35g,1.44mmol) as starting materials, and dried in vacuo to give 0.22g of a white solid in 48% yield.¹H NMR(400MHz,DMSO-d₆)δ11.21(s,1H),7.99(d,J＝8.5Hz,2H),7.72(d,J＝8.2Hz,2H),4.68(s,2H),3.52–3.44(m,2H),3.00–2.89(m,2H),2.30(s,3H),1.91(d,J＝14.1Hz,2H),1.39(s,9H),1.33–1.25(m,2H),1.10(s,3H).MS(ESI)m/z:309.1[M+H]⁺.

(b) 4-methyl-N- ((4-methylbenzyl) sulfonyl) piperidine-4-carboxamide

Prepared by the method of (c) in example 1 starting from tert-butyl 4-methyl-4- (((4-methylbenzyl) sulfonyl) carbamoyl) piperidine-1-carboxylate (0.2g,0.49 mmol), and dried in vacuo to give 0.144g of a white solid in 95% yield.¹H NMR(400MHz,DMSO-d₆)δ8.12(s,1H),7.12(d,J＝8.0Hz,2H),7.06(d,J＝8.0Hz,2H),4.22(s,2H),3.11–3.05(m,2H),2.82–2.72(m,2H),2.26(s,3H),2.12(d,J＝13.0Hz,2H),1.35–1.25(m,2H),0.99(s,3H).MS(ESI)m/z:311.2[M+H]⁺.

(c) Preparation of 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -4-methyl-N- ((4-methylbenzyl) sulfonyl) piperidine-4-carboxamide

With 4-methyl-N- ((4-methylbenzyl) sulfonyl) piperidine-4-carboxamide (250mg,0.806mmol) and 2-chloro-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (160mg,0.806mmol) was prepared as in example 5 (g) and dried in vacuo to give 260mg of a white solid in 73% yield.¹H NMR(500MHz,DMSO-d₆)δ11.31(s,1H),8.55(s,1H),7.22–7.17(m,4H),5.26(s,2H),4.71(s,2H),4.08–4.00(m,2H),3.56–3.48(m,2H),2.28(s,3H),2.16–2.11(m,2H),1.59–1.52(m,2H),1.19(s,3H).¹³C NMR(126MHz,DMSO-d₆)δ176.37,170.71,167.66,161.38,143.25,138.12,130.61,129.05,125.95,117.44,108.14,92.91,69.87,57.60,44.71,42.19,33.16,23.22,20.70.MS(ESI)m/z:467.2[M-H]^-.

EXAMPLE 33N- (benzylsulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -4-fluoropiperidine-4-carboxamide (compound 33)

(a)1- (3-cyano-5-oxo-5, 7-dihydrofuran [3,4-b ] pyridin-2-yl) -4-fluoropiperidine-4-carboxylic acid

2-chloro-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (0.15g, 0.77mmol) and 4-fluoropiperidinecarboxylic acid (0.125g,0.85mmol as starting materials were dissolved in 5ml of ethanol, DIPEA (0.5ml,3mmol) was added thereto and the mixture was refluxed overnight, the reaction was monitored by TLC (oil ether/ethyl acetate ═ 5/1), after completion of the reaction, low-boiling ethanol was distilled off, 5ml of water was added, dichloromethane was extracted (2 × 10ml), the organic phases were combined, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate ═ 2/1) and dried under vacuum to give 0.187g of a white solid in 80% yield.¹H NMR(500MHz,CDCl₃)δ8.21(s,1H),5.12(s,2H),4.65(d,J＝13.6Hz,2H),3.55(d,J＝12.0Hz,2H),2.24–2.21(m,2H),2.02–1.99(m,2H).MS(ESI)m/z:306.1[M+H]⁺.

(b)1- (3-cyano-5-oxo-5, 7-dihydrofuran [3,4-b ] pyridin-2-yl) -4-fluoropiperidine-4-carbonyl chloride

1- (3-cyano-5-oxo-5, 7-dihydrofuran [3,4-b ] pyridin-2-yl) -4-fluoropiperidine-4-carboxylic acid (0.1g,0.327mmol) was dissolved in dry dichloromethane (5ml), thionyl chloride (0.13ml,1.64mmol) was added thereto, and after the reaction was refluxed for about 1 hour, the low boiling solvent was distilled off under reduced pressure, and the reaction was carried out in the next step.

(c) Preparation of N- (benzylsulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -4-fluoropiperidine-4-carboxamide

1- (3-cyano-5-oxo-5, 7-dihydrofuran [3, 4-b)]Pyridin-2-yl) -4-fluoropiperidine-4-carbonyl chloride (105mg,0.327mmol) was dissolved in dry dichloromethane (5ml), triethylamine (66mg,0.654mmol) was added, benzylsulfonamide (45mg,0.26mmol) was added under ice-bath conditions, and the reaction was transferred to room temperature after the addition. The reaction was monitored by TLC (dichloromethane/methanol) ═ 20/1) until the time of reactionAfter completion of the reaction, the solvent was distilled off. Column chromatography (dichloromethane/methanol-30/1) afforded the crude product, which was recrystallized from methanol and dried in vacuo to yield 92mg of a white solid in 78% yield.¹H NMR(400MHz,DMSO-d₆)δ12.02(s,1H),8.63(s,1H),7.44–7.36(m,3H),7.34–7.26(m,2H),5.29(s,2H),4.76(s,2H),4.51(d,J＝13.6Hz,2H),3.47–3.39(m,2H),2.04–1.97(m,2H).¹³C NMR(126MHz,DMSO-d₆)δ170.72,167.61,161.44,143.27,130.73,128.70,128.59,117.32,108.71,94.08,93.35,92.58,69.93,57.70,43.23,31.37,31.20.MS(ESI)m/z:457.2[M-H]^-.

EXAMPLE 34 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -4-fluoro-N- ((4-methylbenzyl) sulfonyl) piperidine-4-carboxamide (Compound 34)

With 1- (3-cyano-5-oxo-5, 7-dihydrofuran [3,4-b ]]Pyridin-2-yl) -4-fluoropiperidine-4-carbonyl chloride (60mg,0.185mmol) and p-methylbenzylsulfonamide (57mg,0.275mmol) were prepared as in (c) of example 33 and dried in vacuo to give 60mg of a white solid in 69% yield.¹H NMR(500MHz,DMSO-d₆)δ11.97(s,1H),8.60(s,1H),7.22–7.13(m,4H),5.28(s,2H),4.60(s,2H),4.54–4.43(m,2H),3.48–3.39(m,3H),2.30(s,3H),2.24–2.09(m,2H),2.04–1.94(m,2H).¹³C NMR(126MHz,DMSO-d₆)δ171.44,170.74,167.63,161.42,143.26,137.75,130.56,128.99,128.81,117.34,108.63,94.09,93.28,92.60,69.93,57.23,45.73,43.42,31.70,31.53,20.73.MS(ESI)m/z:471.2[M-H]^-.

EXAMPLE 35N- ((4-chlorobenzyl) sulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -4-fluoropiperidine-4-carboxamide (Compound 35)

With 1- (3-cyano-5-oxo-5, 7-dihydrofuran [3,4-b ]]Pyridin-2-yl) -4-fluoropiperidine-4-carbonyl chloride (60mg,0.185mmol) and p-tert-butyl acetateTosylamide (57mg,0.277mmol) was used as a starting material, prepared according to the method of (c) in example 33, and dried in vacuo to give 52mg of a white solid in a yield of 57%.¹H NMR(500MHz,DMSO-d₆)δ8.61(s,1H),7.48(d,J＝8.2Hz,2H),7.31(d,J＝8.3Hz,2H),5.28(s,2H),4.75(s,2H),4.51(d,J＝13.6Hz,2H),3.47–3.40(m,2H),2.25–2.09(m,1H),2.05–1.98(m,2H).¹³C NMR(126MHz,DMSO-d₆)δ170.75,170.01,167.66,161.50,143.28,133.60,132.58,128.64,128.06,117.35,108.75,94.16,93.41,92.66,69.96,56.91,43.28,31.45,31.27.MS(ESI)m/z:491.2[M-H]^-.

Example 36N- ((5-chlorothien-2-yl) sulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -4-fluoropiperidine-4-carboxamide (Compound 36)

With 1- (3-cyano-5-oxo-5, 7-dihydrofuran [3,4-b ]]Pyridin-2-yl) -4-fluoropiperidine-4-carbonyl chloride (60mg,0.185mmol) and 5-chlorothiophene-2-sulfonamide (60mg,0.30mmol) were prepared according to the method of (c) in example 33, and dried in vacuo to give 50mg of a white solid in a yield of 56%.¹H NMR(500MHz,DMSO-d₆)δ8.56(s,1H),7.25(d,J＝3.9Hz,1H),7.00(d,J＝3.9Hz,1H),5.28(s,2H),4.44–4.37(m,2H),3.46–3.40(m,2H),2.17–2.08(m,2H),1.90–1.84(m,2H).¹³C NMR(126MHz,DMSO-d₆)δ174.46,170.86,167.72,161.46,146.07,143.24,130.88,128.21,125.79,117.41,108.38,94.00,93.10,92.56,69.95,44.11,32.86,32.68.MS(ESI)m/z:483.1[M-H]^-.

EXAMPLE 37 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -4-fluoro-N- ((1-phenylethyl) sulfonyl) piperidine-4-carboxamide (Compound 37)

With 1- (3-cyano-5-oxo-5, 7-dihydrofuran [3,4-b ]]Pyridin-2-yl) -4-fluoropiperidine-4-carbonyl chloride (60mg,0.185mmol) and 1-phenylethane-1-sulfonic acidAmide (35mg,0.185mmol) was prepared as in (c) in example 33, and dried in vacuo to give 50mg of a white solid in 55% yield.¹H NMR(500MHz,DMSO)δ11.93(s,1H),8.61(s,1H),7.41–7.36(m,5H),5.28(s,2H),4.85(q,J＝7.2Hz,1H),4.52–4.45(m,2H),3.45–3.37(m,2H),2.22–2.07(m,2H),2.06–1.96(m,2H),1.69(d,J＝7.2Hz,3H).¹³C NMR(126MHz,DMSO)δ171.20,168.10,161.93,143.75,134.35,129.63,129.40,129.04,117.80,109.23,94.56,93.86,93.06,70.42,62.62,43.68,15.22.MS(ESI)m/z:471.1[M-H]^-.

EXAMPLE 38 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((2-fluorobenzyl) sulfonyl) piperidine-4-carboxamide (Compound 38)

(a) (2-fluorophenyl) methanesulfonamide

Prepared by the method of (a), (b) and (c) in example 24 using 1- (chloromethyl) -2-fluorobenzene (5g,34.72mmol) as the starting material and dried in vacuo to give 2.75g of a white solid in 42% yield in three steps.¹H NMR(400MHz,DMSO)δ7.48–7.38(m,2H),7.27–7.20(m,2H),7.02(s,2H),4.32(s,2H).MS(ESI)m/z:190.0[M+H]⁺.

(b)1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) piperidine-4-carbonyl chloride

1- (3-cyano-5-oxo-5, 7-dihydrofuran [3,4-b ] pyridin-2-yl) piperidine-4-carboxylic acid (0.1g,0.327mmol) was dissolved in dry dichloromethane (5ml), thionyl chloride (0.13ml,1.64mmol) was added thereto, the mixture was refluxed for about 1 hour, and then the low boiling point solvent was distilled off under reduced pressure, and the reaction was directly carried out in the next step.

(c) Preparation of 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((2-fluorobenzyl) sulfonyl) piperidine-4-carboxamide

1- (3-cyano-5-oxo-5, 7-dihydrofuro [3, 4-b)]Pyridin-2-yl) piperidine-4-carbonyl chloride (105mg,0.327mmol) was dissolved in dry dichloromethane (5ml), triethylamine (66mg,0.654mmol) was added, (2-fluorophenyl) methanesulfonamide (45mg,0.26mmol) was added under ice-bath conditions and the reaction transferred to room temperature after the addition. The reaction was monitored by TLC (dichloromethane/methanol) 20/1, and after completion of the reaction, the solvent was distilled off. Column chromatography (dichloromethane/methanol-30/1) afforded 80mg of a white solid in 50% yield.¹H NMR(500MHz,DMSO)δ11.74(s,1H),8.55(s,1H),7.48–7.36(m,3H),7.29–7.22(m,2H),5.25(s,2H),4.74(s,2H),4.51(d,J＝13.4Hz,2H),3.27–3.20(m,2H),2.64(ddd,J＝10.7,9.2,3.4Hz,1H),1.93–1.86(m,2H),1.73–1.64(m,2H).¹³C NMR(126MHz,DMSO)δ174.47,171.25,169.50,168.16,161.98,143.77,133.85,131.67,125.15,117.88,116.90,116.17,108.84,93.58,70.39,51.61,47.45,41.83,27.87.MS(ESI)m/z:457.2[M-H]^-.

EXAMPLE 39 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((3-fluorobenzyl) sulfonyl) piperidine-4-carboxamide (Compound 39)

(a) (3-fluorophenyl) methanesulfonamide

Prepared as in (a), (b) and (c) in example 24 starting from 1- (chloromethyl) -3-fluorobenzene (3g,20.83mmol) and dried in vacuo to give 1.50g of a white solid in 38% yield in three steps.¹H NMR(400MHz,DMSO)δ7.46–7.39(m,1H),7.24–7.15(m,3H),6.90(s,2H),4.30(s,2H).MS(ESI)m/z:190.1[M+H]⁺.

(b) Preparation of 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((3-fluorobenzyl) sulfonyl) piperidine-4-carboxamide

With (3-fluorophenyl) methylSulfonamide (66mg,0.35mmol) was used as a starting material, and compound 39 was prepared according to the procedure of example 38 (c). The reaction was monitored by TLC (petroleum ether/ethyl acetate 5/1) and, after completion of the reaction, the solvent was distilled off. Column chromatography (dichloromethane/methanol-30/1) afforded 85mg of a white solid in 53% yield.¹H NMR(500MHz,DMSO)δ11.68(s,1H),8.55(s,1H),7.48–7.42(m,1H),7.20–7.21(m,1H),7.15–7.09(m,2H),5.25(s,2H),4.74(s,2H),4.49(d,J＝13.5Hz,2H),3.26–3.19(m,2H),2.64–2.57(m,1H),1.89–1.81(m,2H),1.71–1.61(m,2H).¹³C NMR(126MHz,DMSO)δ174.57,171.23,168.15,161.98,143.77,131.12,131.05,127.37,117.97,117.87,116.17,116.01,108.86,93.59,70.39,57.42,47.41,41.73,27.89.MS(ESI)m/z:457.3[M-H]^-.

EXAMPLE 40 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((3, 5-dichlorobenzyl) sulfonyl) piperidine-4-carboxamide (Compound 40)

(a) (3, 5-dichlorophenyl) methanesulfonamide

Prepared as in (a), (b) and (c) in example 24 starting from 1, 3-dichloro-5- (chloromethyl) benzene (5g,25.77mmol) and dried in vacuo to give 2.14g of a white solid in 35% yield in three steps.¹H NMR(400MHz,DMSO)δ7.62(t,J＝1.9Hz,1H),7.43(d,J＝1.9Hz,2H),6.96(s,2H),4.34(s,2H).MS(ESI)m/z:240.1[M+H]⁺.

(b)4- (((3, 5-dichlorobenzyl) sulfonyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl ester

Prepared by the method of (b) in example 1 starting from (3, 5-dichlorophenyl) methanesulfonamide (0.3g,1.25mmol) and 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (0.29g,1.25mmol) and dried in vacuo to give 0.32g of a white solid in 56% yield.¹H NMR(400MHz,DMSO)δ11.68(s,1H),7.71–7.69(m,1H),7.58–7.51(m,1H),7.48–7.38(m,1H),4.78(s,2H),3.95–3.88(m,2H),2.43–2.35(m,2H),2.18–2.10(m,1H),1.82–1.71(m,2H),1.66–1.59(m,2H),1.39(s,9H).MS(ESI)m/z:451.1[M+H]⁺.

(c) N- ((3, 5-dichlorobenzyl) sulfonyl) piperidine-4-carboxamide

Prepared by the method of (c) in example 1 starting from tert-butyl 4-methyl-4- (((4-methylbenzyl) sulfonyl) carbamoyl) piperidine-1-carboxylate (0.3g,0.67 mmol), and dried in vacuo to give 0.22g of a white solid in 94% yield.¹HNMR(400MHz,DMSO)δ8.25(s,1H),7.51–7.45(m,1H),7.23(d,J＝1.9Hz,2H),4.29(s,2H),3.18(dt,J＝7.8,3.5Hz,2H),2.86(dd,J＝11.9,2.9Hz,2H),2.15(tt,J＝10.9,4.0Hz,1H),1.85–1.74(m,2H),1.72–1.58(m,2H).MS(ESI)m/z:351.0[M+H]⁺.

(d) Preparation of 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((3, 5-dichlorobenzyl) sulfonyl) piperidine-4-carboxamide

With N- ((3, 5-dichlorobenzyl) sulfonyl) piperidine-4-carboxamide (200mg,0.57mmol) and 2-chloro-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (110mg,0.57mmol) was prepared as in (g) in example 5, and dried under vacuum to give 200mg of a white solid in 70% yield.¹H NMR(600MHz,DMSO)δ11.76(s,1H),8.56(s,1H),7.69(s,1H),7.33(s,2H),5.26(s,2H),4.78(s,2H),4.51(d,J＝10.5Hz,2H),3.27–3.22(m,2H),2.68–2.56(m,1H),1.92–1.82(m,2H),1.71–1.64(m,2H).¹³C NMR(151MHz,DMSO)δ174.14,170.80,167.73,161.55,143.33,134.07,133.24,129.41,128.40,117.39,108.47,93.20,69.96,56.29,46.95,41.34,27.50.MS(ESI)m/z:507.2[M-H]^-.

EXAMPLE 41 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -N- ((2-fluorobenzyl) sulfonyl) piperidine-4-carboxamide (Compound 41)

(a)1- (3-cyano-5-oxo-5, 7-dihydrofuran [3,4-b ] pyridin-2-yl) -4-methylpiperidine-4-carboxylic acid

2-chloro-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (1.65g, 8.53mmol) and 4-fluoropiperidinecarboxylic acid (1.22g,8.53mmol as starting materials were dissolved in 20mL of ethanol, DIPEA (3.3mL,25.59mmol) were added thereto and the mixture was refluxed overnight, the reaction was monitored by TLC (oil ether/ethyl acetate ═ 5/1), after completion of the reaction, low-boiling ethanol was distilled off, 5mL of water was added, dichloromethane was extracted (2 × 100mL), the organic phases were combined, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate ═ 2/1) and dried under vacuum to give 1.6g of a white solid with a yield of 70%.¹H NMR(400MHz,CDCl₃)δ8.20(s,1H),5.11(s,2H),4.42(d,J＝14.0Hz,2H),3.51(t,J＝12.3Hz,2H),2.32(d,J＝13.7Hz,2H),1.62(t,J＝10.6Hz,2H),1.36(s,3H).MS(ESI)m/z:302.1[M+H]⁺.

(b) Preparation of N- (benzylsulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -4-methylpiperidine-4-carboxamide

1- (3-cyano-5-oxo-5, 7-dihydrofuran [3, 4-b)]Pyridin-2-yl) -4-methylpiperidine-4-carboxylic acid (80mg,0.26mmol) was dissolved in 5ml of dichloromethane, EDCI (99mg,0.52mmol), HOBt (70mg,0.52mmol) and DIPEA (101mg,0.78mmol) were added thereto, the mixture was stirred at room temperature under Ar gas, and after stirring for about 45 minutes, benzylsulfonamide (45mg,0.26mmol) was added thereto, and the mixture was stirred at room temperature. The reaction was monitored by TLC (DCM/MeOH) ═ 20/1), and after completion of the reaction, the solvent was distilled off. Column chromatography (DCM/MeOH ═ 30/1) afforded 92mg of a white solid in 78% yield.¹H NMR(500MHz,DMSO)δ11.35(s,1H),8.55(s,1H),7.40–7.37(m,3H),7.34–7.31(m,2H),5.26–5.25(m,2H),4.76(s,2H),4.07–4.02(m,2H),3.58–3.52(m,2H),2.16–2.10(m,2H),2.02–1.97(m,1H),1.59–1.53(m,2H),1.18(s,3H).¹³C NMR(126MHz,DMSO)δ176.41,170.71,167.67,161.37,143.26,130.72,129.62,128.66,128.51,117.45,108.14,92.90,69.87,57.86,44.72,42.19,33.16,23.14.MS(ESI)m/z:453.2[M-H]^-.

EXAMPLE 42 1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -4-methyl-N- ((1-phenylethyl) sulfonyl) piperidine-4-carboxamide (Compound 42)

1- (3-cyano-5-oxo-5, 7-dihydrofuran [3, 4-b)]Pyridin-2-yl) -4-methylpiperidine-4-carboxylic acid (100mg,0.33mmol) was dissolved in 10mL of dichloromethane, EDCI (95mg,0.50mmol), HOBt (68mg,0.50mmol) and DIPEA (101mg,0.99mmol) were added thereto, the mixture was stirred at room temperature under Ar gas, and after stirring for about 45 minutes, 1-phenylethane-1-sulfonamide (62mg,0.33mmol) was added and the mixture was stirred at room temperature. The reaction was monitored by TLC (DCM/MeOH) ═ 20/1), and after completion of the reaction, the solvent was distilled off. Column chromatography (DCM/MeOH ═ 30/1) afforded 120mg of a white solid in 78% yield.¹H NMR(500MHz,DMSO)δ11.32(s,1H),8.54(s,1H),7.41–7.34(m,5H),5.25(s,2H),4.90(q,J＝6.6Hz,J＝6.5,1H),4.10–3.95(m,2H),3.58–3.37(m,2H),2.16–2.03(m,2H),1.68(d,J＝5.4Hz,2H),1.58–1.45(m,2H),1.12(s,3H).¹³C NMR(126MHz,DMSO)δ176.30,170.72,167.68,161.34,143.26,134.29,129.10,128.82,128.47,117.45,92.87,69.87,62.02,44.73,33.12,23.14,15.00.MS(ESI)m/z:467.2[M-H]^-.

EXAMPLE 43 (R) -N- (benzylsulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) pyrrolidine-3-carboxamide (Compound 43)

(a) R-3- ((benzylsulfonyl) carbamoyl) pyrrolidine-1-carboxylic acid tert-butyl ester

Prepared as in (b) of example 1 starting from R-1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid (0.5g, 2.3mmol) and benzylsulfonamide (0.55g, 2.9mmol) and dried in vacuo to give 0.6g of a white solid in 44% yield.¹H NMR(400MHz,DMSO-d₆)δ11.70(s,1H),7.40(dd,J＝5.0,1.8Hz,3H),7.32–7.26(m,2H),4.70(s,2H),3.46–3.33(m,2H),3.27–3.16(m,2H),3.03–2.92(m,1H),2.06–1.94(m,2H),1.41(s,9H).(ESI)m/z:369.1[M+H]⁺.

(b) R-N- (benzylsulfonyl) pyrrolidine-3-carboxamide

Prepared by the method of (c) in example 1 starting from tert-butyl R-3- ((benzylsulfonyl) carbamoyl) pyrrolidine-1-carboxylate (0.55g, 1.49mmol) and dried in vacuo to give 0.30g of a white solid in 75% yield.¹H NMR(400MHz,DMSO-d₆)δ8.57(s,1H),7.30–7.20(m,5H),4.26(s,2H),3.29–3.25(m,2H),3.12–3.05(m,2H),2.82–2.74(m,1H),1.99–1.90(m,2H).(ESI)m/z:269.1[M+H]⁺.

(c) Preparation of (R) -N- (benzylsulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) pyrrolidine-3-carboxamide

R-N- (benzylsulfonyl) pyrrolidine-3-carboxamide (80mg, 0.30mmol) and 2-chloro-5-oxo-5, 7-dihydrofuro [3,4-b ]]Pyridine-3-carbonitrile (58mg, 0.30mmol) was prepared as starting material in example 5 (g) and dried in vacuo to give 72mg of a white solid in 57% yield.¹H NMR(400MHz,DMSO-d₆)δ11.89(s,1H),8.53(s,1H),7.40–7.35(m,3H),7.30(dd,J＝6.3,3.0Hz,2H),5.26(s,2H),4.71(s,2H),3.98–3.80(m,4H),3.22–3.13(m,1H),2.27–2.06(m,2H).¹³C NMR(126MHz,DMSO-d₆)δ172.50,171.16,167.91,157.83,143.04,130.62,129.14,128.62,128.57,128.52,117.96,106.89,90.90,69.83,57.53,51.16,48.70,28.13.MS(ESI)m/z:439.1[M-H]^-.

EXAMPLE 44 sodium N- ((4-chlorobenzyl) sulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3,4-b ] pyridin-2-yl) -4-fluoropiperidine-4-carboxylate (compound 44)

N- ((4-chlorobenzyl) sulfonyl) -1- (3-cyano-5-oxo-5, 7-dihydrofuro [3, 4-b)]Pyridin-2-yl) -4-fluoropiperidine-4-carboxamide (0.3g,0.61mmol) was dissolved in 3.5ml of THF and H₂To a mixed solvent of O (v/v ═ 2.5:1), 2M NaOH (0.35ml,1.15eq) was slowly added dropwise, and a solid precipitated with no more progress. Heating the mixture to 50 ℃ in an oil bath to clarify the reaction solution, and naturally cooling the reaction solution to room temperature to precipitate a solid. The precipitated solid was filtered, slurried in isopropanol, filtered and vacuum dried to give 0.25g of a white solid in 82% yield.¹H NMR(500MHz,DMSO-d₆)δ8.51(s,1H),7.43(d,J＝8.2Hz,2H),7.31(d,J＝8.3Hz,2H),5.28(s,2H),4.75(s,2H),4.51(d,J＝13.6Hz,2H),3.47–3.40(m,2H),2.25–2.09(m,1H),2.05–1.98(m,2H).¹³C NMR(126MHz,DMSO-d₆)δ170.75,170.01,167.66,161.50,143.28,133.60,132.58,128.64,128.06,117.35,108.75,94.16,93.41,92.66,69.96,56.91,43.28,31.45,31.27.MS(ESI)m/z:513.0[M-H]^-.

Biological activity assay

1. Evaluation of inhibitory Effect of representative Compounds of the present invention on human platelet aggregation

a) Purpose of experiment

In the research, the influence of the compound on the function of the human platelet is observed through a platelet aggregation experiment, and the inhibition effect of the compound with different concentrations and the positive drug on the platelet aggregation is detected. The antiplatelet effect of the compounds of the present invention was evaluated by measuring the inhibition rate of platelet aggregation by different concentrations of the compounds.

b) Experimental methods

Whole blood of volunteers was sampled for venous blood anticoagulated with L: 6D citric acid ACD (85mmol/L sodium citrate, 71.38mmol/L citric acid, 27.78mmol/L glucose), centrifuged at 300g for 10 minutes at room temperature, and platelet-rich plasma (PRP) was isolated. A turbidimetric platelet aggregation test is carried out on a dual-channel optical platelet aggregation instrument of Chono-Log company, the walking speed of an icon recorder is set to be 1cm/min, and an aggregation curve is recorded. Firstly, preheating a platelet aggregation instrument to 37 ℃, adding 400 mu L of platelet suspension and a stirrer into a turbidimetric tube, taking PPP as a reference, tracing a baseline under constant-temperature and constant-speed magnetic stirring at 37 ℃, adding antagonists or other reagents with different concentrations to treat platelets for 2 minutes according to an experimental plan after the baseline is stable, and then adding an inducer ADP (ADP system concentration is 10 mu mol/L) to observe and record the change of an aggregation curve.

c) Experimental data processing

The concentration of the positive control drug AZD-1283 and the concentration of the experimental group are set to be 3, 10, 30, 100 and 300 mu M in the experiment. The measurement was repeated three times for each compound to obtain IC₅₀. DMSO was also used as a solvent control. The platelet aggregation inhibition rate was calculated as follows: inhibition (%) - (control tube maximum aggregation-test tube maximum aggregation)/control tube maximum aggregation]×100％。

TABLE 2 Activity data of the present invention on ADP (adenosine diphosphate) -induced platelet aggregation rates

Compound (I)	IC50(μM)
		5	3.52±1.38
9	2.30±0.49
		29	2.949
32	3.0049
		33	2.2±0.82
AZD-1283	3.68±0.52

As can be seen from the data in Table 2, the representative compound of the invention has good biological activity, and the in vitro anti-platelet aggregation activity of the compounds 5, 9, 29, 32 and 33 is obviously superior to that of AZD-1283.

2. Study on inhibition of the representative Compounds of the present invention against the major subtypes of CYP enzymes

a) Purpose of experiment

Cytochrome P405 enzymes are the major enzyme system for drug metabolism in the human body. When used with other drugs, inhibitors of CYP450 enzymes may alter the metabolic parameters of the other drug and thereby cause potential drug-drug interactions. The lead compound AZD-1283 has strong inhibition effect on CYP2C9 and CYP3A4 enzymes, and has drug interaction risk. This experiment measures the inhibitory activity of the compounds of the invention on the major subtypes of CYP450 enzymes to assess the risk of potential drug interactions.

b) Experimental methods

The incubation system was performed in a total volume of 200. mu.l in 100nM phosphate buffered saline (PBS, pH 7.4) containing the recombinant enzyme, test compound and 1mM NADPH (reduced coenzyme II) at a final concentration of 25 pmol/ml. And (3) incubating by adopting a water bath at 37 ℃, initiating the reaction after incubating for 5min, and adding acetonitrile with the same volume to stop the reaction after reacting for a certain time. Respectively taking phenacetin, tolbutamide, s-mephenytoin, dextromethorphan, midazolam and testosterone, carrying out vortex mixing, adding 25 mu l of internal standard solution and 225 mu l of methanol, carrying out vortex mixing for 1min, centrifuging for 5min, taking supernatant, carrying out blow-drying under air flow at 40 ℃, adding 150 mu l of mobile phase into residue, carrying out vortex mixing for 1min, and absorbing 20 mu l for LC/MS/MS analysis.

c) Experimental data processing

The test compounds were examined for inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 enzymes, and IC was determined₅₀(50% inhibition of enzyme Activity by concentration of test Compound)

TABLE 3 inhibition of CYP enzymes by some of the compounds of the invention

Note: a: taking phenacetin as a substrate; b: toluene yellow butylurea is taken as a substrate; c: s-mephenytoin is taken as a substrate; d: dextromethorphan is used as a substrate; e: taking midazolam as a substrate; f: testosterone is taken as a substrate;

as can be seen from the data in Table 3, the compound of the invention has no inhibitory activity on the main subtypes of CYP enzymes, no clinical drug interaction risk exists, and the druggability is better.

3. Stability test of partial Compounds of the invention against rat and human liver microsomes

a) Purpose of experiment

One of the reasons for clinical termination of the lead compound AZD-1283 is metabolic instability, and in order to examine the metabolic properties of the compound of the present invention, the representative compound was subjected to microsome stability experiments in rat and human liver.

b) Experimental methods

Rat and human liver microsomes were used for this experiment, and the incubation method was as follows: the microsomes were placed in 0.1mol/l tris (hydroxymethyl) aminomethane/hydrochloric acid buffer (pH 7.4) to a final concentration of microsomal protein of 0.33mg/ml, followed by addition of the cofactor MgCl₂(5nM), test animals (final concentration 0.1. mu. mol/l, 0.01% dimethyl sulfoxide, 0.005% bovine serum albumin) and reduced coenzyme II, incubated at 37 ℃ for 60 min. The reaction is started when liver microsomes, test compounds or NADPH (reduced coenzyme II) are added. Samples were taken at 0, 7, 17, 30 and 60min of incubation and the enzymatic reaction was stopped by precipitation of the protein by addition of methanol. After centrifugation, the samples were analyzed by LC/MS/MS. The metabolic stability of the test compounds was evaluated by measuring their in vitro half-life and hepatic microsomal clearance.

c) Data processing

The data acquisition and control system software is analyst1.5.1 software (Applied Biosystem). The peak integration mode of the atlas sample is automatic integration; and (4) taking the ratio of the peak area of the sample to the peak area of the internal standard as an index, and performing regression with the concentration of the sample. The regression mode is as follows: and (6) linear regression. Pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin Professional v6.3(Pharsight, USA).

TABLE 4 half-life and clearance of representative compounds of the invention in rat and human liver microparticles

Note: t is_1/2: a half-life; cl_intc: intrinsic clearance; MF: metabolic bioavailability

As can be seen from Table 4, the stability of the compound represented by the invention part in rat and human liver particles is greatly superior to that of the lead compound AZD-1283. AZD-1283 is particularly unstable in rat liver microsomes.

4. In vivo pharmacokinetic assay of representative Compounds of the invention in rats

a) Purpose of experiment

One of the reasons for clinical termination of the lead compound AZD-1283 is poor metabolism. In order to examine the pharmacokinetics condition in the representative compound of the invention, an in vivo pharmacokinetic experiment was conducted in rats

b) Experimental methods

Healthy male SD rats 6 with the weight of 200-220g are prepared by 5% DMSO/95% sodium carboxymethyl cellulose (0.5%) as a solution for intragastric administration, the administration dose is 5mg/kg, the administration volume is 10ml/kg, and the collection time points of the test compound intragastric administration group are as follows: pre-subject and 0.25, 0.5, 1,2, 4, 8 and 24h post-subject. Blood samples were collected on ice and plasma was centrifuged within 1 hour (centrifugation conditions: 5000 rpm, 10 minutes, 4 ℃). The collected plasma was stored in a-20 ℃ freezer before analysis.

c) Data processing

The data acquisition and control system software is analyst1.5.1 software (Applied Biosystem). The peak integration mode of the atlas sample is automatic integration; and (4) taking the ratio of the peak area of the sample to the peak area of the internal standard as an index, and performing regression with the concentration of the sample. The regression mode is as follows: and (6) linear regression. Pharmacokinetic parameters were assigned using a non-compartmental model using WinNonlin Professional v6.3(Pharsight, USA)And (6) performing analysis treatment. C_maxThe area AUC (0 → T) under the curve of blood concentration-time is calculated by trapezoidal method for the maximum blood concentration measured, T_maxIs the time of peak blood concentration after administration. The experimental data are expressed as "Mean. + -. standard deviation" (Mean. + -. SD, n. gtoreq.3) or "Mean" (Mean, n. gtoreq.2).

c) Experimental results (Table 5)

TABLE 5 Primary pharmacokinetic parameters of Compounds representative of the invention after gastric gavage in SD rats

Note: t is_max: time to peak; t is_1/2: a half-life; c_max: maximum blood concentration; AUC: area under the plasma concentration-time curve; MRT: average residence time;

the results of the five-drug experiments show that the compound has ideal metabolic characteristics, the drug exposure and the maximum blood concentration of the compound are improved by more than 10 times, and the pharmacokinetic performance of the compound is far better than that of a positive control drug AZD-1283.

5. In vivo anticoagulant Activity test of representative Compounds of the invention

a) Purpose of experiment

The inhibition effect of the series of representative compounds 32 on rat carotid artery thrombosis is evaluated, and the in vivo antithrombotic activity of the compounds is preliminarily screened.

b) Experimental methods

Rats, 110, were acclimatized overnight in the laboratory, fasted for 8 hours, room temperature 22. + -. 2 ℃ and humidity 60%. No abnormal reaction is observed in the adaptation period. Rats were randomly divided into 11 groups of 10 rats each, each group consisting of a model control group of 0.5% CMC-Na (sodium carboxymethylcellulose), a compound 32 different dose group (2.5,5,10,20,40,80mg/kg), and a clopidogrel different dose group (2.5,5,10,20mg/kg), according to sex and body weight. Weighing a certain amount of corresponding compounds, grinding, suspending with 0.5% CMC-Na solution, and performing intragastric administration according to the volume of 10 ml/kg. After the rat is administrated by stomach filling for 90min, 2 percent sodium pentobarbital is used for intraperitoneal injection and anesthesia (50mg/kg), the supine fixation is carried out,incising neck skin, separating left carotid artery 1.5cm long by blunt, placing 1.0 × 1.5cm plastic strip to protect nearby tissue, and soaking with 20% FeCl₃A20. mu.l strip of filter paper (0.8X 1.0cm) of the solution was wrapped around the isolated common carotid artery and sealed with a plastic strip. After 10min, the filter paper strip was removed and rinsed 3 times with a cotton ball soaked with physiological saline to allow thrombosis to form for 30 min.

c) Observation index and calculation

Thrombus weight: when the experiment is completed, ligating blood vessels at two ends of the filter paper by using a cotton rope, accurately cutting off a blood vessel section (0.8cm) wrapped by the filter paper strip, sucking residual blood in the blood vessel by using clean filter paper, accurately weighing the weight of the blood vessel containing thrombus, weighing the weight after taking out the thrombus, and subtracting the two weights to obtain the weight of the thrombus.

d) Data processing and statistical analysis

The data are expressed as mean value plus or minus standard deviation (x plus or minus s), statistical analysis is carried out on the data by Student-t test, and p <0.05 is the statistical difference.

e) Experimental results (Table 6)

TABLE 6 in vivo antithrombotic drug efficacy test results for inventive compound 32

(^*P≤0.05；^**P≤0.01；^***P≤0.001)

The experimental result proves that the compound has strong antithrombotic bioactivity, the lowest effective dose is only 5mg/kg, and the drug effect has good dose dependence.

6. Evaluation of bleeding Risk in vivo test for representative Compounds of the invention

a) Purpose of experiment

Through a rat tail-broken bleeding time experiment, the influence of different doses of the compound 32 and clopidogrel on the bleeding time of rats 90min after administration is observed.

b) Experimental methods

Rats, 100, were acclimatized overnight in the laboratory to fasting for 8 hours at room temperature 22. + -. 2 ℃ and 60% humidity. No abnormal reaction is observed in the adaptation period. Rats were randomly divided into 10 groups of 10 rats each based on sex and body weight, and each group was a model control group of 0.5% CMC-Na (sodium carboxymethylcellulose), a compound 32 different dose group (2.5,5,10,20,40mg/kg) and a clopidogrel different dose group (2.5,5,10,20 mg/kg). Weighing a certain amount of corresponding compounds, grinding, suspending with 0.5% CMC-Na solution, and performing intragastric administration according to the volume of 10 ml/kg. After 90min of intragastric administration to rats, 2% sodium pentobarbital was used for intraperitoneal injection for anesthesia (50 mg/kg). After anaesthesia, the tail was fixed to a rat board and disinfected with iodine and alcohol. Pre-warming rat tail in 37 deg.C physiological saline for 3min, and cutting off at a distance of 4mm from tail tip of rat tail with scalpel to induce bleeding. The 3cm tail of the tail tip part was vertically immersed in physiological saline at 37 ℃ to observe bleeding.

c) Observation index and calculation

The "bleeding time" from the time of transection of the rat tail to the time when bleeding completely stopped (no more blood was flowing out at the transection at the tip of the tail, and continued for at least 30 seconds) was recorded on a stopwatch.

d) Data processing and statistical analysis

The data are expressed as mean ± standard deviation (x ± s), and statistical analysis is performed on the data by Student-test, and p <0.05 is the statistical difference.

e) Experimental results Table 7

TABLE 7 evaluation of the in vivo bleeding Risk test results for Compound 32 representative of the invention

(^*P≤0.05；^**P≤0.01；^***P≤0.001)

As can be seen from tables 6 and 7, the compound 32 of the present invention has significant, dose-dependent antithrombotic effect, and more importantly, the ED of the compound 32 of the present invention and clopidogrel at the bleeding time in the tail-biting experiment of rats₁₀₀Respectively as follows: 7.58mg/kg and 2.36mg/kg, which shows that the compound of the invention has lower bleeding risk than clopidogrel and higher safety.

The clinical daily dose of clopidogrel is 75 mg/tablet, and the corresponding average thrombus inhibition activity is about 60% (Thrombosi research 134(2014) 693-703). As can be seen from table 8, when the same in vivo thrombus-inhibiting activities (57%) of rats were the same, the bleeding time and amount of the compound of the present invention were significantly lower than those of clopidogrel, suggesting that the bleeding risk of the compound of the present invention was significantly lower than that of clopidogrel, the therapeutic window was wider than that of clopidogrel, and the safety was higher.

TABLE 8 comparison of in vivo efficacy and bleeding time of representative Compound 32 of the invention and clopidogrel

(^***P≤0.001)

In conclusion, the compound overcomes the defects of the existing medicines, has good medicine property and safety, is expected to become an antiplatelet medicine for long-term oral administration, and is used for preventing or treating diseases related to thrombus.

Claims (10)

1. A compound shown in a general formula (I), enantiomers, diastereoisomers, racemes and mixtures thereof, and pharmaceutically acceptable salts thereof,

wherein the content of the first and second substances,

R₁selected from hydrogen or C₁-C₆An alkyl group;

R₂selected from H, halogen, C₁-C₆Alkyl, hydroxy, C₁-C₆An alkoxy group;

R₃is selected from substituted or unsubstituted 5-7 membered aromatic heterocyclic group, and the substituent is selected from halogen and C₁-C₆One or more of alkyl, cyano, trifluoromethyl, said aromatic heterocyclic group containing one or more heteroatoms selected from N, O, S; or

Wherein R is₆And R₇Each independently selected from hydrogen and C₁-C₆Alkyl, halogen, or R₆、R₇Together with the linking carbon atom to form a 3-6 membered alicyclic ring, R₈Selected from substituted or unsubstituted C₆-C₁₂Aryl or substituted or unsubstituted C₆-C₁₂Aralkyl, said substituent being selected from halogen, cyano, C₁-C₆Alkyl radical, C₁-C₆One or more of alkoxy, trifluoromethyl;

x is O,

Preferably X is O;

R₄is H or halogen; r₅Is H or C₁-C₆An alkyl group;

n is 0, 1 or 2; preferably n is 0 or 1;

the B ring is 4-8 membered saturated nitrogen heterocycle.

2. The compound of the general formula (I), its enantiomers, diastereomers, racemates and mixtures thereof according to claim 1, and pharmaceutically acceptable salts thereof, wherein,

R₁selected from hydrogen or C₁-C₆An alkyl group;

R₂selected from H, halogen, C₁-C₆Alkyl, hydroxy, C₁-C₆An alkoxy group;

R₃is selected from substituted or unsubstituted 5-7 membered aromatic heterocyclic group, and the substituent is selected from halogen and C₁-C₆One or more of alkyl, cyano, trifluoromethyl, said aromatic heterocyclic group containing one or more heteroatoms selected from N, O, S; or

Wherein R is₆And R₇Each independently selected from hydrogen and C₁-C₆Alkyl, halogen, or R₆、R₇Together with the linking carbon atom to form a 3-6 membered alicyclic ring, R₈Selected from substituted or unsubstituted C₆-C₁₂Aryl or substituted or unsubstituted C₆-C₁₂Aralkyl, said substituent being selected from halogen, cyano, C₁-C₆Alkyl radical, C₁-C₆1,2 or 3 of alkoxy, trifluoromethyl,

x is O,

R₄Is H or halogen; r₅Is H or C₁-C₆An alkyl group;

n is 0, 1 or 2;

the B ring is 4-6 membered saturated nitrogen heterocycle.

3. The compound of the general formula (I), its enantiomers, diastereomers, racemates and mixtures thereof according to claim 1, and pharmaceutically acceptable salts thereof, wherein,

R₁selected from hydrogen or C₁-C₆An alkyl group;

R₂selected from H, halogen, C₁-C₆Alkyl, hydroxy, C₁-C₆An alkoxy group;

R₃is selected from substituted or unsubstituted 5-7 membered aromatic heterocyclic group, and the substituent is selected from halogen and C₁-C₆One or more of alkyl, cyano, trifluoromethyl, said aromatic heterocyclic group containing one or more heteroatoms selected from N, O, S; or

Wherein R is₆And R₇Each independently selected from hydrogen and C₁-C₆Alkyl, halogen, or R₆、R₇Together with the linking carbon atom to form a 3-6 membered alicyclic ring, R₈Selected from substituted or unsubstituted phenyl or substituted or unsubstituted benzylThe substituent is selected from halogen, cyano and C₁-C₃One or more, preferably 1,2 or 3, alkyl, trifluoromethyl;

x is O,

Preferably, X is O;

R₄is H or halogen; preferably H, fluorine or chlorine;

R₅is H or C₁-C₆Alkyl, preferably H, methyl, ethyl or propyl;

n is 0, 1 or 2; preferably n is 0 or 1;

the B ring is a 4-6 membered saturated azacyclo, preferably an azetidine ring, a pyrrolidine ring or a piperidine ring.

4. The compound of the general formula (I), its enantiomers, diastereomers, racemates and mixtures thereof according to claim 1, and pharmaceutically acceptable salts thereof, wherein,

R₁selected from hydrogen, methyl, ethyl or propyl;

R₂selected from H, halogen, C₁-C₃Alkyl, hydroxy, C₁-C₃An alkoxy group;

R₃selected from unsubstituted or halogen-substituted thienyl, or

Wherein R is₆And R₇Each independently selected from hydrogen and C₁-C₆Alkyl, halogen, or R₆、R₇Together with the linking carbon atom to form a 3-6 membered alicyclic ring, R₉Represents a group selected from hydrogen, halogen, cyano, C₁-C₆Alkyl radical, C₁-C₆One or more, preferably 1,2 or 3, substituents of alkoxy, trifluoromethyl;

x is O,

Preferably, X is O;

R₄is H or halogen; preferably H, fluorine or chlorine;

R₅is H or C₁-C₆Alkyl, preferably H, methyl, ethyl or propyl;

n is 0, 1 or 2;

the B ring is a 4-6 membered saturated azacyclo, preferably an azetidine ring, a pyrrolidine ring or a piperidine ring.

5. The compound of the general formula (I), its enantiomers, diastereomers, racemates and mixtures thereof according to claim 1, and pharmaceutically acceptable salts thereof, wherein,

R₁selected from hydrogen, methyl, ethyl or propyl;

R₂selected from H, halogen, C₁-C₃Alkyl, hydroxy, C₁-C₃An alkoxy group;

R₃selected from unsubstituted or fluorine-or chlorine-substituted thienyl, or

Wherein R is₆And R₇Each independently selected from hydrogen and C₁-C₃Alkyl, fluoro, chloro, or R₆、R₇Together with the linking carbon atom to form a 3-6 membered alicyclic ring, R₉Represents hydrogen, fluorine, chlorine, cyano, C₁-C₃One or more, preferably 1,2 or 3, substituents of alkyl, trifluoromethyl;

x is O,

Preferably, X is O;

R₄is H or halogen; preferably H, fluorine or chlorine;

R₅is H or C₁-C₆Alkyl, preferably H, methyl, ethyl or propyl;

n is 0, 1 or 2;

the B ring is a 4-6 membered saturated azacyclo, preferably an azetidine ring, a pyrrolidine ring or a piperidine ring.

6. The compound of the general formula (I), its enantiomers, diastereomers, racemates and mixtures thereof as well as pharmaceutically acceptable salts thereof according to any one of claims 1 to 5, wherein the compound of the general formula (I) is a compound of the following general formula (II):

wherein R is₁、R₂、R₃X and n are as defined in the corresponding claims 1 to 5, Y and Z are each independently selected from the group consisting of methylene, ethylene, propylene and butylene;

alternatively, the compound represented by the general formula (I) is the following compound:

wherein R is₁、R₂、R₃X and n are as defined in the corresponding claims 1 to 5.

7. The compound of general formula (I), its enantiomers, diastereomers, racemates and mixtures thereof according to any one of claims 1 to 5, as well as pharmaceutically acceptable salts thereof, wherein the compound is selected from the group consisting of:

the enantiomers for example comprise

The pharmaceutically acceptable salt for example comprises

8. A process for the preparation of a compound of general formula (I) according to any one of claims 1 to 7, wherein said process is selected from one of the following routes:

route 1

Wherein R is₂、R₃、R₅And ring B is as defined in the corresponding claims 1 to 7,

(a) reacting compound A with sulfonamide R₃S(＝O)₂NH₂In the presence of a condensing agent and organic base or inorganic base, taking a polar aprotic solvent as a solvent to react to obtain a compound I-1;

(b) removing a tert-butoxycarbonyl protecting group from the compound I-1 in a polar aprotic solvent under the action of acid to obtain a compound I-2;

(c) reacting the compound I-3 with trimethyl orthoformate in the presence of anhydride to generate a corresponding compound I-4;

(d) reacting the compound I-4 with cyanoacetamide in a polar protic solvent in the presence of organic base or inorganic base to generate a corresponding compound I-5;

(e) adding acyl chloride and DMF into the compound I-5 in a polar aprotic solvent to perform catalytic reaction to generate a corresponding compound I-6;

(f) reacting the compound I-6 with the compound I-2 in a polar protic solvent in the presence of an organic base to generate a corresponding compound I-7;

(g) compound I-7 with Ammonia or C₁-C₆Alkylamine aqueous solution reacts in a polar solvent to generate a compound I-I;

route 2

Wherein R is₂、R₃、R₄And ring B is as defined in the corresponding claims 1 to 7,

(a) reacting 1, 3-cyclohexanedione with N, N-dimethylformamide dimethyl acetal to generate a corresponding compound II-1;

(b) reacting the compound II-1 with malononitrile in a polar aprotic solvent in the presence of an inorganic base to generate a corresponding compound II-2;

(c) reacting the compound II-2 with a halogenating reagent in a polar aprotic solvent to generate a compound II-3;

(d) adding acyl chloride and DMF into the compound II-3 in a polar solvent to perform catalytic reaction to generate a corresponding compound II-4;

(e) reacting the compound II-4 with the compound I-2 obtained in the route 1 in a polar protic solvent in the presence of an organic base to generate a compound I-II;

route 3

Wherein R is₁、R₂、R₃And ring B is as defined in the corresponding claims 1 to 7,

(a) reacting the compound III-1 with benzyl alcohol in a polar solvent in the presence of strong base to obtain a compound III-2;

(b) the compound III-2 reacts in a polar protic solvent under the action of Pd/C to remove a benzyl protecting group, so that a compound III-3 is obtained;

(c) reacting the compound III-3 with TBSCl in a polar aprotic solvent in the presence of an organic base to generate a corresponding compound III-4;

(d) reacting the compound III-4 with N, N-dimethylformamide dimethyl acetal to generate a corresponding compound III-5;

(e) reacting the compound III-5 with cyanoacetamide in a polar aprotic solvent in the presence of an organic base to generate a corresponding compound III-6;

(f) reacting the compound III-6 with a fluorinating reagent in a polar aprotic solvent to generate a corresponding compound III-7;

(g) hydrolyzing the compound III-7 in a polar solvent in the presence of strong base to obtain a compound III-8;

(h) reacting the compound III-8 in the presence of phosphorus oxychloride to generate a corresponding compound III-9;

(i) reacting the compound III-9 with the compound I-2 obtained in the scheme 1 in a polar protic solvent in the presence of an organic base to generate a compound I-III;

route 4

Wherein, ring B and R₃Are as defined in the corresponding claims 1 to 7,

(a) reacting the compound IV-1 with benzyloxy chloromethane in a polar aprotic solvent in the presence of strong base to generate a compound IV-2;

(b) the compound IV-2 reacts in a polar protic solvent in the presence of Pd/C to remove a benzyl protecting group, so that a compound IV-3 is obtained;

(c) reacting the compound IV-3 with TBSCl in a polar aprotic solvent in the presence of an organic base to generate a corresponding compound IV-4;

(d) reacting the compound IV-4 with N, N-dimethylformamide dimethyl acetal to generate a corresponding compound IV-5;

(e) reacting the compound IV-5 with cyanoacetamide in a polar aprotic solvent in the presence of an organic base to generate a corresponding compound IV-6;

(f) reacting the compound IV-6 with a fluorinating reagent in a polar aprotic solvent to generate a corresponding compound IV-7;

(g) hydrolyzing the compound IV-7 in a polar protic solvent in the presence of strong base to obtain a compound IV-8;

(h) reacting the compound IV-8 in the presence of phosphorus oxychloride to generate a corresponding compound IV-9;

(i) reacting the compound IV-9 with the compound I-2 obtained in the scheme 1 in a polar protic solvent in the presence of an organic base to generate a compound I-IV;

route 5

Wherein R is₂、R₆、R₇And R₈Are as defined in the corresponding claims 1 to 7,

(a) reacting the compound V-1 with bis (3, 4-dimethylbenzyl) amine in a polar aprotic solvent in the presence of an organic base to generate a corresponding compound V-2;

(b) reacting the compound V-2 with a fluorinating reagent or an alkylating reagent in a polar aprotic solvent in the presence of a strong base to generate a compound V-3;

(c) reacting the compound V-3 with an acid in a polar aprotic solvent to form a compound V-4;

(d) reacting the compound III-9 obtained in the route 3 with piperidinecarboxylic acid in a polar protic solvent in the presence of an organic base to form a corresponding compound V-5;

(e) reacting the compounds V-5 and V-4 with a polar aprotic solvent as a solvent under the conditions of a condensing agent and organic base or inorganic base to obtain compounds I-V;

route 6

Wherein R is₂Are as defined in the corresponding claims 1 to 7, R₉Are as defined in the corresponding claims 4 to 7,

(a) reacting the compound VI-1 with thiourea in a polar protic solvent to obtain a corresponding compound VI-2;

(b) reacting the compound VI-2 with a chlorinating agent in a polar aprotic solvent to obtain a corresponding compound VI-3;

(c) reacting the compound VI-3 with ammonia water in a polar aprotic solvent to obtain a corresponding compound VI-4;

(d) compound VI-4 and

in the presence of a condensing agent and organic base or inorganic base, taking a polar aprotic solvent as a solvent to react to obtain a compound VI-5;

(e) removing a tert-butoxycarbonyl protecting group from the compound VI-5 in a polar aprotic solvent in the presence of an acid to obtain a compound VI-6;

(f) reacting the compound VI-6 with the compound III-9 obtained in the scheme 3 in a polar protic solvent in the presence of an organic base to generate a corresponding compound I-VI;

route 7

Wherein R is₂、R₉The definitions are the same as in the corresponding claims 4 to 7;

(a) reacting compound III-9 prepared according to scheme 3 with 4-fluoropiperidinecarboxylic acid in a polar protic solvent in the presence of an organic base to form the corresponding compound VII-1;

(b) adding acyl chloride into a polar aprotic solvent to obtain a compound VII-1, and carrying out a catalytic reaction on DMF to obtain a corresponding compound VII-2;

(c-1) reacting compound VII-2 with compound VI-4 prepared in scheme 6 in a polar aprotic solvent in the presence of an organic base to form compound I-VII;

(c-2) reacting the compound VII-2 with 5-chlorothiophene-2-sulfonamide in a polar aprotic solvent in the presence of an organic base to produce a compound 36.

9. A pharmaceutical composition comprising one or more selected from the compounds of any one of claims 1 to 8, enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier or excipient.

10. Use of a compound according to any one of claims 1 to 8, enantiomers, diastereomers, racemates thereof and mixtures thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 9 for the manufacture of a medicament for the prophylaxis or treatment of thromboembolic disorders, in particular coronary syndrome (ACS), stroke, coronary heart disease, atrial fibrillation.