A plasmin inhibitor, its preparation method and application

Abstract

The invention relates to compounds of formula (I) that can inhibit plasmin activity and have coagulation and hemostatic activities, including pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, wherein R1 to R3 are as defined in the specification.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, specifically to a plasmin inhibitor, its preparation method, and its application in the pharmaceutical field. Background Technology

[0002] Plasmin is a proteolytic enzyme that degrades fibrin. When tissue damage causes blood vessel rupture, it triggers hemostasis mechanisms: vasoconstriction, platelet embolism, and the initiation of coagulation, ultimately leading to the formation of stable fibrin. Simultaneously, due to fibrin deposition, the fibrinolytic system is activated. This system maintains a balance between fibrin formation and breakdown, playing a role in maintaining vascular patency and remodeling damaged tissue during the repair of damaged blood vessel walls (Tengborn L, M, Berntorp E. Thromb Res. 2015 Feb; 135(2):231-42).

[0003] The fibrinolytic system includes plasminogen, tissue-type plasminogen activator (tPA), and urokinase-type plasminogen activator (uPA). Plasminogen binds to lysine residues on the fibrin surface and is converted into plasmin via an activator (i.e., tPA) released from endothelial cells. Fibrinolysis inhibition can be used to treat bleeding. The use of antifibrinolytic drugs can reduce blood loss in cardiac surgery, trauma, orthopedic surgery, solid organ transplantation, obstetrics and gynecology, neurosurgery, and non-surgical conditions (Ng W, Jerath A, ...). M. Anaesthesiol Intensive Ther. 2015; 47(4):339-50). In the early 1950s, it was discovered that lysine amino acids inhibited the activation of plasminogen, but the effect was too weak to be used to treat fibrinolytic hemorrhage. In 1953, Shosuke Okamoto et al. showed that several thiol groups and aminocarbonates had anti-plasma protein effects, and found that the synthetic derivative of lysine, ε-aminohexanoic acid (EACA), had a strong inhibitory effect on plasminogen. EACA has been widely used in clinical practice, but in addition to mild gastrointestinal side effects such as nausea, a larger dose is required. In 1962, 4-amino-methyl-cyclohexane-carbonic acid (AMCHA) was discovered. This compound contains two stereoisomers. Further studies showed that its trans form (trans-4-aminomethylcyclohexanecarboxylic acid, i.e., tranexamic acid, TXA) has anti-fibrinolytic ability, with an activity about 10 times that of EACA, and has been shown to have stronger tolerance (Tengborn L, M, Berntorp E. Thromb Res. 2015 Feb; 135(2):231-42).

[0004] Tranexamic acid is a synthetic lysine derivative and antifibrinolytic agent that forms a reversible complex with plasminogen. By binding to plasminogen, it blocks the interaction between plasminogen and the plasmin heavy chain and fibrin lysine residues, thereby preventing plasminogen from binding to the fibrin surface and thus delaying fibrinolysis. Tranexamic acid has been approved for the treatment of severe menstrual bleeding and various surgical bleeding disorders, and is currently the most commonly used hemostatic drug in clinical practice. However, numerous literature reports indicate that oral administration of tranexamic acid easily causes gastrointestinal adverse reactions such as nausea, vomiting, diarrhea, and indigestion, and its dosage is relatively high; patients may also experience complications such as epilepsy after taking the drug.

[0005] Other similar hemostatic drugs, such as aminocaproic acid, have problems such as rapid excretion from the body, weak hemostatic effect, short duration of action, and more toxic reactions. Excessive dosage can lead to thrombosis, limiting their use in patients with a tendency to thrombosis, a history of thrombotic vascular disease, or renal insufficiency. Tranexamic acid has a similar mechanism to aminocaproic acid but is 4-5 times stronger. It is effective for general chronic bleeding but has no hemostatic effect on traumatic bleeding or cancerous bleeding. Furthermore, excessive dosage can also promote thrombosis. Aprotinin, a commonly used hemostatic drug in coronary artery bypass surgery, was withdrawn from the market by the FDA in 2008 due to its potential to induce renal failure, myocardial infarction, and heart failure.

[0006] Other hemostatic drugs with different mechanisms of action, such as carbazoline which acts on blood vessels, can induce epilepsy with repeated use; thrombin, a hemostatic drug that promotes the coagulation process, can only be used for gastrointestinal bleeding or local bleeding.

[0007] Given the very limited selection of hemostatic drugs available in clinical practice, and the deficiencies in dosage and clinical indications, as well as the problems of high dosage, numerous adverse reactions, and the potential to cause complications such as epilepsy, it is necessary to develop a new hemostatic drug to better meet clinical needs. Summary of the Invention

[0008] One of the objectives of this invention is to overcome the aforementioned deficiencies of the prior art and to provide a novel compound with coagulation and hemostatic activities.

[0009] Specifically, the present invention provides compounds of Formula I, including pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures thereof:

[0010]

[0011] Wherein, R1 is selected from hydrogen, hydroxyl, amino, alkyl, alkoxy, -NH-alkyl, cycloalkyl, aryl, alicyclic, and aromatic heterocyclic; wherein R1 may be selectively substituted by 1-2 groups selected from hydroxyl, alkyl, arylalkyl, halogen, aryl, and cycloalkyl.

[0012] R2 is independently selected from hydrogen, carboxyl, amide, alkyl, -NH-alkyl, -CH2O-alkyl, -CH2NH-alkyl, -COO-alkyl, -CONH-alkyl, cycloalkyl, aryl, alicyclic, aromatic heterocyclic, arylalkyl, and cycloalkylalkyl; R2 may be selectively substituted by 1-2 groups selected from hydroxyl, alkyl, and alkoxy groups; or two R2s together with the attached carbon atom form a cycloalkyl or alicyclic group;

[0013] R3 is selected from hydrogen and halogens; specifically, R3 is selected from hydrogen, fluorine, chlorine, and bromine.

[0014] In one embodiment, the present invention provides compounds represented by Formula I', pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures thereof:

[0015]

[0016] Wherein, R1 is selected from hydrogen, hydroxyl, amino, alkyl, alkoxy, -NH-alkyl, cycloalkyl, aryl, alicyclic, and aromatic heterocyclic; wherein R1 may be selectively substituted by 1-2 groups selected from hydroxyl, alkyl, halogen, aryl, and cycloalkyl.

[0017] R2 is selected from hydrogen, carboxyl, amide, alkyl, -NH-alkyl, -CH2O-alkyl, -CH2NH-alkyl, -COO-alkyl, -CONH-alkyl, cycloalkyl, aryl, alicyclic, and aromatic heterocyclic groups; R2 may be selectively substituted by 1-2 groups selected from hydroxyl and alkyl groups;

[0018] R3 is selected from hydrogen and halogens; specifically, R3 is selected from hydrogen, fluorine, chlorine, and bromine.

[0019] In some specific embodiments, R1 is selected from hydrogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-C1 to C6 alkyl, C3-C6 cycloalkyl, 6 to 10 aryl, 4 to 10 alicyclic, and 5 to 10 aromatic heterocyclic; R1 may optionally be substituted by 1 to 2 groups selected from hydroxyl, C1-C4 alkyl, halogen, 6-10 aryl-C1 to C4 alkyl, 6-10 aryl or aromatic heterocyclic, and C3-C6 cycloalkyl.

[0020] In some specific embodiments, R1 is selected from hydrogen, hydroxyl, amino, phenyl, pyridyl, C1-C6 alkyl, C1-C6 alkoxy, -NH-C1 to C6 alkyl, C3-C6 cycloalkyl, 4 to 7-membered alicyclic alkyl; said R1 may optionally be substituted by 1 to 2 groups selected from hydroxyl, C1-C4 alkyl, F, Cl, Br, phenyl, benzyl, cyclopropyl.

[0021] In some specific embodiments, R1 is selected from hydrogen, hydroxyl, amino, phenyl, benzyl, pyridyl, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, morpholinyl, piperazine, thiomorpholinyl, 1-oxide-4-thiomorpholinyl, 1,1-dioxide-4-thiomorpholinyl; said R1 may optionally be substituted by 1-2 groups selected from hydroxyl, F, Cl, Br, methyl, ethyl, propyl, isopropyl, phenyl, benzyl, cyclopropyl.

[0022] In some specific embodiments, R1 is selected from hydrogen, C1-C4 alkoxy, morpholino, piperazine, thiomorpholino, 1-oxide-4-thiomorpholino, and 1,1-dioxide-4-thiomorpholino, and R1 may be optionally substituted with 1-2 groups selected from hydroxyl and benzyl.

[0023] In some specific embodiments, R2 is selected from hydrogen, carboxyl, amide, C1-C6 alkyl, -CH2O-C1 to C6 alkyl, -CH2NH-C1 to C6 alkyl, -COO-C1 to C6 alkyl, -CONH-C1 to C6 alkyl, C3-C8 cycloalkyl, 6 to 10 aryl, 4 to 10 alicyclic, and 5 to 10 aromatic heterocyclic; R2 may optionally be substituted by 1 to 2 groups selected from hydroxyl and C1-C4 alkyl.

[0024] In some specific embodiments, R2 is selected from hydrogen, carboxyl, amide, C1-C6 alkyl, -CH2O-C1 to C6 alkyl, -CH2NH-C1 to C6 alkyl, -COO-C1 to C6 alkyl, -CONH-C1 to C6 alkyl, C3-C6 cycloalkyl, 6-membered aryl, 4 to 7-membered alicyclic, and 6-membered aromatic heterocyclic; R2 may optionally be substituted by 1-2 groups selected from hydroxyl and C1-C4 alkyl groups;

[0025] In certain specific embodiments, R2 is selected from hydrogen, carboxyl, amide, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, pentyl, -CH2OCH3, -CH2OCH2CH3, -CH2OCH2CH2CH3, -CH2NHCH3, -CH2NHCH2CH3, -CH2NHCH2CH2CH3, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -CONHCH3, -CONHCH2CH3, -CONHCH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, pyridyl, piperidinyl, morpholinyl, thiomorpholinyl, 1-oxide-thiomorpholinyl, 1,1-dioxide-4-thiomorpholinyl; wherein R2 may be substituted by 1-2 groups selected from hydroxyl, methyl, ethyl, propyl, and isopropyl.

[0026] In some specific embodiments, R2 is independently selected from hydrogen, carboxyl, C1-C6 alkyl, -CH2O-C1 to C6 alkyl, -COO-C1 to C6 alkyl, C3-C6 cycloalkyl, phenyl-C1 to C4 alkyl, and C3-C6 cycloalkyl-C1 to C4 alkyl, wherein the alkyl, cycloalkyl, and phenyl groups may be optionally substituted with 1-2 groups selected from hydroxyl and C1-C4 alkoxy groups; or the two R2s together with the attached carbon atom form a C3-C6 cycloalkyl or tetrahydropyranyl group.

[0027] In some specific embodiments, one of R2 is hydrogen. In some specific embodiments, R3 is selected from hydrogen and fluorine.

[0028] In some specific implementations, R1 and R2 are not both hydrogen;

[0029] In some specific implementations, R1, R2, and R3 are not all hydrogen.

[0030] In some specific embodiments, the compound of formula I of the present invention has the following structure:

[0031]

[0032]

[0033]

[0034] Another object of the present invention is to provide a pharmaceutical composition comprising at least one of the aforementioned compounds, or a pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, and at least one pharmaceutically acceptable excipient.

[0035] Another object of the present invention is to provide the aforementioned compound or its pharmaceutically acceptable salts, hydrates, isomers, prodrugs, mixtures, or pharmaceutical compositions for use in the preparation of a medicament. The medicament possesses therapeutic activities of coagulation and hemostasis, and can be used for abnormal bleeding caused by hyperfibrinolysis, surgical and postoperative bleeding, etc.

[0036] Another object of the present invention is to provide a method for treating and / or alleviating bleeding disorders or conditions, comprising administering to a patient the foregoing one or more of the aforementioned pharmaceutical compositions or compounds of Formula I or thereof, or pharmaceutically acceptable salts, hydrates, isomers, prodrugs or mixtures thereof.

[0037] Terminology Definition

[0038] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0039] The term "pharmaceutically acceptable" as used herein means that it is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0040] The term "pharmaceutically acceptable salt" refers to the salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.

[0041] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, racemic mixtures thereof, and other mixtures, all of which are within the scope of the present invention.

[0042] "Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, such as C1-C4 alkyl and C1-C6 alkyl, which are saturated aliphatic hydrocarbon groups containing 1 to 4 carbon atoms and 1 to 6 carbon atoms, respectively, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, 3,3-dimethylbutyl, and their various isomers.

[0043] "Alkoxy" refers to -O-alkyl; for example, C1-C6 alkoxy refers to straight-chain or branched alkoxy with 1 to 6 carbons, and C1-C3 alkoxy refers to straight-chain or branched alkoxy with 1 to 3 carbons. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy.

[0044] "Cycloalkyl" refers to a monocyclic or polycyclic cyclic hydrocarbon substituent that is saturated or partially unsaturated. For example, "C3-C6 cycloalkyl" refers to a cycloalkyl group containing 3 to 6 carbon atoms. Typical C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.

[0045] "Alicyclic group" refers to a saturated monocyclic hydrocarbon substituent in which one or more ring atoms are replaced by heteroatoms selected from N, O, and S, the remaining ring atoms are carbon, and the S heteroatoms may be selectively oxidized. For example, "3-8 membered alicyclic" refers to a saturated cyclic hydrocarbon substituent containing 3-8 ring atoms, in which one or more ring atoms are replaced by heteroatoms selected from N, O, and S, the remaining ring atoms are carbon, and the S heteroatoms may be selectively oxidized. Specific examples of alicyclic groups described in this invention include, but are not limited to: oxadiazolyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, piperazineyl, morpholinyl, thiomorpholinyl, 1-oxide-4-thiomorpholinyl, and 1,1-dioxide-4-thiomorpholinyl, etc.

[0046] "Aromatic heterocyclic group" refers to an aromatic cyclic substituent in which one or more ring atoms are replaced by heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. For example, "5-6 membered aromatic heterocyclic group" refers to an aromatic heterocyclic group containing 5 to 6 ring atoms, and specific examples include, but are not limited to, pyridinyl, pyrimidinyl, imidazolyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, and 1,2,4-oxadiazolyl.

[0047] "Aryl" refers to an aromatic cyclic group. For example, "6-10 aryl" refers to an aromatic cyclic group containing 6 to 10 carbon ring atoms. Examples of aryl moiety include phenyl, naphthyl, etc.

[0048] Halogens include fluorine, chlorine, bromine, and iodine.

[0049] "Optional" means that the event or situation described below may occur but is not required to occur.

[0050] All abbreviations used in this invention are known to those skilled in the art and, unless otherwise stated, represent the meanings known in the art. For example: DMF refers to N,N-dimethylformamide; THF refers to tetrahydrofuran; and Me refers to methyl.

[0051] Experiments have shown that the compound of this invention has excellent coagulation and hemostatic activity, which is significantly better than tranexamic acid, the most widely used hemostatic drug in clinical practice, and has great clinical application value. Detailed Implementation

[0052] The following examples illustrate the synthesis methods of the compounds and intermediates of this invention. These examples are merely illustrative and should not be construed as limiting the scope of the invention. Unless otherwise specified, the raw materials and reagents involved in this invention are commercially available, and the specific source does not affect the implementation of the technical solution of this invention.

[0053] Preparation Example 1: Preparation of tert-butyl 2-chloro-8-hydroxy-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0054]

[0055] Step 1: Preparation of tert-butyl 2-chloro-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0056] 5 g of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthidine hydrochloride was dissolved in 50 ml of dichloromethane, 10 ml of triethylamine was added, and 6.7 ml of di-tert-butyl dicarbonate was slowly added dropwise. After the addition was complete, the reaction was carried out at room temperature for 1 hour, and LC-MS showed that the reaction was complete. The system was concentrated to obtain an oily crude product, and the title compound (6 g) was separated by column chromatography.

[0057]

[0058] MS(ESI)m / z(M+H) + =269.1.

[0059] Step 2: Preparation of 6-(tert-Butoxycarbonyl)-2-chloro-5,6,7,8-tetrahydro-1,6-naphthidine-1-oxide

[0060] 9 g of tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate was weighed and dissolved in 100 mL of dichloromethane. 11.7 g of m-chloroperoxybenzoic acid was added in portions under ice bath conditions. The reaction was allowed to proceed for 1 hour at room temperature, and LC-MS showed complete reaction. Dichloromethane and water were added, and the mixture was extracted separately. The organic phase was concentrated to dryness. The crude product was purified by column chromatography to give the title compound (7.0 g).

[0061]

[0062] MS(ESI)m / z(M+H) + =285.1.

[0063] Step 3: Preparation of tert-butyl 8-acetoxy-2-chloro-7,8-dihydro-1,6-naphthylpyridine-6(5H)-formate

[0064] 7 g of 6-(tert-Butoxycarbonyl)-2-chloro-5,6,7,8-tetrahydro-1,6-naphthidine-1-oxide was dissolved in acetic anhydride (80 mL), purged three times with nitrogen, and heated to 70 °C overnight. LC-MS showed that the reaction was complete. The mixture was concentrated under reduced pressure to remove a large amount of acetic anhydride, and ethyl acetate and water were added. The mixture was extracted three times with ethyl acetate, washed twice with saturated sodium bicarbonate solution, dried and concentrated the organic phase, and purified by column chromatography to obtain the title compound (5 g).

[0065]

[0066] MS(ESI)m / z(M+H) + =327.1.

[0067] Step 4: Preparation of tert-butyl 2-chloro-8-hydroxy-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0068] 3 g of tert-butyl 8-acetoxy-2-chloro-7,8-dihydro-1,6-naphthyl-6-(5H)-carboxylate was weighed and dissolved in methanol (30 ml). Potassium carbonate (635 mg) was added, and the mixture was reacted at room temperature for 0.5 hours. LC-MS showed that the reaction was complete. Ethyl acetate and water were added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried and concentrated, and the system was concentrated to obtain an oily crude product. The product was purified by column chromatography to obtain the title compound (1.9 g).

[0069]

[0070] MS(ESI)m / z(M+H) + =285.1.

[0071] Preparation Example 2: Preparation of 6-(tert-butyl)-7-methyl-2-chloro-7,8-dihydro-1,6-naphthidine-6,7(5H)-dicarboxylate

[0072]

[0073] Step 1: Preparation of 1-oxide of 2,3-bis(methoxycarbonyl)pyridine

[0074] Dimethyl pyridine-2,3-dicarboxylate (4.90 g) was dissolved in acetonitrile (60 mL). Urea peroxide (4.71 g) was added under ice bath conditions, followed by slow dropwise addition of trifluoroacetic anhydride (10.5 g). After the addition was complete, the system became a clear solution. The mixture was heated to room temperature and reacted for 4 hours. TLC showed that the reaction was essentially complete. The reaction was quenched with an aqueous sodium metabisulfite solution. Dichloromethane and water were added, and the mixture was separated. The aqueous phase was extracted with a mixed solvent (DCM / MeOH = 10 / 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound (5.15 g).

[0075]

[0076] MS(ESI)m / z(M+H) + =212.1.

[0077] Step 2: Preparation of dimethyl 6-chloropyridine-2,3-dicarboxylate

[0078] Weigh 5.15 g of 2,3-bis(methoxycarbonyl)pyridine 1-oxide, add 30 mL of phosphorus oxychloride under ice bath conditions, and react at 105 °C for 4 hours. TLC showed that the reaction was complete. Concentrate under reduced pressure, dilute with ethyl acetate, add dropwise to crushed ice, adjust the pH to 10 with sodium carbonate aqueous solution, extract with ethyl acetate, and wash the organic phase with sodium chloride aqueous solution. Concentrate the organic phase to dryness, and purify the crude product by column chromatography to obtain the title compound (3.52 g).

[0079]

[0080] MS(ESI)m / z(M+H) + =230.1.

[0081] Step 3: Preparation of (6-chloropyridine-2,3-diyl)diethanol

[0082] 3.50 g of dimethyl 6-chloropyridine-2,3-dicarboxylate was dissolved in tetrahydrofuran (72 mL) and methanol (1.5 mL). Lithium borohydride (0.84 g) was added in portions under ice bath conditions, and the mixture was heated to room temperature for 3 hours. TLC showed complete reaction of the starting material. The reaction mixture was poured into an aqueous sodium bicarbonate solution, ethyl acetate was added, and the mixture was extracted separately. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound (2.63 g).

[0083]

[0084] MS(ESI)m / z(M+H) + =174.1.

[0085] Step 4: Preparation of 6-chloro-2,3-bis(chloromethyl)pyridine

[0086] Weigh 2.63 g of (6-chloropyridin-2,3-diyl)diethanol and add 40 mL of thionyl chloride under ice bath conditions. React at room temperature for 3 hours. A portion of the monochlorinated intermediate was present; the reaction was then carried out at 35 °C for 3 hours, and TLC showed complete reaction. The mixture was concentrated under reduced pressure, diluted with ethyl acetate, and added dropwise to crushed ice. The pH was adjusted to 10 with sodium carbonate aqueous solution. The mixture was extracted with ethyl acetate, and the organic phase was washed with sodium chloride aqueous solution. The organic phase was concentrated to dryness, and the crude product was purified by column chromatography to give the title compound (2.1 g).

[0087]

[0088] MS(ESI)m / z(M+H) + =210.1.

[0089] Step 5: Preparation of dimethyl 6-acetyl-2-chloro-5,6-dihydro-1,6-naphthidine-7,7(8H)-dicarboxylate

[0090] 2.10 g of 6-chloro-2,3-bis(chloromethyl)pyridine was dissolved in 15 mL of N,N-dimethylformamide. Dimethyl acetaminomalonate (2.17 g) and sodium hydride (0.40 g) were added sequentially under ice bath conditions. The reaction was allowed to proceed for 1 hour at room temperature, followed by the addition of sodium hydride (0.40 g) under ice bath conditions, and the reaction was allowed to continue overnight at room temperature. TLC showed that the reaction was complete. Ethyl acetate and water were added, and the mixture was extracted separately. The organic phase was concentrated to dryness. The crude product was purified by column chromatography to give the title compound (1.74 g).

[0091]

[0092] MS(ESI)m / z(M+H) + =327.1.

[0093] Step 6: Preparation of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyl-7-carboxylate

[0094] Weigh 1.74 g of dimethyl 6-acetyl-2-chloro-5,6-dihydro-1,6-naphthidine-7,7(8H)-dicarboxylate, add 15 mL of 6M hydrochloric acid, and react in a sealed container at 100 °C for 4 hours. TLC showed that the reaction was complete. The system was concentrated to dryness under reduced pressure to give the title compound (1.16 g).

[0095]

[0096] MS(ESI)m / z(M+H) + =213.1.

[0097] Step 7: Preparation of methyl 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyl-7-carboxylate hydrochloride

[0098] 1.16 g of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyl-7-carboxylate was dissolved in 20 mL of methanol, and 1.67 g of thionyl chloride was slowly added dropwise under ice bath conditions. The mixture was refluxed at 70 °C for 2 hours, and TLC showed that the reaction was complete. The system was concentrated to dryness under reduced pressure to give the title compound (1.23 g).

[0099]

[0100] MS(ESI)m / z(M+H) + =227.1.

[0101] Step 8: Preparation of 6-(tert-butyl)-7-methyl-2-chloro-7,8-dihydro-1,6-naphthidine-6,7(5H)-dicarboxylate

[0102] 1.23 g of methyl 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyl-7-carboxylate hydrochloride was dissolved in 25 mL of dichloromethane, followed by the addition of 1.89 g of triethylamine and 1.53 g of ditert-butyl dicarbonate. The reaction was carried out at room temperature for 2 hours, and TLC showed complete reaction. Dichloromethane and water were added, and the mixture was extracted separately. The organic phase was concentrated to dryness. The crude product was purified by column chromatography to give the title compound (1.19 g).

[0103]

[0104] MS(ESI)m / z(M+H) + =327.1.

[0105] 1H NMR(400MHz,Chloroform-d)δ7.42(dd,J=12.5,8.0Hz,1H),7.21(d,J=8.1Hz,1H),5.34(d,J=6.7Hz,0.5H),5.07(dd,J=7.2,2.9Hz,0.5H),4.7 9(dd,J=22.4,17.0Hz,1H),4.52(dd,J=31.0,17.1Hz,1H),3.68(d,J=7.7Hz,3H),3.55–3.38(m,1H),3.38–3.20(m,1H),1.52(d,J=17.9Hz,9H).

[0106] Example 1: Preparation of 5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0107]

[0108] Step 1: Preparation of tert-butyl 2-chloro-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0109] 0.9 g of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthylidine hydrochloride was weighed and suspended in 15 mL of dichloromethane. 1.4 g of N,N-diisopropylethylamine was added to release the free sample, followed by 1.15 g of ditert-butyl dicarbonate. The reaction was carried out at room temperature for 1 h. TLC showed that the starting material was completely consumed, and column chromatography purified the sample to give the title compound (1.12 g).

[0110]

[0111] MS(ESI)m / z(M+H) + =269.0.

[0112] Step 2: Preparation of tert-butyl 2-cyano-7,8-dihydro-1,6-naphthidine-6(5H)-formate

[0113] 1.12 g of tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate was dissolved in 20 mL of N,N-dimethylformamide. Zinc cyanide (2.44 g) and tetrakis(triphenylphosphine)palladium (483 mg) were added. The mixture was purged three times with argon gas and reacted at 120 °C for 3 h. TLC showed that the starting material was completely consumed. The mixture was diluted with ethyl acetate, filtered through diatomaceous earth, extracted twice with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the title compound (1.1 g).

[0114]

[0115] MS(ESI)m / z(M+H)+ =260.0.

[0116] Step 3: Preparation of 5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0117] 1.1 g of tert-butyl 2-cyano-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate was dissolved in 25 mL of 6 M hydrochloric acid aqueous solution and reacted overnight at 120 °C. LCMS showed that the starting material was completely consumed. The reaction solution was concentrated to dryness and separated by pre-HPLC to obtain a light yellow solid (726 mg).

[0118]

[0119] MS(ESI)m / z(M+H) + =179.0.

[0120] 1 H NMR (400MHz, Methanol-d4) δ8.21(d,J=8.1Hz,1H),8.12(d,J=8.0Hz,1H),4.60(s,2H),3.71(t,J=6.4Hz,2H),3.42(t,J=6.4Hz,2H).

[0121] Example 2 Preparation of 8-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0122]

[0123] Step 1: Preparation of tert-butyl 2-chloro-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0124] 5 g of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthidine hydrochloride was dissolved in 50 ml of dichloromethane, 10 ml of triethylamine was added, and 6.7 ml of di-tert-butyl dicarbonate was slowly added dropwise. After the addition was complete, the reaction was carried out at room temperature for 1 hour, and LC-MS showed that the reaction was complete. The system was concentrated to obtain an oily crude product, and the title compound (5.5 g) was separated by column chromatography.

[0125]

[0126] MS(ESI)m / z(M+H) + =269.1.

[0127] Step 2: Preparation of 6-(tert-Butoxycarbonyl)-2-chloro-5,6,7,8-tetrahydro-1,6-naphthidine-1-oxide

[0128] Weigh 2 g of tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate and dissolve it in 50 mL of dichloromethane. Add 2.6 g of m-chloroperoxybenzoic acid in portions under ice bath conditions. React overnight at room temperature; LC-MS showed complete reaction. Add dichloromethane and water, extract separately, and concentrate the organic phase to dryness. Purify the crude product by column chromatography to give the title compound (1.5 g).

[0129]

[0130] MS(ESI)m / z(M+H) + =285.1.

[0131] Step 3: Preparation of tert-butyl 8-acetoxy-2-chloro-7,8-dihydro-1,6-naphthyl-6(5H)-formate

[0132] 300 mg of 6-(tert-butoxycarbonyl)-2-chloro-5,6,7,8-tetrahydro-1,6-naphthidine-1-oxide was dissolved in acetic anhydride (5 mL), purged three times with nitrogen, and heated to 70 °C overnight. LC-MS showed that the reaction was complete. The mixture was concentrated under reduced pressure to remove a large amount of acetic anhydride, and then extracted three times with ethyl acetate and water. The mixture was washed twice with saturated sodium bicarbonate solution, dried over an organic dryness, concentrated, and purified by column chromatography to obtain the title compound (280 mg).

[0133]

[0134] MS(ESI)m / z(M+H) + =327.1.

[0135] Step 4: Preparation of tert-butyl 8-acetoxy-2-cyano-7,8-dihydro-1,6-naphthidine-6-(5H)-carboxylate

[0136] 150 mg of tert-butyl 8-acetoxy-2-chloro-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate was dissolved in 6 mL of N,N-dimethylformamide. Zinc cyanide (270 mg) and tetrakis(triphenylphosphine)palladium (105.9 mg) were added. The mixture was purged three times with nitrogen and heated to 120 °C for 3 hours. LC-MS showed the reaction was complete. Ethyl acetate and water were added, and the mixture was extracted three times with ethyl acetate. The organic compound was dried, concentrated, and purified by column chromatography to give the title compound (60 mg).

[0137]

[0138] MS(ESI)m / z(M+H) + =318.1.

[0139] Step 5: Preparation of tert-butyl 8-hydroxy-2-(imino(methoxy)methyl)-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0140] 60 mg of tert-butyl 8-acetoxy-2-cyano-7,8-dihydro-1,6-naphthyl-6-(5H)-carboxylate was dissolved in a solution of methanol (1 mL), tetrahydrofuran (1 mL), and water (1 mL). Lithium hydroxide monohydrate (32 mg) was added, and the reaction was carried out at room temperature for 1 hour. LC-MS showed that the reaction was complete. Ethyl acetate and water were added, and the mixture was extracted three times with ethyl acetate. The organic compound was dried and concentrated to give the title compound (50 mg).

[0141]

[0142] MS(ESI)m / z(M+H) + =308.1.

[0143] Step 6: Preparation of 8-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0144] 50 mg of tert-butyl 8-hydroxy-2-(imino(methoxy)methyl)-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylic acid was dissolved in 4 mL of 6 M hydrochloric acid aqueous solution and heated to 120 °C for 5 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated and purified by pre-HPLC to obtain the title compound (35 mg).

[0145]

[0146] MS(ESI)m / z(M+H) + =195.0.

[0147] 1 H NMR (400MHz, Deuterium Oxide) δ8.13(d,J=8.1Hz,1H),7.96(d,J=8.1Hz,1H),5.07(s,1H),4.64–4.45(m,2H),3.79–3.57(m,2H).

[0148] Example 3 Preparation of 8-amino-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylic acid dihydrochloride

[0149]

[0150] Step 1: Preparation of tert-butyl 2-chloro-8-((methanesulfonyl)oxy)-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0151] Weigh 100 mg of tert-butyl 2-chloro-8-hydroxy-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate and dissolve it in 4 mL of dichloromethane. Add 106 mg of triethylamine under ice bath conditions. Purge the solution three times with nitrogen, then add 80 mg of methanesulfonyl chloride dropwise. React at room temperature for 1 hour. LC-MS showed the reaction was complete. Add dichloromethane and water, extract by separation, and concentrate the organic phase to dryness to give the title compound (126.7 mg).

[0152]

[0153] MS(ESI)m / z(M+H) + =363.1.

[0154] Step 2: Preparation of tert-butyl 8-azido-2-chloro-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0155] Weigh 126 mg of tert-butyl 2-chloro-8-((methanesulfonyl)oxy)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate and dissolve it in 4 ml of N,N-dimethylformamide. Add 30 mg of sodium azide under ice bath conditions. Heat to 85 °C and react for 1 hour. TLC showed that the reaction was complete. Add ethyl acetate and water, extract separately, and concentrate the organic phase to dryness. Purify the crude product by column chromatography to give the title compound (90 mg).

[0156]

[0157] MS(ESI)m / z(M+H) + =310.1.

[0158] Step 3: Preparation of tert-butyl 8-amino-2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0159] 90 mg of tert-butyl 8-azido-2-chloro-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate was dissolved in tetrahydrofuran (3 mL) and water (0.3 mL). Triphenylphosphine (152 mg) was added, and the reaction was carried out at room temperature for 18 hours. LC-MS showed that the reaction was complete. Ethyl acetate and water were added, and the mixture was extracted three times with ethyl acetate. The organic compound was dried, concentrated, and purified by column chromatography to give the title compound (70 mg).

[0160]

[0161] MS(ESI)m / z(M+H) + =284.1.

[0162] Step 4: Preparation of tert-butyl 8-((tert-butoxycarbonyl)amino)-2-chloro-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0163] 70 mg of tert-butyl 8-amino-2-chloro-7,8-dihydro-1,6-naphthylpyridine-6(5H)-carboxylate was dissolved in 6 mL of dichloromethane. Triethylamine (37 mg) was added, followed by the slow addition of 80 mg of ditert-butyl dicarbonate. The reaction was carried out at room temperature for 2 hours. LC-MS showed that the reaction was complete. The system was concentrated and purified by column chromatography to obtain the title compound (70 mg).

[0164]

[0165] MS(ESI)m / z(M+H) + =384.1.

[0166] Step 5: Preparation of tert-butyl 8-((tert-butoxycarbonyl)amino)-2-cyano-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0167] 30 mg of tert-butyl 8-((tert-butoxycarbonyl)amino)-2-chloro-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate was dissolved in 3 mL of N,N-dimethylformamide, and zinc cyanide (90 mg) and tetrakis(triphenylphosphine)palladium (72 mg) were added. The mixture was purged with nitrogen three times and heated to 120 °C for 2 hours. LC-MS showed that the reaction was complete. Ethyl acetate and water were added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried, concentrated, and purified by column chromatography to give the title compound (25 mg).

[0168]

[0169] MS(ESI)m / z(M+H) + =375.2.

[0170] Step 6: Preparation of 8-amino-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0171] 25 mg of tert-butyl 8-((tert-butoxycarbonyl)amino)-2-cyano-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylic acid was dissolved in 4 mL of 6 M hydrochloric acid aqueous solution and heated to 120 °C for 5 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated and purified by pre-HPLC to obtain the title compound (13 mg).

[0172]

[0173] MS(ESI)m / z(M+H) +=193.9.

[0174] 1 H NMR(400MHz, Deuterium Oxide)δ8.09(d,J=8.1Hz,1H),7.90(d,J=8.1Hz,1H),4.96(dd,J=9.9,6.2Hz,1H), 4.58(d,J=2.6Hz,2H), 4.11(dd,J=13.0,6.1Hz,1H), 3.63(dd,J=13.0,9.9Hz,1H).

[0175] Example 4 Preparation of 8-((2-hydroxyethyl)amino)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylic acid dihydrochloride

[0176]

[0177] Step 1: Preparation of tert-butyl 2-chloro-8-((2-hydroxyethyl)amino)-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0178] At room temperature, 100 mg of tert-butyl 2-chloro-8-((methanesulfonyl)oxy)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate was dissolved in acetonitrile (4 mL), and N,N-diisopropylethylamine (0.23 mL) and ethanolamine (34 mg) were added. The reaction was heated to 60 °C and carried out overnight; TLC showed that the reaction was complete. Dichloromethane and water were added, the mixture was separated, extracted with dichloromethane, and the organic phase was concentrated to dryness. The crude product was purified by silica gel column chromatography to give the title compound (54 mg).

[0179]

[0180] MS(ESI)m / z(M+H) + =328.0.

[0181] Step 2: Preparation of tert-butyl 8-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)-2-chloro-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0182] At room temperature, tert-butyl 2-chloro-8-((2-hydroxyethyl)amino)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (53 mg) was dissolved in dichloromethane (4 mL), and triethylamine (32 mg) and di-tert-butyl dicarbonate (53 mg) were added. The mixture was stirred overnight. LC-MS showed that the reaction was complete. Dichloromethane and water were added, and the mixture was separated, extracted with dichloromethane, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the title compound (60 mg).

[0183]

[0184] MS(ESI)m / z(M+H) + =428.1.

[0185] Step 3: Preparation of tert-butyl 8-((tert-butyloxycarbonyl)(2-hydroxyethyl)amino)-2-cyano-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0186] At room temperature, 43 mg of tert-butyl 8-((tert-butyloxycarbonyl)(2-hydroxyethyl)amino)-2-chloro-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate was dissolved in 5 mL of N,N-dimethylformamide. Zinc cyanide (246 mg) and tetrakis(triphenylphosphine)palladium (808 mg) were added. The mixture was purged with nitrogen three times, heated to 120 °C, and stirred overnight. LC-MS showed complete reaction. The mixture was filtered, and ethyl acetate and water were added. The mixture was separated, extracted three times with ethyl acetate, and the organic phase was dried and concentrated. The crude product was purified by pre-TLC to give the title compound (30 mg).

[0187]

[0188] MS(ESI)m / z(M+H) + =419.1.

[0189] Step 4: Preparation of 8-((2-hydroxyethyl)amino)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylic acid dihydrochloride

[0190] 30 mg of tert-butyl 8-((tert-butyloxycarbonyl)(2-hydroxyethyl)amino)-2-cyano-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylic acid was dissolved in 5 mL of 6 M hydrochloric acid aqueous solution and heated to 120 °C for 5 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated and purified by pre-HPLC to obtain the title compound (15.8 mg).

[0191]

[0192] MS(ESI)m / z(M+H) + =238.0.

[0193] 1 H NMR(400MHz, Deuterium Oxide)δ8.20–7.78(m,2H),4.97(s,1H),4.53(s,2H),4.18(d,J=12.0Hz,1H),3.87(s,2H),3.70(d,J=12.0Hz,1H),3.34(d,J=28.0Hz,2H).

[0194] Example 5 Preparation of 8-morpholino-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0195]

[0196] Step 1: Preparation of tert-butyl 2-chloro-8-((methanesulfonyl)oxy)-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0197] Weigh 270 mg of tert-butyl 2-chloro-8-hydroxy-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate and dissolve it in 8 mL of dichloromethane. Add triethylamine (300 mg) under ice bath conditions. Purge the solution three times with nitrogen, then add 230 mg of methanesulfonyl chloride dropwise. React at room temperature for 1 hour; LC-MS showed the reaction was complete. Add dichloromethane and water, extract by separation, and concentrate the organic phase to dryness. The title compound (310 mg) is obtained.

[0198]

[0199] MS(ESI)m / z(M+H) + =363.1.

[0200] Step 2: Preparation of tert-butyl 2-chloro-8-morpholino-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0201] Weigh 150 mg of tert-butyl 2-chloro-8-((methanesulfonyl)oxy)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate, dissolve it in 2 ml of N,N-dimethylformamide and 2 ml of acetonitrile, and add potassium carbonate (138 mg) and morpholine (174 mg). Heat to 60 °C and react overnight; TLC showed the reaction was complete. Add ethyl acetate and water, extract separately, and concentrate the organic phase to dryness. Purify the crude product by column chromatography to give the title compound (120 mg).

[0202]

[0203] MS(ESI)m / z(M+H) + =354.1.

[0204] Step 3: Preparation of tert-butyl 2-cyano-8-morpholino-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0205] 120 mg of tert-butyl 2-chloro-8-morpholino-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate was dissolved in 5 mL of N,N-dimethylformamide. Zinc cyanide (318 mg) and tetrakis(triphenylphosphine)palladium (196 mg) were added. The mixture was purged with nitrogen three times and heated to 120 °C for 2 hours. LC-MS showed the reaction was complete. Ethyl acetate and water were added, and the mixture was extracted three times with ethyl acetate. The organic compound was dried, concentrated, and purified by column chromatography to give the title compound (100 mg).

[0206]

[0207] MS(ESI)m / z(M+H) + =345.1.

[0208] Step 4: Preparation of 8-morpholino-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0209] 42 mg of tert-butyl 2-cyano-8-morpholino-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate was dissolved in 4 mL of 6 M hydrochloric acid aqueous solution and heated to 120 °C for 5 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated and purified by pre-HPLC to obtain the title compound (31 mg).

[0210]

[0211] MS(ESI)m / z(M+H) + =264.0.

[0212] 1 H NMR(400MHz, Deuterium Oxide)δ7.90(d,J=8.0Hz,1H),7.80(d,J=8.1Hz,1H),4.63–4.35(m,3H),3.83(q,J=4.8,3.7Hz,6H),2.96(tq,J=12.4,7.4,6.0Hz,4H).

[0213] Example 6 Preparation of 8-(1,1-dioxothiomorpholino)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0214]

[0215] Step 1: Preparation of tert-butyl 2-chloro-8-(1,1-dioxothiomorpholino)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate

[0216] 65 mg of tert-butyl 2-chloro-8-((methanesulfonyl)oxy)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate was dissolved in acetonitrile (5 mL), and 540 mg of thiomorpholine 1,1-dioxide and 550 mg of potassium carbonate were added sequentially. The mixture was heated to 75 °C overnight, and TLC showed that the reaction was essentially complete. Ethyl acetate and water were added, and the mixture was extracted separately. The organic phase was concentrated to dryness. The crude product was purified by column chromatography to give the title compound (28 mg).

[0217]

[0218] MS(ESI)m / z(M+H) + =402.1.

[0219] Step 2: Preparation of tert-butyl 2-cyano-8-(1,1-dioxothiomorpholino)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate

[0220] 28 mg of tert-butyl 2-chloro-8-(1,1-dioxothiomorpholino)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate was dissolved in 2.5 mL of N,N-dimethylformamide, and zinc cyanide (82 mg) and tetrakis(triphenylphosphine)palladium (81 mg) were added sequentially. The mixture was purged with nitrogen three times and reacted at 120 °C for 6 hours. TLC showed that the reaction was essentially complete. Ethyl acetate was added, and the mixture was filtered. The filtrate was washed with ammonium chloride aqueous solution, and the organic phase was concentrated to dryness. The crude product was purified by column chromatography to give the title compound (25 mg).

[0221]

[0222] MS(ESI)m / z(M+H) + =393.1.

[0223] Step 3: Preparation of 8-(1,1-dioxothiomorpholino)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0224] 25 mg of 2-cyano-8-(1,1-dioxothiomorpholino)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylic acid tert-butyl ester was weighed and added to 2.5 mL of 6 M hydrochloric acid. The mixture was reacted at 120 °C under sealed conditions for 4 hours. TLC showed that the reaction was essentially complete. The system was concentrated to dryness and purified by pre-HPLC to obtain the title compound (4.5 mg).

[0225]

[0226] MS(ESI)m / z(M+H) + =312.0.

[0227] 1 H NMR(400MHz, Deuterium Oxide)δ7.81(d,J=8.1Hz,1H),7.74(d,J=8.1Hz,1H),4.54–4.35(m,2H),4.32(dd,J=6.2,4.3Hz,1H),3. 68(dd,J=13.2,6.2Hz,1H),3.59(dd,J=13.2,4.3Hz,1H),3.29–3.12(m,4H),3.04(dt,J=7.5,3.7Hz,4H).

[0228] Example 7 Preparation of 7-((3-hydroxypropoxy)methyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate salt

[0229]

[0230] Step 1: Preparation of tert-butyl 2-chloro-7-(hydroxymethyl)-7,8-dihydro-1,6-naphthyl-6-(5H)-carboxylate

[0231] At room temperature, 1.00 g of 6-(tert-butyl)-7-methyl-2-chloro-7,8-dihydro-1,6-naphthidine-6,7(5H)-dicarboxylate was dissolved in a tetrahydrofuran (20 mL) / methanol (1 mL) system. Lithium borohydride (0.340 g) was added under ice bath conditions, and the mixture was stirred for 2 hours. The reaction was confirmed to be complete by LC-MS. The reaction was quenched dropwise with saturated ammonium chloride solution under ice bath conditions. The mixture was extracted with ethyl acetate / water solution, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography to give the title compound (0.90 g).

[0232]

[0233] MS(ESI)m / z(M+H) + =299.0.

[0234] Step 2: Preparation of tert-butyl 7-((3-((tert-butyldimethylsilyl)oxy)propoxy)methyl)-2-chloro-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylic acid

[0235] At room temperature, sodium hydride (0.024 g) was added to a reaction flask. Under a nitrogen atmosphere, N,N-dimethylformamide (2 mL) was added, and the mixture was cooled in an ice bath for 10 minutes. 3-bromopropoxy tert-butyldimethylsilane (1.77 g), 2-chloro-7-(hydroxymethyl)-7,8-dihydro-1,6-naphthyl-6-(5H)-carboxylic acid tert-butyl ester (208 mg), and tetrabutylammonium iodide (26 mg) were added. After the addition was complete, the mixture was heated to 40 °C and stirred for 1 hour. TLC showed that the reaction was complete. The reaction was quenched dropwise with saturated ammonium chloride solution in an ice bath. Ethyl acetate / water was added, and the mixture was extracted with ethyl acetate, washed with saturated ammonium chloride solution, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give the title compound (40 mg).

[0236]

[0237] MS(ESI)m / z(M+H) + =471.1.

[0238] Step 3: Preparation of 6-(tert-butyl)2-methyl 7-((3-((tert-butyldimethylsilyl)oxy)propoxy)methyl)-7,8-dihydro-1,6-naphthidine-2,6(5H)-dicarboxylate

[0239] At room temperature, tert-butyl 7-((3-((tert-butyldimethylsilyl)oxy)propoxy)methyl)-2-chloro-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (37 mg) was dissolved in methanol (20 mL), followed by the addition of palladium acetate (9 mg), 1,1'-bis(diphenylphosphine)ferrocene (44 mg), and triethylamine (8 mg). After the addition was complete, the system was purged with carbon monoxide and heated to 65 °C overnight under a carbon monoxide atmosphere with stirring. The reaction was monitored by LCMS until complete, and the solvent was removed under reduced pressure. The crude product was purified by pre-TLC to give the title compound (33 mg).

[0240]

[0241] MS(ESI)m / z(M+H)+=495.0.

[0242] Step 4: Preparation of 6-(tert-butoxycarbonyl)-7-((3-((tert-butyldimethylsilyl)oxy)propoxy)methyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylic acid

[0243] At room temperature, 58 mg of 6-(tert-butyl)2-methyl 7-((3-((tert-butyldimethylsilyl)oxy)propoxy)methyl)-7,8-dihydro-1,6-naphthyl-2,6(5H)-dicarboxylate was dissolved in a tetrahydrofuran (1 mL) / methanol (1 mL) / water (1 mL) system. Lithium hydroxide monohydrate (10 mg) was added, and the mixture was stirred for 30 minutes. LC-MS analysis confirmed the reaction was complete. The solution was adjusted to weakly acidic pH using 1,4-dioxane hydrochloric acid solution (4 M) and concentrated under reduced pressure to obtain the crude product of the title compound, which was used directly in the next step.

[0244]

[0245] MS(ESI)m / z(M+H) + =481.1.

[0246] Step 5: Preparation of 7-((3-hydroxypropoxy)methyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate salt

[0247] At room temperature, the crude product of 6-(tert-butoxycarbonyl)-7-((3-((tert-butyldimethylsilyl)oxy)propoxy)methyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylic acid prepared in step 4 was added to a 1,4-dioxane solution of hydrochloric acid (4M, 2mL), stirred for 30 minutes, and the reaction was confirmed to be complete by LCMS. The mixture was concentrated under reduced pressure and purified by pre-HPLC to obtain the title compound (28.3 mg).

[0248]

[0249] MS(ESI)m / z(M+H) + =267.1.

[0250] 1 H NMR (400MHz, Deuterium Oxide) δ7.69(s,2H),4.44(s,2H),3.98–3.80(m,2H),3.70–3.56(m,5H),3.14(dd,J=17.4,7.9Hz,2H),1.77(p,J=6.3Hz,2H).

[0251] Example 8 Preparation of 7-carbamoyl-5,6,7,8-tetrahydro-1,6-naphthyl-2-carbamate

[0252]

[0253] Step 1: Preparation of tert-butyl 7-carbamoyl-2-chloro-7,8-dihydro-1,6-naphthyl-6-(5H)-carboxylate

[0254] At room temperature, 6-(tert-butoxycarbonyl)-2-chloro-5,6,7,8-tetrahydro-1,6-naphthyl-7-carboxylic acid (86 mg) was dissolved in N,N-dimethylformamide (4 mL). Under ice bath conditions, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (157 mg), ammonium chloride (87 mg), and N,N-diisopropylethylamine (356 mg) were added sequentially. After the addition was complete, the mixture was stirred overnight at room temperature, and the reaction was confirmed to be complete by LC-MS. Sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, washed with saturated ammonium chloride solution, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by pre-TLC to give the title compound (46 mg).

[0255]

[0256] MS(ESI)m / z(M+H) + =312.0.

[0257] Step 2: Preparation of 6-(tert-butyl)-2-methyl-7-carbamoyl-7,8-dihydro-1,6-naphthidine-2,6(5H)-dicarboxylate

[0258] At room temperature, 40 mg of 7-carbamoyl-2-chloro-7,8-dihydro-1,6-naphthyl-6-(5H)-carboxylic acid tert-butyl ester was dissolved in methanol (20 mL). Palladium acetate (15 mg), 1,1'-bis(diphenylphosphine)ferrocene (72 mg), and triethylamine (65 mg) were added. After the addition was complete, the system was purged with carbon monoxide and heated to 65 °C overnight under a carbon monoxide atmosphere with stirring. The reaction was monitored by LC-MS until complete, and the mixture was concentrated under reduced pressure. The crude product was purified by pre-TLC to give the title compound (39 mg).

[0259]

[0260] MS(ESI)m / z(M+H) + =336.0.

[0261] Step 3: Preparation of 6-(tert-Butoxycarbonyl)-7-carbamoyl-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylic acid

[0262] At room temperature, 39 mg of 6-(tert-butyl)-2-methyl-7-carbamoyl-7,8-dihydro-1,6-naphthidine-2,6(5H)-dicarboxylate was dissolved in a tetrahydrofuran (1 mL) / methanol (1 mL) / water (1 mL) system, and 10 mg of lithium hydroxide monohydrate was added and stirred for 30 minutes. The reaction was confirmed to be complete by LCMS, and the solution was concentrated under reduced pressure to obtain the crude product of the title compound.

[0263]

[0264] MS(ESI)m / z(M+H) + =322.0.

[0265] Step 4: Preparation of 7-carbamoyl-5,6,7,8-tetrahydro-1,6-naphthyl-2-carbamate

[0266] At room temperature, the crude product of 6-(tert-butoxycarbonyl)-7-carbamoyl-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylic acid obtained in step 3 was added to a 1,4-dioxane system (4M, 2 mL) containing hydrochloric acid. The mixture was stirred for 30 minutes, and the reaction was confirmed to be complete by LCMS. The mixture was then concentrated under reduced pressure. The title compound (10 mg) was obtained by pre-HPLC purification.

[0267]

[0268] MS(ESI)m / z(M+H) + =222.1.

[0269] 1 H NMR (400MHz, Deuterium Oxide) δ8.16–7.86(m,2H),4.63–4.58(m,1H),4.55–4.42(m,2H),3.74–3.49(m,1H),3.46–3.22(m,1H).

[0270] Example 9 Preparation of 7-(1-hydroxycyclopropyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0271]

[0272] Step 1: Preparation of tert-butyl 2-chloro-7-(1-hydroxycyclopropyl)-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0273] 98 mg of 6-(tert-butyl)-7-methyl-2-chloro-7,8-dihydro-1,6-naphthyl-6,7(5H)-dicarboxylate and 85 mg of tetraisopropyl titanate were weighed into a dry reaction flask, purged three times with nitrogen, and 2.5 mL of tetrahydrofuran was injected. Under ice bath conditions, 1.2 mL (1.0 M) of tetrahydrofuran solution of magnesium ethyl bromide was slowly added dropwise, and the mixture was slowly brought to room temperature for 2 hours. TLC showed that the reaction was complete. The reaction was quenched with saturated ammonium chloride aqueous solution, followed by the addition of ethyl acetate and water. The mixture was extracted separately, and the organic phase was concentrated to dryness. The crude product was purified by column chromatography to give the title compound (50 mg).

[0274]

[0275] MS(ESI)m / z(M+H) + =325.1.

[0276] Step 2: Preparation of 6-(tert-butyl)-2-methyl-7-(1-hydroxycyclopropyl)-7,8-dihydro-1,6-naphthidine-2,6(5H)-dicarboxylate

[0277] 50 mg of tert-butyl 2-chloro-7-(1-hydroxycyclopropyl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate was dissolved in methanol (8 mL), and palladium acetate (17 mg), 1,1'-bis(diphenylphosphine)ferrocene (83 mg), and triethylamine (76 mg) were added sequentially. The mixture was purged three times with carbon monoxide and reacted overnight at 65 °C under a carbon monoxide atmosphere. TLC showed that the reaction was essentially complete. The solution was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography to give the title compound (40 mg).

[0278]

[0279] MS(ESI)m / z(M+H) + =349.1.

[0280] Step 3: Preparation of 7-(1-hydroxycyclopropyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0281] 40 mg of 6-(tert-butyl)-2-methyl-7-(1-hydroxycyclopropyl)-7,8-dihydro-1,6-naphthidine-2,6(5H)-dicarboxylate was dissolved in methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL). Lithium hydroxide monohydrate (10 mg) was added. The reaction was carried out at room temperature for 1 hour, and TLC showed that the reaction was essentially complete. The system was concentrated to dryness, and 3 mL of dichloromethane and 1 mL of 1,4-dioxane solution of hydrogen chloride (4.0 M) were added. The reaction was carried out at room temperature for 1 hour, and TLC showed that the reaction was essentially complete. The system was concentrated to dryness and purified by pre-HPLC to obtain the title compound (14.8 mg).

[0282]

[0283] MS(ESI)m / z(M+H) + =235.1.

[0284] 1 H NMR (400MHz, Deuterium Oxide) δ7.71 (s, 2H), 4.43 (s, 2H), 3.29 (d, J = 15.6Hz, 1H), 3.21 (s, 2H), 0.9 (s, 2H), 0.74 (s, 2H).

[0285] Example 10 Preparation of 7-(4-hydroxybutyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0286]

[0287] Step 1: Preparation of (3-((tert-butyldimethylsilyl)oxy)propyl)triphenylphosphonium bromide

[0288] At room temperature, 1.012 g of 3-bromopropoxy-tert-butyldimethylsilane and 1.048 g of triphenylphosphine were dissolved in 15 mL of acetonitrile. The mixture was heated to 80 °C and stirred overnight. The reaction was confirmed to be complete by LC-MS, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the title compound (1.176 g).

[0289]

[0290] MS(ESI)m / z(M+H) + =435.2.

[0291] Step 2: Preparation of tert-butyl 7-(4-((tert-butyldimethylsilyl)oxy)but-1-en-1-yl)-2-chloro-7,8-dihydro-1,6-naphthidium-6(5H)-carboxylate

[0292] Under a nitrogen atmosphere, (3-((tert-butyldimethylsilyl)oxy)propyl)triphenylphosphonium bromide (178 mg) was dissolved in tetrahydrofuran. Sodium hydride (8 mg) was added and stirred for 30 minutes in an ice bath. Then, tert-butyl 2-chloro-7-formyl-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate (96 mg) was added. The reaction was confirmed to be complete by LC-MS. The reaction system was placed in an ice bath, quenched dropwise with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give the title compound (38 mg).

[0293]

[0294] MS(ESI)m / z(M+H-Boc) + =353.1.

[0295] Step 3: Preparation of 6-(tert-butyl)2-methyl-7-(4-((tert-butyldimethylsilyl)oxy)but-1-en-1-yl)-7,8-dihydro-1,6-naphthidine-2,6(5H)-dicarboxylate

[0296] At room temperature, tert-butyl 7-(4-((tert-butyldimethylsilyl)oxy)but-1-en-1-yl)-2-chloro-7,8-dihydro-1,6-naphthidium-6(5H)-carboxylate (36 mg) was dissolved in methanol (20 mL), followed by the addition of palladium acetate (9 mg), 1,1'-bis(diphenylphosphine)ferrocene (44 mg), and triethylamine (16 mg). After the addition was complete, the system was purged with carbon monoxide and heated to 65 °C overnight with stirring. The reaction was monitored by LCMS until complete, and the mixture was concentrated under reduced pressure. The crude product was purified by pre-TLC to give the title compound (26 mg).

[0297]

[0298] MS(ESI)m / z(M+H) + =477.2.

[0299] Step 4: Preparation of 6-(tert-butyl)2-methyl7-(4-((tert-butyldimethylsilyl)oxy)butyl)-7,8-dihydro-1,6-naphthidine-2,6(5H)-dicarboxylate

[0300] At room temperature, 26 mg of 6-(tert-butyl)-2-methyl-7-(4-((tert-butyldimethylsilyl)oxy)but-1-en-1-yl)-7,8-dihydro-1,6-naphthidine-2,6(5H)-dicarboxylate was dissolved in 20 mL of ethyl acetate. 5 mg of palladium on carbon was added. After the addition was complete, the system was purged with hydrogen gas and stirred for 3 hours under a hydrogen atmosphere. The reaction was confirmed to be complete by LC-MS. The mixture was filtered, concentrated under reduced pressure, and the crude product of the title compound (25 mg) was obtained.

[0301]

[0302] MS(ESI)m / z(M+H) + =479.3.

[0303] Step 5: Preparation of 6-(tert-Butoxycarbonyl)-7-(4-((tert-Butyldimethylsilyl)oxy)butyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylic acid

[0304] At room temperature, 6-(tert-butyl)2-methyl7-(4-((tert-butyldimethylsilyl)oxy)butyl)-7,8-dihydro-1,6-naphthidine-2,6(5H)-dicarboxylate (25 mg) was dissolved in a tetrahydrofuran (1 mL) / methanol (1 mL) / water (1 mL) system, and lithium hydroxide monohydrate (21 mg) was added and stirred for 1 hour. The reaction was confirmed to be complete by LCMS. The solution was adjusted to weak acidity by a 1,4-dioxane system (4 M) with hydrochloric acid and concentrated under reduced pressure to obtain the crude product of the title compound.

[0305]

[0306] MS(ESI)m / z(M+H) + =465.1.

[0307] Step 6: Preparation of 7-(4-hydroxybutyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0308] At room temperature, the crude product of 6-(tert-butoxycarbonyl)-7-(4-((tert-butyldimethylsilyl)oxy)butyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylic acid prepared in step 5 was added to a 1,4-dioxane system (4M, 2mL) containing hydrochloric acid and stirred for 30 minutes. The reaction was confirmed to be complete by LCMS. The mixture was concentrated under reduced pressure and purified by pre-HPLC to obtain the title compound (2.3 mg).

[0309]

[0310] MS(ESI)m / z(M+H)+=251.1.

[0311] 1H NMR(400MHz,Deuterium Oxide)δ7.66(s,2H),4.38(s,2H),3.72–3.60(m,1H),3.56(t,J=6.1Hz,2H),3.25(dd,J =18.0,4.8Hz,1H),2.93(dd,J=18.0,10.8Hz,1H),1.91–1.65(m,2H),1.62–1.39(m,4H).

[0312] Example 11 Preparation of 7-(((3-hydroxypropyl)amino)methyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylic acid dihydrochloride

[0313]

[0314] Step 1: Preparation of tert-butyl 2-chloro-7-(((3-hydroxypropyl)amino)methyl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylic acid

[0315] At room temperature, tert-butyl 2-chloro-7-formyl-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (97 mg) was dissolved in 1,2-dichloroethane (5 mL), and 3-amino-1-propanol (34 mg) was added and stirred for 30 minutes. Sodium triacetoxyborohydride (254 mg) was added and stirred overnight. The reaction was confirmed to be complete by LC-MS. The solution was diluted with dichloromethane (20 mL), washed with water, extracted with dichloromethane, and the organic phase was separated. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude title compound, which was used directly in the next reaction.

[0316]

[0317] MS(ESI)m / z(M+H) + =356.1.

[0318] Step 2: Preparation of tert-butyl 7-(((tert-butoxycarbonyl)(3-hydroxypropyl)amino)methyl)-2-chloro-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylic acid

[0319] At room temperature, tert-butyl 2-chloro-7-(((3-hydroxypropyl)amino)methyl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate obtained in step 1 was dissolved in methanol (5 mL), and di-tert-butyl dicarbonate (87 mg) was added and stirred for 1 hour. The reaction was confirmed to be complete by LC-MS. The solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the title compound (67 mg).

[0320]

[0321] MS(ESI)m / z(M+1) + =456.0.

[0322] Step 3: Preparation of 6-(tert-butyl)2-methyl 7-(((tert-butoxycarbonyl)(3-hydroxypropyl)amino)methyl)-7,8-dihydro-1,6-naphthidine-2,6(5H)-dicarboxylate

[0323] At room temperature, 67 mg of tert-butyl 7-(((tert-butoxycarbonyl)(3-hydroxypropyl)amino)methyl)-2-chloro-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate was dissolved in 20 mL of methanol. Palladium acetate (17 mg), 81 mg of 1,1'-bis(diphenylphosphine)ferrocene, and 30 mg of triethylamine were added. After the addition was complete, the system was purged with carbon monoxide and heated to 65 °C overnight with stirring. The reaction was monitored by LCMS until complete, and the mixture was concentrated under reduced pressure. The crude product was purified by pre-TLC to give the title compound (43 mg).

[0324]

[0325] MS(ESI)m / z(M+H) + =480.0.

[0326] Step 4: Preparation of methyl 7-(((3-hydroxypropyl)amino)methyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0327] At room temperature, 43 mg of 6-(tert-butyl)2-methyl-7-(((tert-butoxycarbonyl)(3-hydroxypropyl)amino)methyl)-7,8-dihydro-1,6-naphthidine-2,6(5H)-dicarboxylate was added to a 1,4-dioxane system (4 M, 2 mL) containing hydrochloric acid. The mixture was stirred for 30 minutes, and the reaction was confirmed to be complete by LC-MS. The solution was then concentrated under reduced pressure to obtain the crude product of the title compound.

[0328]

[0329] MS(ESI)m / z(M+H) + =280.1.

[0330] Step 5: Preparation of 7-(((3-hydroxypropyl)amino)methyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate salt

[0331] At room temperature, the crude methyl 7-(((3-hydroxypropyl)amino)methyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate prepared in step 4 was dissolved in a tetrahydrofuran (1 mL) / methanol (1 mL) / water (1 mL) system. Lithium hydroxide monohydrate (38 mg) was added and stirred for 30 minutes. The reaction was confirmed to be complete by LCMS. The solution was adjusted to weak acidity by a 1,4-dioxane system (4 M) with hydrochloric acid, the solvent was removed under reduced pressure, and the title compound (21.8 mg) was obtained by pre-HPLC purification.

[0332]

[0333] MS(ESI)m / z(M+H) + =266.1.

[0334] 1 H NMR(400MHz, Deuterium Oxide)δ7.91(s,2H),4.53–4.26(m,2H),3.88(s,1H),3.65(t,J=5.8Hz,2H),3.39(d,J=29.3Hz,3H),3.20(s,2H),3.05(s,1H),1.90(s,2H).

[0335] Example 12 Preparation of 7-(hydroxy(phenyl)methyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate salt

[0336]

[0337] Step 1: Preparation of tert-butyl 2-chloro-7-(hydroxy(phenyl)methyl)-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0338] Under a nitrogen atmosphere, tert-butyl 2-chloro-7-formyl-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (97 mg) was dissolved in tetrahydrofuran (10 mL). Phenyl magnesium bromide (0.42 mL) was added dropwise under ice bath conditions, and the mixture was stirred for 1.5 hours. The reaction was confirmed to be complete by LC-MS. The mixture was quenched with ammonium chloride solution, and the aqueous / ethyl acetate system was separated. The extract was obtained with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the title compound (86 mg).

[0339]

[0340] MS(ESI)m / z(M+H) + =375.1.

[0341] Step 2: Preparation of 6-(tert-butyl)-2-methyl-7-(hydroxy(phenyl)methyl)-7,8-dihydro-1,6-naphthidine-2,6(5H)-dicarboxylate

[0342] At room temperature, tert-butyl 2-chloro-7-(hydroxy(phenyl)methyl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (86 mg) was dissolved in methanol (20 mL), followed by the addition of palladium acetate (23 mg), ferrocene 1,1'-bis(diphenylphosphine) (127 mg), and triethylamine (47 mg). After the addition was complete, the system was purged with carbon monoxide and heated to 65 °C overnight with stirring. The reaction was monitored by LCMS until complete, and the mixture was concentrated under reduced pressure. The crude product was purified by pre-TLC to give the title compound (67 mg).

[0343]

[0344] MS(ESI)m / z(M+H)+=399.1.

[0345] Step 3: Preparation of methyl 7-(hydroxy(phenyl)methyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0346] At room temperature, 40 mg of 6-(tert-butyl)-2-methyl-7-(hydroxy(phenyl)methyl)-7,8-dihydro-1,6-naphthidine-2,6(5H)-dicarboxylate was added to a 1,4-dioxane system (4 M, 2 mL) containing hydrochloric acid. The mixture was stirred for 30 minutes, and the reaction was confirmed to be complete by LC-MS. The solution was then concentrated under reduced pressure to obtain the crude product of the title compound.

[0347]

[0348] MS(ESI)m / z(M+H) + =299.0.

[0349] Step 4: Preparation of 7-(hydroxy(phenyl)methyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0350] At room temperature, the crude methyl 7-(hydroxy(phenyl)methyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate prepared in step 3 was dissolved in a tetrahydrofuran (1 mL) / methanol (1 mL) / water (1 mL) system, and lithium hydroxide monohydrate (42 mg) was added and stirred for 30 minutes. The reaction was confirmed to be complete by LCMS. The solution was adjusted to weak acidity by a 1,4-dioxane system (4 M) with hydrochloric acid, concentrated under reduced pressure, and purified by pre-HPLC to obtain the title compound (17.2 mg).

[0351]

[0352] MS(ESI)m / z(M+H) + =285.1.

[0353] 1 H NMR(400MHz, Deuterium Oxide)δ8.20–8.14(m,1H),8.11(d,J=8.2Hz,1H),7.57–7.29(m,5H),5.26(dd,J=3.7,1.5 Hz,1H),4.63(s,2H),4.12–4.00(m,1H),3.30(dd,J=18.5,11.9Hz,1H),3.16–3.05(m,1H).

[0354] Example 13 Preparation of 7-(1,4-dihydroxybutyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0355]

[0356] Step 1: Preparation of 6-(tert-Butoxycarbonyl)-2-chloro-5,6,7,8-tetrahydro-1,6-naphthyl-7-carboxylic acid

[0357] At room temperature, 1 g of 6-(tert-butyl)-7-methyl-2-chloro-7,8-dihydro-1,6-naphthidine-6,7(5H)-dicarboxylate was dissolved in a mixture of 3 mL tetrahydrofuran, 3 mL methanol, and 3 mL water. 0.257 g of lithium hydroxide hydrate was added, and the mixture was stirred for 30 minutes. The reaction was confirmed to be complete by LC-MS. Under ice bath conditions, the pH was adjusted to 4-5 with dilute hydrochloric acid (1 M). The mixture was extracted with ethyl acetate / water, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 0.95 g of the title compound.

[0358]

[0359] MS(ESI)m / z(M+H) + =313.1.

[0360] Step 2: Preparation of tert-butyl 2-chloro-7-(methoxy(methyl)carbamoyl)-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0361] At room temperature, 0.95 g of 6-(tert-butoxycarbonyl)-2-chloro-5,6,7,8-tetrahydro-1,6-naphthyl-7-carboxylic acid was dissolved in 20 mL of dichloromethane. Then, 3.0 mL of N,N-diisopropylethylamine, 1.28 g of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and 0.6 g of methoxymethylamine hydrochloride were added sequentially, and the mixture was stirred overnight. TLC showed that the reaction was complete. The mixture was then extracted with dichloromethane / water, washed with saturated sodium chloride solution, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give the title compound (900 mg).

[0362]

[0363] MS(ESI)m / z(M+H) + =356.1.

[0364] Step 3: Preparation of tert-butyl 2-chloro-7-formyl-7,8-dihydro-1,6-naphthidine-6(5H)-formate

[0365] 0.9 g of tert-butyl 2-chloro-7-(methoxy(methyl)carbamoyl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate was dissolved in 20 mL of anhydrous tetrahydrofuran. Under a nitrogen atmosphere, the system was cooled to -78 °C, and 7.6 mL of diisobutylaluminum hydride solution was added. After the addition was complete, the system was slowly heated to room temperature and stirred for 3 hours. LC-MS analysis confirmed the reaction was complete. The reaction system was placed in an ice bath, quenched with water dropwise for 10 minutes, and then 20 mL of saturated sodium potassium tartrate solution was added and stirred for 20 minutes. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the title compound (0.54 g).

[0366]

[0367] MS(ESI)m / z(M+H) + =297.0.

[0368] Step 4: Preparation of tert-butyl 7-(4-((tert-butyldimethylsilyl)oxy)-1-hydroxybutyl)-2-chloro-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0369] 128 mg of tert-butyl 2-chloro-7-formyl-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate was dissolved in 20 mL of anhydrous tetrahydrofuran. The mixture was purged with nitrogen three times, and the system was cooled to 0 °C. 0.42 mL of 2 M 3-(tert-butyldimethylsilyloxy)propylmagnesium bromide was added dropwise, and the reaction was maintained at this temperature for 20 minutes. The reaction was confirmed to be complete by LC-MS. The reaction mixture was then placed in an ice bath and quenched with water for 10 minutes. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the title compound (70 mg).

[0370]

[0371] MS(ESI)m / z(M+H) + =471.2

[0372] Step 5: Preparation of 6-(tert-butyl)2-methyl 7-(4-(((tert-butyldimethylsilyl)oxy)-1-hydroxybutyl)-7,8-dihydro-1,6-naphthidine-2,6(5H)-dicarboxylate

[0373] 70 mg of 7-(4-((tert-butyldimethylsilyl)oxy)-1-hydroxybutyl)-2-chloro-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylic acid tert-butyl ester was weighed and dissolved in methanol (10 mL). Triethylamine (30.1 mg), palladium acetate (16.7 mg), and 1,1'-bis(diphenylphosphine)ferrocene (82.5 mg) were added. Carbon monoxide gas was introduced, and the mixture was heated to 65 °C and reacted overnight. LC-MS showed that the reaction was complete. The system was concentrated, purified by column chromatography, and the title compound (80 mg) was obtained.

[0374]

[0375] MS(ESI)m / z(M+H) + =495.2.

[0376] Step 6: Preparation of methyl 7-(1,4-dihydroxybutyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0377] Weigh 80 mg of 6-(tert-butyl)-2-methyl-7-(4-(((tert-butyldimethylsilyl)oxy)-1-hydroxybutyl)-7,8-dihydro-1,6-naphthidine-2,6(5H)-dicarboxylate and dissolve it in 3 mL of dichloromethane solution. Add 3 mL of 4 M 1,4-dioxane hydrochloride solution dropwise under ice bath conditions, maintaining the temperature for 30 minutes. LC-MS showed the reaction was complete. The system was concentrated to give 50 mg of the crude title compound.

[0378]

[0379] MS(ESI)m / z(M+H) + =281.1.

[0380] Step 7: Preparation of 7-(1,4-dihydroxybutyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0381] 70 mg of methyl 7-(1,4-dihydroxybutyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate was dissolved in tetrahydrofuran (1 mL), water (1 mL), and methanol (1 mL). Lithium hydroxide monohydrate (13.44 mg) was added under ice bath conditions, and the reaction was carried out at room temperature for 30 minutes. LC-MS showed that the reaction was complete. The pH was adjusted to 4-5 with hydrochloric acid solution, and the system was concentrated to obtain a crude product. Pre-HPLC purification yielded the title compound (7 mg).

[0382]

[0383] MS(ESI)m / z(M+H) +=267.0

[0384] 1 H NMR(400MHz, Deuterium Oxide)δ7.63–7.51(m,2H),4.02(d,J=7.8Hz,2H),3.77(dt,J=7.6,3.8Hz,1H),3.57(q, J=4.4,2.9Hz,2H),3.10(dt,J=11.2,4.2Hz,1H),3.01–2.70(m,2H),1.73–1.44(m,4H).

[0385] Example 14 Preparation of 8-((3-isobutylpiperazin-1-yl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate salt)

[0386]

[0387] Step 1: Preparation of tert-butyl 8-(4-(tert-butoxycarbonyl)-3-isobutylpiperazin-1-yl)-2-chloro-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0388] 50 mg of tert-butyl 2-chloro-8-((methanesulfonyl)oxy)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate was dissolved in a mixed solvent of 0.5 mL N,N-dimethylformamide and 0.5 mL acetonitrile. Then, 51 mg of tert-butyl 2-isobutylpiperazine-1-carboxylate and 40 mg of potassium carbonate were added. The mixture was heated to 70 °C and reacted overnight. TLC monitoring showed the disappearance of the starting material. After cooling to room temperature, the mixture was quenched with water, extracted with ethyl acetate, and the organic phases were combined. The organic phase was then washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the title compound (30 mg).

[0389]

[0390] MS(ESI)m / z(M+H) + =509.0 / 510.9.

[0391] Step 2: Preparation of tert-butyl 8-(4-(tert-butoxycarbonyl)-3-isobutylpiperazin-1-yl)-2-cyano-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0392] Weigh 30 mg of tert-butyl 8-(4-(tert-butyloxycarbonyl)-3-isobutylpiperazin-1-yl)-2-chloro-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate and dissolve it in a mixed solvent of 1 mL of 1,4-dioxane and 0.5 mL of water. Then add potassium acetate (12 mg), potassium hexacyanoferrate trihydrate (13 mg), 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl (3 mg), and methanesulfonic acid (2-dicyclohexylphospho-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (3 mg). The system was purged with nitrogen three times and then sealed. The reaction was carried out at 125 °C for 1 h. The reaction was monitored by LC-MS until it was complete. Cool to room temperature, filter, wash the filter cake several times with ethyl acetate, add water to the filtrate to separate the organic layer, extract the aqueous phase three times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure to dryness, and purify by column chromatography to obtain the title compound (20 mg).

[0393]

[0394] MS(ESI)m / z(M+H) + =500.0.

[0395] Step 3: Preparation of 8-((3-isobutylpiperazin-1-yl)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate salt)

[0396] Weigh 20 mg of tert-butyl 8-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-cyano-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate and dissolve it in 2 mL of 6 M hydrochloric acid aqueous solution. React at 110 °C overnight, and monitor the reaction until complete by LC-MS. Concentrate under reduced pressure and purify by pre-HPLC to give the title compound (1.48 mg).

[0397]

[0398] MS(ESI)m / z(M+H) + =319.1.

[0399] 1H NMR(400MHz, Deuterium Oxide)δ7.84-7.78(dd,J=13.3,8.0Hz,1H),7.72-7.68(m,1H),4.20-4.14( dd,J=16.8,4.3Hz,1H),4.10-4.03(m,2H),3.43-3.32(m,2H),3.25-3.20(m, 1H),3.18-2.67(m,5H),2.65-2.45(dt,J=56.1,11.6Hz,1H),1.50-1.42(dq, J=13.2,6.7Hz,1H),1.32-1.28(q,J=8.4,7.6Hz,2H),0.74(t,J=5.2Hz,6H).

[0400] Example 15 Preparation of 8-(2-benzylmorpholino)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0401]

[0402] Step 1: Preparation of tert-butyl 8-(2-benzylmorpholino)-2-chloro-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0403] 50 mg of tert-butyl 2-chloro-8-((methanesulfonyl)oxy)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate was dissolved in a mixed solvent of 0.5 mL N,N-dimethylformamide and 0.5 mL acetonitrile. 38 mg of 2-benzylmorpholine and 40 mg of potassium carbonate were then added. The mixture was heated to 70 °C and reacted overnight. TLC monitoring showed the disappearance of the starting material. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the title compound (25 mg).

[0404]

[0405] MS(ESI)m / z(M+H) + =444.0 / 446.0.

[0406] Step 2: Preparation of tert-butyl 8-(2-benzylmorpholino)-2-cyano-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0407] Weigh 25 mg of tert-butyl 8-(2-benzylmorpholino)-2-chloro-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate and dissolve it in a mixed solvent of 1,4-dioxane (1 mL) and water (0.5 mL). Then add potassium acetate (12 mg), potassium hexacyanoferrate trihydrate (13 mg), 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl (3 mg), and methanesulfonic acid (2-dicyclohexylphospho-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (3 mg). The system was purged with nitrogen three times and then sealed. The reaction was carried out at 125 °C for 2 h. The reaction was monitored by LC-MS until it was complete. Cool to room temperature, filter, wash the filter cake several times with ethyl acetate, add water to the filtrate to separate the organic layer, extract the aqueous phase three times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure to dryness, and purify by column chromatography to obtain the title compound (20 mg).

[0408]

[0409] MS(ESI)m / z(M+H) + =435.0.

[0410] Step 3: Preparation of 8-(2-benzylmorpholino)-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0411] Weigh 20 mg of tert-butyl 8-(2-benzylmorpholino)-2-cyano-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate and dissolve it in 2 mL of 6 M hydrochloric acid aqueous solution. React overnight at 105 °C, and monitor the reaction until complete by LC-MS. Concentrate under reduced pressure and purify by pre-HPLC to obtain the title compound (10.34 mg).

[0412]

[0413] MS(ESI)m / z(M+H) + =354.0.

[0414] 1 H NMR (400MHz, Methanol-d4) δ7.99-7.97(d,J=8.0Hz,1H),7.77-7.74(d,J=8.1Hz,1H),7.29-7.16(m,5H),4.43-4.27(m,3H),4.21- 4.16(m,1H),3.95-3.92(m,1H),3.82-3.72(m,2H),3.50-3.46(dd,J=13.3,3.6Hz,1H),2.90(d,J=10.9Hz,1H),2.84-2.51(m,5H).

[0415] Example 16 Preparation of 5,6,7,8-tetrahydro-1,6-naphthyl-2,7-dicarboxylate

[0416]

[0417] Step 1: Preparation of 6-(tert-butyl)2,7-dimethyl 7,8-dihydro-1,6-naphthidine-2,6,7(5H)-tricarboxylate

[0418] 100 mg of 6-(tert-butyl)-7-methyl-2-chloro-7,8-dihydro-1,6-naphthidine-6,7(5H)-dicarboxylate was dissolved in 10 mL of methanol. Triethylamine (0.085 mL), palladium acetate (34.3 mg), and 1,1'-bis(diphenylphosphine)ferrocene (169.5 mg) were added. Carbon monoxide gas was introduced, and the mixture was heated to 65 °C and reacted overnight. LC-MS showed that the reaction was complete. The system was concentrated, and the mixture was purified by column chromatography to give the title compound (70 mg).

[0419]

[0420] MS(ESI)m / z(M+H) + =351.1.

[0421] Step 2: Preparation of 6-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydro-1,6-naphthyl-2,7-dicarboxylic acid

[0422] 70 mg of 6-(tert-butyl)-2,7-dimethyl-7,8-dihydro-1,6-naphthyl-2,6,7(5H)-tricarboxylate was dissolved in tetrahydrofuran (3 mL), water (3 mL), and methanol (3 mL). Lithium hydroxide monohydrate (16.6 mg) was added under ice bath conditions, and the reaction was allowed to proceed overnight at room temperature. LC-MS showed that the reaction was complete. The pH was adjusted to weakly acidic with hydrochloric acid solution, and the system was concentrated to give 100 mg of the crude title compound.

[0423]

[0424] MS(ESI)m / z(M+H) + =323.1.

[0425] Step 3: Preparation of 5,6,7,8-tetrahydro-1,6-naphthyl-2,7-dicarboxylate

[0426] 6-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydro-1,6-naphthidine-2,7-dicarboxylic acid (63.4 mg) was weighed and dissolved in dichloromethane (3 mL). 4M 1,4-dioxane hydrochloride solution (3 mL) was added dropwise under ice bath conditions, and the reaction was maintained at this temperature for 30 minutes. LC-MS showed that the reaction was complete. The system was concentrated and purified by pre-HPLC to obtain the title compound (35 mg).

[0427]

[0428] MS(ESI)m / z(M+H) + =223.0.

[0429] 1 H NMR (400MHz, Deuterium Oxide) δ7.75 (s, 2H), 4.45 (q, J = 16.1Hz, 2H), 4.10 (dd, J = 11.7, 5.1Hz, 1H), 3.55–3.38 (m, 1H), 3.19 (dd, J = 18.0, 11.7Hz, 1H).

[0430] Example 17 Preparation of 3-fluoro-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0431]

[0432] Step 1: Preparation of 2-chloro-5-fluoro-6-((4-methoxybenzyl)oxy)nicotinonitrile

[0433]

[0434] Weigh 5.0 g of 2,6-dichloro-5-fluoronicotinonitrile and dissolve it in 50 mL of tetrahydrofuran. The solution was cooled to -78 °C and stirred. Potassium tert-butoxide (3.5 g) was added under nitrogen protection. A 50 mL solution of tetrahydrofuran containing 3.95 g of 4-methoxybenzyl chloride was added dropwise to -78 °C. After the addition was complete, the mixture was heated to room temperature and reacted overnight. TLC showed that the reaction was complete. The solution was concentrated under reduced pressure, ethyl acetate and water were added, and the mixture was extracted separately. The organic phase was concentrated to dryness. The crude product was purified by column chromatography to give the title compound (6.2 g).

[0435] MS(ESI)m / z(M+H) + =293.1.

[0436] Step 2: Preparation of 5-fluoro-6-((4-methoxybenzyl)oxy)-2-vinylnicotinonitrile

[0437]

[0438] 2-Chloro-5-fluoro-6-((4-methoxybenzyl)oxy)nicotinonitrile (6.0 g), potassium vinyltrifluoroborate (5.5 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.29 g), and cesium fluoride (6.23 g) were weighed into a reaction flask. 1,4-dioxane (60 mL) and water (6 mL) were added, and the mixture was purged with nitrogen. The reaction was carried out overnight at 90 °C. TLC showed that the reaction was essentially complete. The mixture was concentrated to dryness under reduced pressure, and ethyl acetate and water were added. The mixture was extracted separately, and the organic phase was concentrated to dryness. The crude product was purified by column chromatography to give the title compound (2.68 g).

[0439] MS(ESI)m / z(M+H) + =285.1.

[0440] Step 3: Preparation of 6-benzyl-3-fluoro-2-((4-methoxybenzyl)oxy)-7,8-dihydro-1,6-naphthidium-5(6H)-one

[0441]

[0442] 2.68 g of 5-fluoro-6-((4-methoxybenzyl)oxy)-2-vinylnicotinonitrile was dissolved in 20 mL of methanol and 4 mL of water, and 12.44 g of benzylamine was added. The reaction was carried out overnight at 80 °C, and TLC showed that the reaction was essentially complete. The mixture was concentrated under reduced pressure, and dichloromethane and water were added. The mixture was extracted by separation, and the organic phase was washed with 1 M dilute hydrochloric acid and concentrated to dryness. The crude product was purified by column chromatography to give the title compound (2.37 g).

[0443] MS(ESI)m / z(M+H) + =393.1.

[0444] Step 4: Preparation of 6-benzyl-3-fluoro-2-((4-methoxybenzyl)oxy)-5,6,7,8-tetrahydro-1,6-naphthidine

[0445]

[0446] 1.19 g of 6-benzyl-3-fluoro-2-((4-methoxybenzyl)oxy)-7,8-dihydro-1,6-naphthidium-5(6H)-one was dissolved in 20 mL of tetrahydrofuran. Lithium aluminum hydride (0.29 g) was added in portions under ice bath conditions. The reaction was carried out at 70 °C for 4 hours, and TLC showed that the reaction was essentially complete. Then, 0.5 mL of water, 0.5 mL of 15% sodium hydroxide aqueous solution, and 1.5 mL of water were added dropwise under ice bath conditions. After stirring at room temperature for 15 minutes, anhydrous magnesium sulfate was added and stirred for another 15 minutes. The mixture was filtered through diatomaceous earth and anhydrous sodium sulfate. The residue was washed with ethyl acetate, and the filtrate was concentrated to dryness to obtain the title compound (1.15 g).

[0447] MS(ESI)m / z(M+H) + =379.1.

[0448] Step 5: Preparation of 6-benzyl-2-chloro-3-fluoro-5,6,7,8-tetrahydro-1,6-naphthidine

[0449]

[0450] Weigh 1.14 g of 6-benzyl-3-fluoro-2-((4-methoxybenzyl)oxy)-5,6,7,8-tetrahydro-1,6-naphthidine and add 10 mL of phosphorus oxychloride under ice bath conditions. React overnight at 100 °C; TLC showed the reaction was essentially complete. Concentrate under reduced pressure, dilute with ethyl acetate, add dropwise to crushed ice, and adjust the pH to 10 with saturated sodium carbonate solution. Extract with ethyl acetate, wash with saturated sodium chloride aqueous solution, and dry the organic phase with anhydrous sodium sulfate. Filter, wash, and concentrate the filtrate to dryness to obtain the crude title compound (0.82 g).

[0451] MS(ESI)m / z(M+H) + =277.1.

[0452] Step 6: Preparation of 2-chloro-3-fluoro-5,6,7,8-tetrahydro-1,6-naphthidine

[0453]

[0454] Weigh 0.82 g of 6-benzyl-2-chloro-3-fluoro-5,6,7,8-tetrahydro-1,6-naphthidine and dissolve it in 8 mL of 1,2-dichloroethane. Under ice bath conditions, add 1.93 g of N,N-diisopropylethylamine and 2.57 g of 1-chloroethyl chloroformate sequentially. React at 80 °C for 1.5 hours. TLC showed that the reaction was essentially complete. Concentrate the system to dryness, dissolve it in methanol, and react at 60 °C for 1.5 hours. TLC showed that the reaction was essentially complete. Concentrate the system to dryness under reduced pressure to obtain the crude product.

[0455] MS(ESI)m / z(M+H) + =187.1.

[0456] Step 7: Preparation of 6-(tert-Butoxycarbonyl)-2-chloro-3-fluoro-5,6,7,8-tetrahydro-1,6-naphthidine

[0457]

[0458] 2-Chloro-3-fluoro-5,6,7,8-tetrahydro-1,6-naphthidine was weighed and dissolved in dichloroethane (10 mL). Triethylamine (0.91 g) and di-tert-butyl dicarbonate (0.98 g) were added under ice bath conditions. The reaction was carried out at room temperature for 2 hours, and TLC showed that the reaction was essentially complete. Dichloromethane and water were added, and the mixture was extracted separately. The organic phase was concentrated to dryness. The crude product was purified by column chromatography to give the title compound (0.28 g).

[0459] MS(ESI)m / z(M+H) + =287.1.

[0460] Step 8: Preparation of 6-(tert-butyl)-2-methyl-3-fluoro-5,6,7,8-tetrahydro-1,6-naphthidine-2,6-dicarboxylate

[0461]

[0462] 100 mg of 6-(tert-butoxycarbonyl)-2-chloro-3-fluoro-5,6,7,8-tetrahydro-1,6-naphthidine was dissolved in 10 mL of methanol. Palladium acetate (40 mg), 1,1'-bis(diphenylphosphine)ferrocene (200 mg), and triethylamine (71 mg) were added sequentially. The mixture was purged three times with carbon monoxide and reacted overnight at 65 °C under a carbon monoxide atmosphere. TLC showed that the reaction was essentially complete. The solution was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography to give the title compound (100 mg).

[0463] MS(ESI)m / z(M+H) + =311.1.

[0464] Step 9: Preparation of 6-(tert-Butoxycarbonyl)-3-fluoro-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylic acid

[0465]

[0466] 100 mg of 6-(tert-butyl)-2-methyl-3-fluoro-5,6,7,8-tetrahydro-1,6-naphthyl-2,6-dicarboxylate was dissolved in methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL), and lithium hydroxide monohydrate (27 mg) was added. The reaction was carried out at room temperature for 1 hour, and TLC showed that the reaction was basically complete. The system was concentrated to dryness, and the crude product was used directly for the next reaction.

[0467] MS(ESI)m / z(M+H) + =297.1.

[0468] Step 10: Preparation of 3-fluoro-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0469]

[0470] Weigh 94 mg of 6-(tert-butoxycarbonyl)-3-fluoro-5,6,7,8-tetrahydro-1,6-naphthidine-2-carboxylic acid, add 3 mL of dichloromethane and 2 mL of a 1,4-dioxane solution of hydrogen chloride (4.0 M), and react at room temperature for 1 hour. TLC showed that the reaction was essentially complete. The system was concentrated to dryness and separated by reverse-phase preparative column chromatography to give the title compound (62.6 mg).

[0471] MS(ESI)m / z(M+H) + =197.1.

[0472] 1 H NMR (400MHz, Deuterium Oxide) δ7.64(d,J=10.2Hz,1H),4.47(s,2H),3.61(t,J=6.4Hz,2H),3.18(t,J=6.5Hz,2H).

[0473] Example 45 Preparation of 7,7-diethyl-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0474]

[0475] Step 1: Preparation of 2-methyl-N-(pentane-3-yl)propane-2-sulfinamide

[0476] 10.73 g of pentane-3-one was dissolved in 300 mL of tetrahydrofuran. Tetraethyl titanate (46 g) and 2-methylpropane-2-sulfinamide (12 g) were added. The mixture was purged with nitrogen three times, and the reaction was heated to 65 °C for 20 hours. LC-MS was used to monitor the reaction until completion. Water (30 mL) was added to the system, resulting in the precipitation of a large amount of solid. The solid was filtered, dried, concentrated to dryness, and purified by column chromatography to give the title compound (10.8 g).

[0477]

[0478] MS(ESI)m / z(M+H) + =190.1.

[0479] Step 2: Preparation of N-(3-((3-bromo-6-methoxypyridin-2-yl)methyl)pent-3-yl)-2-methylpropane-2-sulfinamide

[0480] 50 mL of tetrahydrofuran was measured and placed in a dry reaction flask. The flask was purged with nitrogen three times, and 25 mL of 2M diisopropylaminolithium was added to lower the temperature to -78 °C. A solution of 9.4 g of 3-bromo-6-methoxy-2-methylpyridine and 50 mL of tetrahydrofuran was added, and the mixture was stirred at -78 °C for 1 hour. A solution of 8 g of 2-methyl-N-(pentane-3-yl)propane-2-sulfinamide and 50 mL of tetrahydrofuran was added, and the temperature was slowly increased from -78 °C to -30 °C, with stirring for 2 hours. The reaction was monitored by LC-MS until complete. The reaction was quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, dried the organic phase, concentrated to dryness, and purified by column chromatography to obtain the title compound (11.3 g).

[0481]

[0482] MS(ESI)m / z(M+H) + =391.1.

[0483] Step 3: Preparation of ethyl 2-(2-((tert-butylsulfinyl)amino)-2-ethylbutyl)-6-methoxynicotinic acid

[0484] 11.3 g of N-(3-((3-bromo-6-methoxypyridin-2-yl)methyl)pent-3-yl)-2-methylpropane-2-sulfinamide was weighed into a dry reaction flask and dissolved in 10 mL of ethanol. 4.73 g of 1,1′-ferrocene diyl-bis(diphenylphosphine)palladium dichloromethane complex and 9.6 mL of triethylamine were added. The mixture was purged three times with carbon monoxide gas and heated to reflux for 6 hours. The reaction was confirmed to be complete by LC-MS, and the system was concentrated to dryness. The title compound (9.3 g) was purified by column chromatography.

[0485]

[0486] MS(ESI)m / z(M+H) + =385.2.

[0487] Step 4: Preparation of 7,7-diethyl-2-methoxy-7,8-dihydro-1,6-naphthidine-5(6H)-one

[0488] 9.3 g of ethyl 2-(2-((tert-butylsulfinyl)amino)-2-ethylbutyl)-6-methoxynicotinic acid was weighed into a dry reaction flask, dissolved in dioxane (10 mL), and sodium hydroxide (4.8 g) was added. The mixture was heated to 100 °C and reacted for 6 hours. The reaction was confirmed to be complete by LC-MS. The system was filtered through diatomaceous earth, and the filtrate was concentrated to dryness. The title compound (4.6 g) was purified by column chromatography.

[0489]

[0490] MS(ESI)m / z(M+H) + =235.1.

[0491] Step 5: Preparation of 7,7-diethyl-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthidine

[0492] Weigh 3 g of 7,7-diethyl-2-methoxy-7,8-dihydro-1,6-naphthidium-5(6H)-one and dissolve it in 100 mL of tetrahydrofuran. Add 1.9 g of lithium aluminum hydride in portions over an ice bath. Heat to reflux and stir overnight. LC-MS was used to confirm the reaction was complete. The mixture was concentrated to dryness under reduced pressure. Purify and separate by silica gel column chromatography to obtain the title compound (2.8 g).

[0493]

[0494] MS(ESI)m / z(M+H) + =221.1.

[0495] Step 6: Preparation of 7,7-diethyl-5,6,7,8-tetrahydro-1,6-naphthidine-2-ol

[0496] Weigh 2.8 g of 7,7-diethyl-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthidine and dissolve it in 20 mL of 33% hydrogen bromide acetic acid. Heat the solution to 80 °C and stir overnight. The reaction was confirmed to be complete by LC-MS. The solution was concentrated to dryness under reduced pressure. Crude acetonitrile was then slurried to obtain the title compound (4.3 g).

[0497]

[0498] MS(ESI)m / z(M+H) + =207.1.

[0499] Step 7: Preparation of 2-chloro-7,7-diethyl-5,6,7,8-tetrahydro-1,6-naphthidine

[0500] Weigh 2.8 g of 7,7-diethyl-5,6,7,8-tetrahydro-1,6-naphthidine-2-ol and dissolve it in 40 mL of phosphorus oxychloride. Heat to 120 °C and react overnight. LC-MS analysis confirmed the reaction was complete. The solution was concentrated to dryness under reduced pressure. Dilute with dichloromethane, add water, and adjust the pH to 9-10 with sodium carbonate. Proceed directly to the next reaction without purification to obtain the crude title compound.

[0501]

[0502] MS(ESI)m / z(M+H) + =225.1.

[0503] Step 8: Preparation of tert-butyl 2-chloro-7,7-diethyl-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate

[0504] Dissolve the crude product from the previous reaction in THF / H2O, treat the system with sodium carbonate, add di-tert-butyl dicarbonate (4.67 mL), stir overnight at room temperature, and check the reaction for completeness by LC-MS. Extract three times with dichloromethane, and concentrate the organic phase after drying. Purify and separate by silica gel column chromatography to obtain the title compound (1.5 g).

[0505]

[0506] MS(ESI)m / z(M+H) + =325.1.

[0507] Step 9: Preparation of 6-(tert-butyl)-2-ethyl 7,7-diethyl-7,8-dihydro-1,6-naphthidine-2,6(5H)-dicarboxylate

[0508] 100 mg of tert-butyl 2-chloro-7,7-diethyl-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate was weighed into a dry reaction flask and dissolved in 10 mL of ethanol. 50.3 mg of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex and 0.11 mL of N,N-diisopropylethylamine were added. Carbon monoxide gas was bubbled through the mixture, and the mixture was heated to 100 °C. The reaction was allowed to proceed overnight. LC-MS was used to confirm the complete reaction, and the mixture was concentrated to dryness. The title compound (80 mg) was purified by column chromatography.

[0509]

[0510] MS(ESI)m / z(M+H) + =363.2.

[0511] Step 10: Preparation of 6-(tert-butoxycarbonyl)-7,7-diethyl-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylic acid

[0512] Weigh 45 mg of 6-(tert-butyl)-2-ethyl-7,7-diethyl-7,8-dihydro-1,6-naphthidine-2,6(5H)-dicarboxylate and dissolve it in a solution of tetrahydrofuran (1 mL), water (1 mL), and methanol (1 mL). Add 10.6 mg of lithium hydroxide hydrate at room temperature and react for 1 hour at room temperature. Monitor the reaction completion by LC-MS. Concentrate the system to obtain a crude white solid.

[0513]

[0514] MS(ESI)m / z(M+H) + =335.1

[0515] Step 11: Preparation of 7,7-diethyl-5,6,7,8-tetrahydro-1,6-naphthyl-2-carboxylate

[0516] In the previous step, the crude solid was dissolved in dichloromethane (1.5 mL), and 4M hydrochloric acid 1,4-dioxane solution (1.5 mL) was added dropwise under ice bath. After the addition was complete, the reaction was carried out at room temperature for 1 hour. LC-MS showed that the reaction was complete. The system was concentrated to obtain the crude product, which was purified by pre-HPLC to obtain the title compound (5 mg).

[0517]

[0518] MS(ESI)m / z(M+H) + =235.1

[0519] 1 H NMR (400MHz, Deuterium Oxide) δ8.32(dd,J=7.9,2.8Hz,1H),8.06(t,J=7.7Hz,1H),4.59(s,2H),3.37(s,2H),1.78(q,J=7.5Hz,4H),0.95(t,J=7.5Hz,6H).

[0520] Using raw materials and reagents purchased through conventional commercial channels, and referring to the preparation method of the foregoing embodiments combined with conventional separation and purification methods in the art, the following compounds were prepared:

[0521]

[0522]

[0523]

[0524]

[0525]

[0526] Biological experiments

[0527] Test Example 1: Plasma Clot Degradation Experiment

[0528] 1. Experimental Objective

[0529] The inhibitory effect of the compounds of this invention on the degradation of human plasma clots was determined.

[0530] 2. Experimental materials and instruments

[0531]

[0532] 3. Experimental Procedure

[0533] 3.1 Collect fresh blood from healthy individuals, use 0.109M trisodium citrate as an anticoagulant, mix 1 part anticoagulant with 9 parts blood, centrifuge at 2000x g for 20 minutes at room temperature, collect the supernatant (i.e., plasma), aliquot and store at -80℃ for later use.

[0534] 3.2 On the day of the experiment, the plasma was thawed in a water bath at 37°C, and all reagents except tPA were preheated at 37°C.

[0535] 3.3 Add 12.5 μL of 80 mM CaCl2 (HEPES buffer, pH 7.4) to a 96-well plate, then add 25 μL of the test compound diluted with physiological saline at different concentrations. Add an equal volume of physiological saline to the negative control wells.

[0536] 3.4 Mix 50 μL of preheated plasma with 12.5 μL of 4 nM tPA (HEPES buffer, pH 7.4) and immediately add to a 96-well plate. Detect the absorbance at 405 nm, reading every 2 minutes for 15 hours.

[0537] 3.5 The absorbance value changes over time, first increasing and then decreasing. The time corresponding to the median absorbance value during the decreasing phase minus the time corresponding to the median absorbance value during the increasing phase is the plasma clot lysis time. Using the plasma clot lysis time of the negative control well as a reference, the inhibition rate was calculated relative to the plasma clot lysis time in wells with different compound concentrations.

[0538] Inhibition rate % = (1 - negative control well) Clot lysis time / compound pores Clot lysis time )×100%

[0539] 3.6 Fitting dose-response curve

[0540] Plotting the logarithmic value of compound concentration on the X-axis and the percentage inhibition rate on the Y-axis, dose-response curves were fitted using the log(inhibitor) vs. response-variable slope method in GraphPadPrism 5 to derive the IC50 of each compound on cell activity. 50 value.

[0541] Calculation formula: Y = min + (max - min) / (1 + 10^(LogIC)) 50 -X)×Hillslope).

[0542] The inhibitory effect of the compound of the present invention on plasma clot degradation was determined by the above experiments, and the IC50 of the compound of the present invention was calculated. 50The values ​​are all significantly lower than those of tranexamic acid, a commonly used hemostatic drug in clinical practice. For example, the IC50 of the compound in Example 1 of this invention for inhibiting plasma clot degradation is only 1 / 4 that of tranexamic acid. The relative coagulation activity (IC50) of this invention relative to tranexamic acid in vitro is also significantly lower. 50 ratio = IC 50实施例 / IC 50氨甲环酸 See the table below:

[0543]

[0544] Experimental data show that the compound of the present invention can effectively inhibit the degradation of plasma clots, has excellent coagulation and hemostatic activity, and its effective dose is far lower than that of the most frequently used hemostatic drugs in clinical practice. It can effectively avoid adverse reactions and complications caused by high-dose medication and has excellent prospects for drug development.

[0545] Test Example 2: Monkey vs. Monkey Experiment Data

[0546] 1. Laboratory animals

[0547] Crab-eating macaque, common grade, male, N=3

[0548] 2. Drug preparation and administration

[0549] Weigh the compound and dissolve it in physiological saline to prepare a clear intravenous injection solution of 0.5 mg / mL.

[0550] On the day of the experiment, the medication was administered according to the protocol shown in the table below. Approximately 1 mL of blood was collected from the forelimb vein at each time point after administration and placed in heparin sodium anticoagulant tubes. After collection, the blood samples were placed on ice and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 2200g, 10 minutes, 2-8℃). Plasma samples were stored at -80℃ before analysis.

[0551]

[0552] 3. Bioanalysis

[0553] The specific method for determining the concentration of compounds in the plasma of cynomolgus monkeys is as follows:

[0554] Instrumentation: LC-MS / MS-19 (TQ5500, AB SCIEX, USA).

[0555] Internal label: Warfarin.

[0556] Chromatographic column: ACQUITY UPLC BEH C18, model 1.7um 2.1*50mm, purchased from Shenzhen Noyadi Chemical Technology Co., Ltd.;

[0557] Flow rate: 0.60 ml / min.

[0558] Column temperature: 40℃.

[0559] Mobile phase A: 0.1% formic acid aqueous solution.

[0560] Mobile phase B: 0.1% formic acid in acetonitrile solution.

[0561] The elution gradients are shown in Table 3.

[0562] Table 3 Elution gradient

[0563] Time (min) Mobile phase A (%) Mobile phase B (%) 0 98 2 0.60 12 88 1.10 12 88 1.11 98 2 1.40 98 2

[0564] MS detection conditions: electrospray ionization (ESI), cation mode, MRM scan.

[0565] Take 30 μL of the plasma sample prepared under section "2" of this embodiment and precipitate proteins with 300 μL of MeOH containing 100 ng / mL internal standard. Vortex the mixture for 1 minute and centrifuge at 18000 g for 7 minutes. Transfer the supernatant to a 96-well plate. Inject 4 μL of the supernatant into LC-MS / MS for analysis.

[0566] Pharmacokinetic parameters were calculated using blood drug concentration data at different time points using Phoenix WinNonlin 7.0.

[0567] The compounds of this invention were determined through the above experiments, and the pharmacokinetic parameters obtained in cynomolgus monkeys are shown in the table below.

[0568] Example Cmax(ng / mL) AUC(h*ng / mL) CL (mL / h / kg) 1 10573.5 4108.2 240

[0569] Experiments show that the compounds of this invention have advantages such as good hemostatic activity, small effective dose, and long duration of action, which can avoid various adverse reactions that may occur with high-dose clinical administration, thus improving the safety and efficacy of medication for patients. Furthermore, the compounds of this invention are easy to prepare, facilitating large-scale industrial production and effectively reducing medication costs. The compounds of this invention have good distribution, metabolism, and excretion characteristics, with a low probability of drug-drug interactions, and can meet the pharmacokinetic parameters required to achieve therapeutic effects in humans.

Claims

1. The compound represented by Formula I or a pharmaceutically acceptable salt thereof: in, R1 is selected from hydrogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-C1 to C6 alkyl, C3-C6 cycloalkyl and 4 to 7-membered alicyclic groups; R1 may be optionally substituted by 1 to 2 groups selected from hydroxyl, C1-C4 alkyl, F, Cl, Br, phenyl, benzyl and cyclopropyl. R2 is independently selected from hydrogen, carboxyl, amide, C1-C6 alkyl, -NH-C1-C6 alkyl, -CH2O-C1-C6 alkyl, -CH2NH-C1-C6 alkyl, -COO-C1-C6 alkyl, -CONH-C1-C6 alkyl, C3-C6 cycloalkyl, 4 to 7-membered alicyclic, phenyl-C1-C4 alkyl, and C3-C6 cycloalkyl-C1-C4 alkyl; R2 may be optionally substituted with 1 to 2 groups selected from hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; or two R2s together with the attached carbon atom form a C3-C6 cycloalkyl or tetrahydropyranyl group; R3 is selected from hydrogen and halogens; "Alicyclic group" refers to a saturated monocyclic hydrocarbon substituent in which one or more ring atoms are replaced by heteroatoms selected from N, O, and S, the remaining ring atoms are carbon, and the S heteroatoms can be selectively oxidized; and R1, R2, and R3 are not all hydrogen at the same time.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula I': in, R1 is selected from hydrogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-C1-C6 alkyl, C3-C6 cycloalkyl and 4 to 7-membered alicyclic groups; R1 may be selectively substituted by 1 to 2 groups selected from hydroxyl, C1-C4 alkyl, F, Cl, Br, phenyl and cyclopropyl. R2 is selected from hydrogen, carboxyl, amide, C1-C6 alkyl, -NH-C1-C6 alkyl, -CH2O-C1-C6 alkyl, -CH2NH-C1-C6 alkyl, -COO-C1-C6 alkyl, -CONH-C1-C6 alkyl, C3-C6 cycloalkyl, and 4- to 7-membered alicyclic groups; R2 may optionally be substituted by 1-2 groups selected from hydroxyl and C1-C6 alkyl groups; R3 is selected from hydrogen and halogens.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from hydrogen, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, morpholinyl, piperazine, thiomorpholinyl, 1-oxide-4-thiomorpholinyl, and 1,1-dioxide-4-thiomorpholinyl; R1 may be selectively substituted by 1-2 groups selected from hydroxyl, F, Cl, Br, methyl, ethyl, propyl, isopropyl, phenyl, benzyl, and cyclopropyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The R1 is selected from hydrogen, C1-C4 alkoxy, morpholino, piperazine, thiomorpholino, 1-oxide-4-thiomorpholino, and 1,1-dioxide-4-thiomorpholino, and the R1 may be selectively substituted by 1-2 groups selected from hydroxyl and benzyl.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, characterized in that: R2 is selected from hydrogen, carboxyl, amide, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, pentyl, -CH2OCH3, -CH2OCH2CH3, -CH2OCH2CH2CH3, -CH2NHCH3, -CH2NHCH2CH3, -CH2NHCH2CH2CH3, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -CONHCH3, -CONHCH2CH3, -CONHCH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, piperidinyl, morpholinyl, thiomorpholinyl, 1-oxide-thiomorpholinyl, and 1,1-dioxide-4-thiomorpholinyl; R2 may be selectively substituted with 1-2 groups selected from hydroxyl, methyl, ethyl, propyl, and isopropyl.

6. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, characterized in that: The R2s are independently selected from hydrogen, carboxyl, C1-C6 alkyl, -CH2O-C1-C6 alkyl, -COO-C1-C6 alkyl, C3-C6 cycloalkyl, phenyl-C1-C4 alkyl, and C3-C6 cycloalkyl-C1-C4 alkyl, wherein the alkyl, cycloalkyl, and phenyl groups may be optionally substituted with 1-2 groups selected from hydroxyl and C1-C4 alkoxy groups; or the two R2s together with the attached carbon atom form a C3-C6 cycloalkyl or tetrahydropyranyl group.

7. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, characterized in that: The R3 is selected from hydrogen, fluorine, chlorine, and bromine.

8. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, characterized in that: R1 and R2 are not both hydrogen.

9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the following structure:

10. A pharmaceutical composition having therapeutic activities of coagulation and hemostasis, comprising at least one compound of formula I or a pharmaceutically acceptable salt thereof: in, R1 is selected from hydrogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-C1 to C6 alkyl, C3-C6 cycloalkyl and 4 to 7-membered alicyclic groups; R1 may be optionally substituted by 1 to 2 groups selected from hydroxyl, C1-C4 alkyl, F, Cl, Br, phenyl, benzyl and cyclopropyl. R2 is independently selected from hydrogen, carboxyl, amide, C1-C6 alkyl, -NH-C1-C6 alkyl, -CH2O-C1-C6 alkyl, -CH2NH-C1-C6 alkyl, -COO-C1-C6 alkyl, -CONH-C1-C6 alkyl, C3-C6 cycloalkyl, 4 to 7-membered alicyclic, phenyl-C1-C4 alkyl, and C3-C6 cycloalkyl-C1-C4 alkyl; R2 may be optionally substituted with 1 to 2 groups selected from hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; or two R2s together with the attached carbon atom form a C3-C6 cycloalkyl or tetrahydropyranyl group; R3 is selected from hydrogen and halogens; "Alicyclic group" refers to a saturated monocyclic hydrocarbon substituent in which one or more ring atoms are replaced by heteroatoms selected from N, O, and S, the remaining ring atoms are carbon, and the S heteroatoms can be selectively oxidized. And at least one pharmaceutically acceptable excipient.

11. The pharmaceutical composition of claim 10, wherein the compound is defined as in claim 9.

12. The pharmaceutical composition according to claim 10, wherein said compound is 13. The use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament, wherein the medicament has therapeutic activities of coagulation and hemostasis: in, R1 is selected from hydrogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-C1 to C6 alkyl, C3-C6 cycloalkyl and 4 to 7-membered alicyclic groups; R1 may be optionally substituted by 1 to 2 groups selected from hydroxyl, C1-C4 alkyl, F, Cl, Br, phenyl, benzyl and cyclopropyl. R2 is independently selected from hydrogen, carboxyl, amide, C1-C6 alkyl, -NH-C1-C6 alkyl, -CH2O-C1-C6 alkyl, -CH2NH-C1-C6 alkyl, -COO-C1-C6 alkyl, -CONH-C1-C6 alkyl, C3-C6 cycloalkyl, 4 to 7-membered alicyclic, phenyl-C1-C4 alkyl, and C3-C6 cycloalkyl-C1-C4 alkyl; R2 may be optionally substituted with 1 to 2 groups selected from hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; or two R2s together with the attached carbon atom form a C3-C6 cycloalkyl or tetrahydropyranyl group; R3 is selected from hydrogen and halogens; "Alicyclic group" refers to a saturated monocyclic hydrocarbon substituent in which one or more ring atoms are replaced by heteroatoms selected from N, O, and S, the remaining ring atoms are carbon, and the S heteroatoms can be selectively oxidized.

14. The use according to claim 13, wherein the compound is as defined in claim 9.

15. The use according to claim 13, wherein said compound is 16. The use according to any one of claims 13-15, characterized in that... The drug is used for abnormal bleeding caused by hyperfibrinolysis, surgical and postoperative bleeding.

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