A quinazoline PAR4 antagonist and its medical application

Abstract

The present invention discloses a quinazoline PAR4 antagonist and its medical application, specifically a compound as shown in formula (I), and a pharmaceutically acceptable salt, ester or solvate thereof. 3 It is a five-membered monocyclic heterocyclic ring, a six-membered aromatic ring or a bicyclic aromatic ring substituted with 0 to 3. These compounds have the ability to inhibit and prevent platelet aggregation induced by PAR4, and can be used to treat and prevent thromboembolic diseases, and thus can be used as antiplatelet drugs.

Description

Technical Field

[0001] The present invention relates to quinazoline compounds that can be used as platelet aggregation antagonists, compositions of such compounds and methods of use thereof, and pharmaceutical compositions containing at least one compound of the present invention, which compositions can be used to treat or prevent thromboembolic diseases. Technical Background

[0002] Thromboembolic disease has become the disease with the highest mortality rate in the world. Existing antiplatelet drugs have limitations, including increased risk of bleeding and large individual differences. The activation of human platelets is mainly mediated by thrombin PAR1 and PAR4. Thrombin produces new binding ligands by cutting the N-termini of PAR1 and PAR4 on the surface of platelets. The new binding ligands interact with the extracellular binding site of the receptor to produce transmembrane signals and activate the receptor. PAR1 can be activated at low concentrations of thrombin, while the activation of PAR4 requires a higher concentration of coagulation. Antithrombotic drugs targeting PAR1 often lead to bleeding accidents. Vorapaxar can significantly reduce the incidence of myocardial infarction. However, when patients have a history of stroke or transient ischemic attack, Vorapaxar increases the risk of intracranial hemorrhage. In recent years, some PAR4 small molecule antagonists have been published, but overall research is still in its infancy. According to the different structural cores, PAR4 small molecule antagonists can be divided into indazole, indole, imidazole [2,1-b] [1,3,4] thiadiazole (IDT) and quinoline and quinoxaline. Among them, Bristol-Myers Squibb's small molecule PAR4 antagonists BMS-986120 and BMS-986141 have entered the clinical phase II trial stage. Early indole and indole PAR4 small molecule antagonists have poor physical and chemical properties and poor drugability, so there is an urgent need to discover antiplatelet drugs with novel structures and low bleeding risks.

[0003] EP1166785A1 and EP0667345 disclose pyrazole derivatives as inhibitors of platelet aggregation.

[0004] PCT applications WO 2013 / 163279, WO 2013 / 163244, WO 2017066863 and WO2013 / 163241 disclose imidazo[2,1-b][1,3,4]thiadiazole-based PAR4 small molecule antagonists.

[0005]

[0006] PCT applications WO 2017019828, WO 2018013776, WO 2018013772, WO2018013774, and WO2018013770 disclose quinoxaline-based PAR4 small molecule antagonists.

[0007]

[0008] There remains a need for compounds that are useful as inhibitors of platelet aggregation. Summary of the invention

[0009] One of the purposes of the present invention is to provide a quinazoline compound having PAR4 antagonistic activity.

[0010] The quinazoline compounds provided by the present invention include stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, and have PAR4 antagonistic activity and can selectively inhibit platelet aggregation activity.

[0011] A second object of the present invention is to provide use of the compound of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs in the preparation of drugs for treating or preventing thromboembolic disorders.

[0012] The specific technical solutions of the present invention are as follows:

[0013] A compound represented by the following formula (I), or a pharmaceutically acceptable salt, ester or solvate thereof:

[0014]

[0015] in:

[0016] R1 is C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluoroalkyl, C 2-4 Alkenyl, C 3-7 Cycloalkyl, C 2-4 Hydroxyalkoxy, C 1-4 Alkyl, C 3-6 Cycloalkoxy, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-3 Fluoroalkylthio, C 1-4 Haloalkoxy, -(CH2) 1-3 O(C 1-4 Alkyl), -COO(C 1-5 Alkyl), -CON(C 1-5 alkyl)2, pyrrolidin-1-yl, furanyl, pyranyl, piperidin-1-yl, C 3-7Fluorocycloalkyl, -S(O)2(C 1-3 alkyl), -S(O)2NRaRa, morpholin-4-yl, piperazin-1-yl, C 1-3 Alkylthio, fluorine, chlorine, hydroxyl;

[0017] R2 is independently H, halogen, -OH, -CN, C 1-4 Alkyl, C 11-4 Fluoroalkyl, C 1-4 Fluoroalkoxy, C 3-7 Cycloalkyl, C 3-7 Cycloalkoxy, C 1-6 Alkoxy, C 1-3 Alkylthio;

[0018] R3 can be selected from substituted or unsubstituted C6~C 14 an aromatic group or a substituted or unsubstituted benzoaromatic heterocycle, wherein the benzoaromatic heterocycle is a bicyclic group or a tricyclic group, wherein the aromatic heterocycle is a 4-7 membered aromatic heterocycle having 1-3 heteroatoms selected from N, O or S; when substituted, R3 is replaced by 0 to 3 R 3a Replacement; R 3a C independently at each occurrence 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-6 Alkoxy, C 1-3 Fluoroalkoxy, C 1-6 Alkylthio, -O(CH2) 1-6 -Aryl, -O(CH2) 1-6 -aromatic group, H, halogen, -CN, -OH.

[0019] As a further preferred embodiment of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof: R2 is selected from -CH3, -OCH3, -H.

[0020] As a preferred embodiment of the present invention, one embodiment provides a compound of formula (Ia), a pharmaceutically acceptable salt, ester, solvate or prodrug thereof:

[0021]

[0022] Wherein, R1 and R3 can be as described above respectively.

[0023] As a further preferred embodiment of the present invention, the compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt, ester or solvate thereof: R1 is selected from -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -(CH2)1-3 O(C 1-4 alkyl); in some specific examples, R1 is selected from -NH2, -NHCH3, -N(CH3)2, -CH3, -OCH3, -OCHF2, -OCH2CH3, or -CH2OCH3; in some preferred examples, R1 is selected from -NHCH3, -N(CH3)2, -OCH3, -CH2OCH3 or -OCHF2.

[0024] As a further preferred embodiment of the present invention, the compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt, ester or solvate thereof:

[0025] R3 is a monocyclic group as follows: phenyl, pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, imidazolyl, furyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazinyl, isoxazolyl, wherein the monocyclic group is surrounded by 0 to 3 R 3a replace; or

[0026] R3 is a bicyclic group as follows: benzo[d]imidazolyl, benzo[b]thienyl, benzo[d]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzofuranyl, indolyl, 1-naphthyl, thiazo[4,5-b]pyridyl; the bicyclic group is surrounded by 0 to 3 R 3a replace; or

[0027] R3 is a tricyclic group Wherein A is a 4-7 membered heterocyclic ring having 1-3 heteroatoms selected from N, O or S; the tricyclic group is surrounded by 0 to 3 R 3a replace;

[0028] R 3a C independently at each occurrence 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-6 Alkoxy, C 1-3 Fluoroalkoxy, C 1-6 Alkylthio, -O(CH2) 1-6 -Aryl, -O(CH2) 1-6 -aromatic group, H, halogen, -CN, -OH.

[0029] In some more specific examples, R3 is a monocyclic group selected from the group consisting of phenyl, pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, imidazolyl, furanyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazinyl, isoxazolyl, wherein the monocyclic group is surrounded by 0 to 3 R 3aor R3 is selected from a bicyclic group: benzo[d]imidazolyl, benzo[b]thienyl, benzo[d]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzofuranyl, indolyl, 1-naphthyl, thiazo[4,5-b]pyridyl; the bicyclic group is substituted by 0 to 3 R 3a Substituted; or R3 is selected from a tricyclic group The tricyclic group is composed of 0 to 3 R 3a replace;

[0030] R 3a Independently selected from C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-6 Alkoxy, C 1-3 Fluoroalkoxy, C 1-6 Alkylthio, -O(CH2) 1-6 -Aryl, -O(CH2) 1-6 -aromatic group, H, halogen, -CN, -OH.

[0031] As a further preferred embodiment of the present invention, the compound of formula (I) or formula (Ia) or a pharmaceutically acceptable salt, ester or solvate thereof: R3 is selected from:

[0032]

[0033] R 3a is 0, 1, 2 or 3, each independently selected from C 1-4 Alkyl, C 1-3 Fluoroalkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Alkylthio, -O(CH2) 1-6 -Aryl, -O(CH2) 1-6 -aromatic group, H, halogen, -CN, -OH.

[0034] The present invention 3a Although only one of the optional structures of R3 is drawn, the R 3a The number can be 0, 1, 2 or 3; in some specific examples, R 3a The number of R3 can be 0, 1 or 2. The substitution position can be any position that R3 can allow from the perspective of chemical structure. 3a Although the substitution position is marked on a certain ring of the bicyclic group or tricyclic group, it does not mean that it is limited to the substitution position of the ring. As mentioned above, it can be any position that R3 can allow from the perspective of chemical structure.

[0035] As a further preferred embodiment of the present invention, the present invention also provides a compound shown in the following structure or a pharmaceutically acceptable salt or ester or solvate thereof selected from any one of the following compounds or a pharmaceutically acceptable salt or ester or solvate thereof:

[0036]

[0037] The pharmaceutically acceptable salts of the compounds mentioned in the present invention refer to salts of the compounds with organic acids or inorganic acids, wherein the organic acids and inorganic acids can be selected from: acetylsalicylic acid, fumaric acid, methanesulfonic acid, ethanesulfonic acid, sulfuric acid, hydrochloric acid, formic acid, acetic acid, benzenesulfonic acid, hydrobromic acid, lactic acid, phosphoric acid, oxalic acid, 2-hydroxyethanesulfonic acid, gentisic acid, tartaric acid, succinic acid, maleic acid, lauric acid, citric acid, camphoric acid, n-dodecylsulfonic acid, adipic acid, ascorbic acid, trifluoroacetic acid, formic acid, tannic acid, and picric acid.

[0038] The present invention also provides a pharmaceutical composition in the form of an ester, a prodrug or a solvate of the aforementioned compound and a pharmaceutically acceptable carrier.

[0039] The compounds of the present invention or pharmaceutically acceptable salts, esters or solvates thereof can inhibit platelet aggregation by antagonizing the expression of PAR4 on platelets, and thus can be used to prevent and treat thromboembolic disorders.

[0040] The present invention also provides use of the compound of the present invention or a pharmaceutically acceptable salt, ester or solvate thereof in the preparation of a PAR4 antagonist.

[0041] The present invention also provides use of the compound of the present invention or a pharmaceutically acceptable salt, ester or solvate thereof in the preparation of a drug for preventing and / or treating thromboembolic disorders.

[0042] The thromboembolic disorders mentioned in the present invention include, but are not limited to, the following: acute coronary syndrome, transient ischemic attack, atherosclerosis, stroke, myocardial infarction, cerebral arterial thrombosis, peripheral arterial occlusive disease, deep vein thrombosis, arterial cardiovascular thromboembolic disorders, and venous cardiovascular thromboembolic disorders.

[0043] The present invention provides a pharmaceutical composition for preventing or treating thromboembolic diseases, such as a PAR4 antagonist formulated into tablets or capsules for oral administration. The capsules or tablets contain standard pharmaceutically acceptable materials. Other preparations include suppositories, sprays, creams, patches, injections, gels, ointments, pills, syrups and other standard preparation forms in pharmaceutical pharmacy.

[0044] The compounds of the present invention also provide pharmaceutical compositions comprising another therapeutic agent for treating thromboembolic diseases. In a preferred embodiment, the present invention provides a pharmaceutical composition wherein the other therapeutic agent is an antiplatelet drug or a combination thereof. Preferably, the antiplatelet drug is aspirin or P2Y 12 Antagonists. Preferably P2Y 12 Antagonists include clopidogrel, prasugrel or ticagrelor. In another preferred embodiment, the invention provides a pharmaceutical composition, wherein the therapeutic agent is an anticoagulant or a combination thereof. Preferably, the anticoagulant is a thrombin inhibitor, a FXa inhibitor or a FXIa inhibitor. Preferably, the thrombin inhibitor is dabigatran. Preferably, the FXa inhibitor is rivaroxaban or apixaban.

[0045] The compounds of the present invention can be prepared in many ways known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below and synthetic methods known in the field of synthetic organic chemistry or by variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction mixture is carried out in a solvent or solvent mixture suitable for the reagents and materials used and suitable for the transformation. Those skilled in the art of organic synthesis will understand that the functional groups present on the molecule should be consistent with the proposed transformation. This sometimes requires judgment to modify the order of the synthesis steps or to select a specific process scheme instead of another to obtain the desired compounds of the present invention.

[0046] It will also be recognized that another major consideration in planning any synthetic route in this art is the judicious choice of protecting groups employed to protect the reactive functional groups present in the compounds described herein.

[0047] As shown in Scheme 1, the compound of formula I of the present invention can be prepared by b The palladium-catalyzed cross-coupling of aryl halides with organometallic species or boronic acids / boronic esters R3-M is used to obtain:

[0048] Solution 1

[0049]

[0050] Alternatively, compounds of formula I can also be prepared by palladium-catalyzed cross-coupling of arylboronic acids or organometallic species of formula Ic with halides R3-X as shown in Scheme 2:

[0051] Solution 2

[0052]

[0053] The method for preparing quinazolines of formula Ib and Ic can be carried out according to conventional chemical synthesis methods. The present invention provides a method for converting the o-aminocarboxylic acid to an aldehyde group by borane reduction, followed by cyclization with guanidine carbonate, and the amino substituent to Ib. The structure of formula Ic can be converted by Suzuki-Miyaura or Stille reaction:

[0054] Solution 3

[0055]

[0056] Unless otherwise specified, the present invention is defined as follows:

[0057] "Halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0058] "Aromatic heterocycle" means a stable monocyclic ring of up to 3-10 atoms in the ring(s) or a bicyclic carbocyclic ring of up to 3-10 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 heteroatoms selected from O, N or S. Non-limiting examples of unsubstituted heteroaryl groups are pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyrimidinyl, quinolyl, isoquinolyl, purinyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, indolyl, benzotriazolyl, benzothienyl, benzofuranyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, tetrazolyl, triazinyl, carbazolyl and the like.

[0059] "Heterocycle" means a saturated cyclic group of 3 to 8 ring atoms, wherein one or two of the ring atoms are heteroatoms selected from N, O or S and the remaining ring atoms are C. More specifically, the term heterocycle includes, but is not limited to, tetrahydropyranyl, 2,2-dimethyl-1,3-dioxolane, piperidino, N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl, pyrrolidinyl, morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, 4-ethoxycarbonylpiperazino, 3-oxopiperazino, 2-imidazolidinone, 2-pyrrolidinone, 2-oxohomopiperazino, tetrahydropyrimidin-2-one, etc. The heterocyclic group is optionally substituted with one or two substituents. DETAILED DESCRIPTION

[0060] The present invention is specifically described below by way of examples. In the present invention, the following examples are intended to better illustrate the present invention and are not intended to limit the scope of the present invention. Various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention.

[0061] Example 1 8-(4-chloro-6-methoxybenzothiazol-2-yl)-N,6-dimethylquinazolin-2-amine (Compound 1)

[0062]

[0063] Compound 1-1 (30.00 g, 198.45 mmol) was dissolved in acetic acid (200 mL), and liquid bromine (38.05 g, 238.14 mmol) was slowly added dropwise under an ice bath. A light yellow solid precipitated during the addition. After the addition was completed, the mixture was reacted at room temperature for 15 min. After the reaction was completed by monitoring by TLC, the reaction solution was poured into ice water (800 mL), stirred for 10 min, and the reaction solution was filtered. The filter cake was washed with water three times and dried to obtain 36.18 g of a white solid. 1 H NMR (500MHz, DMSO-d6) δ7.62 (dd, J=2.0, 0.9Hz, 1H), 7.50 (d, J=2.1Hz, 1H), 2.18 (s, 3H).

[0064] Compound 1-2 (5.00 g, 21.73 mmol) was dissolved in tetrahydrofuran (60 mL), cooled to 0-10 °C, and 1 M borane tetrahydrofuran complex (65.2 mL, 65.2 mmol) was slowly added dropwise under nitrogen protection. After the addition was completed, the mixture was stirred at room temperature for 10 min, and the temperature was raised to 60 °C for reaction for 3 h. The reaction was completed by TLC monitoring, and the temperature was lowered to 0-10 °C. Methanol (10 mL) was slowly added to the reaction solution and stirred for 30 min to quench the reaction. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, and the mixture was stirred and separated. The aqueous phase was washed twice with ethyl acetate (50 mL*2), the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4.16 g of a white solid. 1 H NMR (500MHz, DMSO-d6) δ7.15(d,J=2.0Hz,1H),6.95(d,J=2.0Hz,1H),5.14(s,1H),4.88(s,2H),4.43(s,2H),2.18(s,3H).

[0065] Compound 1-3 (2.00 g, 9.26 mmol) was dissolved in tetrahydrofuran (25 mL) and dichloromethane (2.5 mL), and active manganese dioxide (4.83 g, 55.53 mmol) was added. The mixture was reacted at room temperature for 3 h. The reaction was completed after monitoring by TLC. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The mixture was purified by column chromatography (PE:EA=5:1) to obtain 1.5 g of a light yellow solid. 1 H NMR (500MHz, DMSO-d6) δ9.80 (s, 1H), 7.58 (d, J = 2.1Hz, 1H), 7.47 (dd, J = 2.0, 1.0Hz, 1H), 6.91 (m, 2H), 2.24 (s, 3H).

[0066] Compound 1-4 (0.20 g, 0.93 mmol) was dissolved in N,N-dimethylformamide (5 mL), guanidine carbonate (0.25 g, 1.40 mmol) was added, and the temperature was raised to 140°C for reaction for 2 h. The reaction was completed after monitoring by TLC. The temperature was cooled to room temperature, and the reaction solution was poured into ice water (30 mL), stirred for 10 min, filtered, and the filter cake was washed with water several times to obtain 0.18 g of a dried light yellow solid. 1 H NMR (500MHz, DMSO-d6) δ9.05 (s, 1H), 7.92 (d, J = 1.8Hz, 1H), 7.71–7.45 (m, 1H), 7.05 (s, 2H), 2.56 (s, 3H).

[0067] Compound 1-5 (3.00 g, 12.60 mmol) was dissolved in 1,2-dichloroethane (60 mL), antimony trichloride (5.75 g, 25.20 mmol) was added, the temperature was raised to 60 ° C under nitrogen protection, tert-butyl nitrite (4.29 g, 41.58 mmol) was slowly added dropwise, the reaction was completed for 3 h, TLC monitoring was completed, saturated sodium bicarbonate solution (250 mL) was added to the reaction solution and stirred for 15 min, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with dichloromethane, the filtrate was separated, the aqueous phase was washed with dichloromethane once, the organic phases were combined, washed once with saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.10 g of brown solid, which was directly reacted in the next step. ESI-MS: m / z 258.63 [M+H] + .

[0068] Compound 1-6 (3.10 g, 12.60 mmol) was dissolved in tetrahydrofuran (20 mL), 40% methylamine solution (4 mL) was added, and the mixture was sealed and reacted at 80 ° C for 5 h. After the reaction was completed, water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, stirred and separated, the aqueous phase was extracted twice with ethyl acetate (25 mL * 2), the organic phase was combined and washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 4: 1) to obtain 1.03 g of a light yellow solid. 1 H NMR (300MHz, CDCl3) δ8.86(s,1H),7.87(s,1H),7.41(s,1H),3.19(s,3H),2.44(s,3H).

[0069] Compound 1-7 (200 mg, 0.79 mmol) was dissolved in 1,4-dioxane (5 mL), and diboric acid pinacol ester (402 mg, 1.58 mmol), potassium acetate (193 mg, 1.98 mmol), and Pd(dppf)Cl2 (20 mg, 0.027 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 110 ° C for 10 h. The reaction was completed by TLC monitoring. The reaction solution was cooled to room temperature, and ice water (30 mL) and ethyl acetate (20 mL) were added to the reaction solution. Stir and separate the liquids. The aqueous phase was extracted twice with ethyl acetate (20 mL*2), and the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 210 mg of a brown solid, which was directly used in the next step without purification. ESI-MS: m / z 300.09 [M+H] + .

[0070] Compound 1-8 (240 mg, 0.79 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 2-bromo-4-chloro-6-methoxybenzo[d]thiazole (286 mg, 1.03 mmol), sodium carbonate (167 mg, 1.58 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100°C for reaction for 3 h. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:EA=20:1) to obtain 80 mg of a light yellow solid. 1 H NMR(300MHz,DMSO-d6)δ9.18(s,1H),8.76(s,1H),7.98–7.84(m,1H),7.78(d,J=26.5 Hz,2H),7.27(s,1H),3.89(s,3H),3.15(s,3H),2.54(s,3H).ESI-MS:m / z371.07[M+H] + .

[0071] Example 2 8-(2,4-dichlorophenyl)-N,6-dimethylquinazolin-2-amine (Compound 2)

[0072]

[0073] Compound 1-7 (200 mg, 0.79 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 2,4-dichlorophenylboronic acid (196 mg, 1.03 mmol), sodium carbonate (167 mg, 1.58 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100 ° C for reaction for 3 h. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=4:1) to obtain 170 mg of a light yellow solid. 1 H NMR(300MHz,DMSO-d6)δ9.06(s,1H),7.78–7.60(m,2H),7.55–7.38(m,3H),7.18(s,1H),2.69(s,3H),2.42(s,3H).ESI-MS:m / z 318.06[M] + .

[0074] Example 3 8-(4-methoxyphenyl)-N,6-dimethylquinazolin-2-amine (Compound 3)

[0075]

[0076] Compound 1-7 (150 mg, 0.59 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 4-methoxyphenylboronic acid (196 mg, 1.03 mmol), sodium carbonate (125 mg, 1.18 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100 ° C for reaction for 3 h. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=5:1) to obtain 140 mg of a light yellow solid. 1 H NMR(300MHz,DMSO-d6)δ9.04(s,1H),7.78(d,J=8.1Hz,2H),7.67–7.44(m,2H),7.18(s, 1H),7.08–6.92(m,2H),3.82(s,3H),2.83(s,3H),2.43(s,3H).ESI-MS:m / z280.15[M+H] + .

[0077] Example 4 8-(Benzothiophen-2-yl)-N,6-dimethylquinazolin-2-amine (Compound 4)

[0078]

[0079] Compound 1-7 (150 mg, 0.59 mmol) was dissolved in toluene (10 mL) and water (5 mL), and benzo[b]thiophene-2-ylboronic acid (128 mg, 0.72 mmol), sodium carbonate (125 mg, 1.18 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100 ° C. for reaction for 3 h. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=5:1) to obtain 180 mg of a light yellow solid. 1 H NMR (300MHz, DMSO-d6) δ9.09 (s, 1H), 8.30 (d, J = 16.0Hz, 2H), 7.97 (d, J = 7.5Hz, 1H), 7.88 (d, J = 7. 4Hz,1H),7.62(s,2H),7.36(t,J=7.0Hz,2H),3.10(s,3H),2.49(s,3H).ESI-MS:m / z306.11[M+H] + .

[0080] Example 5 8-(2-Chloro-4-methoxyphenyl)-N-methylquinazolin-2-amine (Compound 5)

[0081]

[0082] Compound 1-7 (150 mg, 0.59 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 2-chloro-4-methoxyphenylboronic acid (139 mg, 0.72 mmol), sodium carbonate (125 mg, 1.18 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100 ° C. for reaction for 5 h. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=4:1) to obtain 130 mg of a light yellow solid. 1H NMR(500MHz,DMSO-d6)δ9.06(s,1H),7.61(d,J=1.8Hz,1H),7.45(d,J=2.1Hz,1H),7.35(d,J=8.5Hz,1H),7.14 (d,J=2.6Hz,1H),7.10(s,1H),7.00(dd,J=8.5,2.6Hz,1H),3.85(s,3H),2.72(s,3H),2.43(s,3H).ESI-MS:m / z 314.11[M+H] + .

[0083] Example 6 8-(2-Fluorophenyl)-N,6-dimethylquinazolin-2-amine (Compound 6)

[0084]

[0085] Compound 1-7 (150 mg, 0.59 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 2-fluorophenylboric acid (139 mg, 0.72 mmol), sodium carbonate (125 mg, 1.18 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100 ° C for 4 hours. After the reaction, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=5:1) to obtain 120 mg of a light yellow solid. 1 H NMR(500MHz,DMSO-d6)δ9.07(s,1H),7.66–7.62(m,1H),7.55(d,J=13.1Hz,2H),7.45(tdd,J=7.5,5 .2,1.8Hz,1H),7.32–7.25(m,2H),7.15(s,1H),2.73(s,3H),2.45(s,3H).ESI-MS:m / z268.13[M+H] + .

[0086] Example 7 8-(Benzothiazol-2-yl)-N,6-dimethylquinazolin-2-amine (Compound 7)

[0087]

[0088] Compound 1-8 (240 mg, 0.79 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 2-bromobenzo[d]thiazole (220 mg, 1.03 mmol), sodium carbonate (167 mg, 1.58 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100°C for reaction for 8 h. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=5:1) to obtain 80 mg of a yellow solid. 1 H NMR (300MHz, DMSO-d6) δ9.16(s,1H),8.82(d,J=2.1Hz,1H),8.16(d,J=7.9Hz,1H),8.08(d,J=8.1Hz,1H),7.86 (d,J=5.4Hz,1H),7.80(s,1H),7.60–7.49(m,1H),7.44(t,J=7.5Hz,1H),3.15(s,3H),2.52(s,3H).ESI-MS:m / z 307.10[M+H] + .

[0089] Example 8 8-(4,6-Dichlorobenzo[d]thiazol-2-yl)-N,6-dimethylquinazolin-2-amine (Compound 8)

[0090]

[0091] Compound 1-8 (240 mg, 0.79 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 2-bromo-4,6-dichlorobenzo[d]thiazole (220 mg, 0.79 mmol), sodium carbonate (167 mg, 1.58 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100 ° C. for reaction for 6 hours. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=5:1) to obtain 80 mg of a yellow solid. 1HNMR(300MHz,DMSO-d6)δ9.18(s,1H),8.79(s,1H),8.29(s,1H),7.87(s,2H),7.74(s,1H),3.14(s,3H),2.54(s,3H).ESI-MS:m / z 375.02[M] + .

[0092] Example 9N, 6-dimethyl-8-(4-methyl-7,8-dihydro-[1,4]dioxacyclo[2',3':3,4]benzo[1,2-d]thiazol-2-yl)quinazolin-2-amine (Compound 9)

[0093]

[0094] Compound 1-8 (240 mg, 0.79 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 2-bromo-7,8-dihydro-[1,4]dioxin [2′,3′:3,4]benzo[1,2-d]thiazole (220 mg, 0.79 mmol), sodium carbonate (167 mg, 1.58 mml), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100°C for reaction for 10 h. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=5:1) to obtain 110 mg of a yellow solid. 1 H NMR (300MHz, DMSO-d6) δ9.15(s,1H),8.76(d,J=2.1Hz,1H),7.85(s,1H),7.77(d,J=1.9Hz,1H),6. 92(s,1H),4.39(ddd,J=24.8,5.8,2.9Hz,4H),3.13(s,3H),2.66(s,3H),2.54(s,3H).ESI-MS:m / z 379.12[M+H] + .

[0095] Example 10 8-(5-Fluoro-6-methoxybenzo[d]thiazol-2-yl)-N,6-dimethylquinazolin-2-amine (Compound 10)

[0096]

[0097] Compound 1-8 (240 mg, 0.79 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 2-bromo-4-fluoro-6-methoxybenzo[d]thiazole (286 mg, 1.03 mmol), sodium carbonate (167 mg, 1.58 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100°C for reaction for 3 h. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:EA=20:1) to obtain 95 mg of a light yellow solid. 1 H NMR(500MHz,DMSO-d6)δ9.16(s,1H),8.75(d,J=2.1Hz,1H),7.92(dd,J=14.4,10.1Hz,2H ),7.84(s,1H),7.78(d,J=2.1Hz,1H),3.97(s,3H),3.16(s,3H),2.51(s,3H).ESI-MS:m / z 355.10[M+H] + .

[0098] Example 11 8-(2,4-dimethoxyphenyl)-N,6-dimethylquinazolin-2-amine (Compound 11)

[0099]

[0100] Compound 1-7 (150 mg, 0.59 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 2,4-dimethoxyphenylboronic acid (130 mg, 0.71 mmol), sodium carbonate (125 mg, 1.18 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100 ° C. for reaction for 6 hours. After the reaction, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=5:1) to obtain 150 mg of an off-white solid. 1H NMR(500MHz,DMSO-d6)δ9.01(s,1H),7.56–7.48(m,1H),7.42(d,J=2.1Hz,1H),7.22(d,J=8.3Hz,1H),7.07–6.91(m,1H),6.6 6(d,J=2.4Hz,1H),6.60(dd,J=8.3,2.4Hz,1H),3.83(s,3H),3.68(s,4H),2.74(s,3H),2.41(s,3H).ESI-MS:m / z310.16[M+H] + .

[0101] Example 12N, 6-dimethyl-8-(thiazol-2-yl)quinazolin-2-amine (Compound 12)

[0102]

[0103] Compound 1-7 (150 mg, 0.59 mmol) was dissolved in toluene (10 mL), and 2-(dibutyl(propyl)stannyl)thiazole (130 mg, 0.71 mmol), potassium acetate (78 mg, 0.80 mmol), and Pd(PPh3)4 (30 mg, 0.026 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 110 ° C. for reaction for 6 hours. After the reaction was completed, saturated potassium fluoride solution (30 mL) and ethyl acetate (10 mL) were added to the reaction solution. After stirring overnight, the liquids were separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=4:1) to obtain 60 mg of a light yellow solid. 1 H NMR (500MHz, DMSO-d6) δ9.14(s,1H),8.67(d,J=2.1Hz,1H),8.01(d,J=3.2Hz,1H),7.85(d ,J=3.2Hz,1H),7.75(s,1H),7.72(d,J=2.1Hz,1H),3.09(s,3H),2.50(s,3H).ESI-MS:m / z 257.09[M+H] + .

[0104] Example 13N, 6-dimethyl-8-(4-methylthiazol-2-yl)quinazolin-2-amine (Compound 13)

[0105]

[0106] Compound 1-7 (150 mg, 0.59 mmol) was dissolved in toluene (10 mL), and 2-(dibutyl(propyl)stannyl)-4-methylthiazole (577 mg, 1.49 mmol), potassium acetate (115 mg, 1.18 mmol), and Pd(PPh3)4 (30 mg, 0.026 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 110°C for reaction for 9 hours. After the reaction was completed, saturated potassium fluoride solution (30 mL) and ethyl acetate (10 mL) were added to the reaction solution. After stirring overnight, the liquids were separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=4:1) to obtain 80 mg of a light yellow solid. 1 H NMR (300MHz, DMSO-d6) δ9.07(s,1H),7.78(s,1H),7.63(s,1H),7.55(s,1H),2.91(s,3H),2.51(s,3H),2.44(s,3H).ESI-MS: m / z271.10[M+H] + .

[0107] Example 14 8-(2,4-dichlorophenyl)-2-(difluoromethoxy)-6-methylquinazoline (Compound 14)

[0108]

[0109] Compound 1-4 (1.00 g, 4.67 mmol) and urea (2.80 g, 46.7 mmol) were reacted without solvent at 160°C for 3 h. After the reaction was completed, the temperature was cooled to room temperature, and water (50 mL) was added to the reaction solution. The mixture was stirred and filtered, and the filter cake was washed with ethyl acetate and dried to obtain 1.1 g of off-white solid. It was directly used in the next step without purification. ESI-MS: m / z 240.17 [M+H] + .

[0110] Compound 14-1 (1.00 g, 4.18 mmol) was dissolved in N,N-dimethylformamide (15 mL), and sodium difluorochloroacetate (3.83 g, 25.10 mmol) and potassium carbonate (3.46 g, 25.10 mmol) were added. The temperature was raised to 110 °C and the reaction was carried out for 20 min. After the reaction was completed, ice water (100 mL) and ethyl acetate (30 mL) were added to the reaction solution, and the mixture was stirred and separated. The aqueous phase was extracted twice with ethyl acetate (20 mL*2), the organic phases were combined, washed twice with saturated brine, and dried over anhydrous sodium sulfate. The residue was purified by column chromatography to obtain 0.25 g of a white solid. 1H NMR(500MHz,Chloroform-d)δ9.25(s,1H),8.10(d,J=1.8Hz,1H),7.82(d,J=71.9Hz,1H),7.73–7.55(m,1H),2.58(s,3H).

[0111] Compound 14-2 (100 mg, 0.35 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 2,4-dichlorophenylboronic acid (85 mg, 0.45 mmol), sodium carbonate (75 mg, 0.70 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100 ° C for reaction for 3 h. After the reaction, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=5:1) to obtain 110 mg of a light yellow solid. 1 H NMR(300MHz,Chloroform-d)δ9.29(s,1H),7.78(s,1H),7.72(s,1H),7.57(d,J=6.8Hz,1 H),7.35(dd,J=11.9,7.1Hz,2H),7.31–7.07(m,1H),2.61(s,3H).ESI-MS:m / z355.02[M] + .

[0112] Example 15 2-(Difluoromethoxy)-8-(2-fluoro-3-methoxyphenyl)-6-methylquinazoline (Compound 15)

[0113]

[0114] Compound 14-2 (200 mg, 0.69 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 2-fluoro-3-methoxyphenylboronic acid (152 mg, 0.90 mmol), sodium carbonate (146 mg, 1.38 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100 ° C for reaction for 3 h. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=4:1) to obtain 130 mg of a light yellow solid. 1H NMR(500MHz,DMSO-d6)δ9.59(d,J=12.7Hz,1H),8.32–8.02(m,1H),8.02–7.86(m,1H),7.88–7.44 (m,1H),7.34–7.21(m,2H),7.12–7.03(m,1H),3.92(s,3H),2.61(s,3H).ESI-MS:m / z335.10[M+H] + .

[0115] Example 16 4-Chloro-2-(2-(difluoromethoxy)-6-methylquinazolin-8-yl)-6-methoxybenzothiazole (Compound 16)

[0116]

[0117] Compound 14-2 (200 mg, 0.69 mmol) was dissolved in 1,4-dioxane (5 mL), and pinacol borate (350 mg, 1.38 mmol), potassium acetate (135 mg, 1.38 mmol), and Pd(dppf)Cl2 (20 mg, 0.027 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 110°C for reaction for 10 h. The reaction was completed by TLC monitoring. The reaction solution was cooled to room temperature, and ice water (30 mL) and ethyl acetate (20 mL) were added to the reaction solution. The mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate twice (20 mL*2). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 130 mg of a brown solid, which was directly used in the next step without purification. ESI-MS: m / z 337.18 [M+H] + .

[0118] Compound 16-1 (232 mg, 0.69 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 2-bromo-4-chloro-6-methoxybenzo[d]thiazole (170 mg, 0.62 mmol), sodium carbonate (146 mg, 1.38 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 90°C for reaction for 9 hours. After the reaction, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:EA=20:1) to obtain 30 mg of a light yellow solid. 1 H NMR (500MHz, DMSO-d6) δ9.63(s,1H),8.89(s,1H),8.11(s,1H),7.97–7.83(m,1H),7.70(s,1H),7.26(s,1H),3.91(s,3H),2.64(s,3H).ESI-MS: m / z 430.02[M+Na] + .

[0119] Example 17 2-(2-(Difluoromethoxy)-6-methylquinazolin-8-yl)-6-methoxybenzothiazole (Compound 17)

[0120]

[0121] Compound 16-1 (232 mg, 0.69 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 2-bromo-6-methoxybenzo[d]thiazole (168 mg, 0.69 mmol), sodium carbonate (146 mg, 1.38 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100°C for reaction for 5 h. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:EA=20:1) to obtain 50 mg of a light yellow solid. 1H NMR(500MHz,Chloroform-d)δ9.36(s,1H),9.08(d,J=2.0Hz,1H),8.05(d,J=8.9Hz,1H),8.03-7.74(t,J=70.0 Hz,1H),7.84(s,1H),7.50(d,J=2.5Hz,1H),7.18(dd,J=8.9,2.5Hz,1H),3.98(s,3H),2.70(s,3H).ESI-MS:m / z 374.08[M+H] + .

[0122] Example 18 2-(Difluoromethoxy)-6-methyl-8-(1H-pyrazol-3-yl)quinazoline (Compound 18)

[0123]

[0124] Compound 14-2 (200 mg, 0.69 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 1H-pyrazole-3-boric acid (100 mg, 0.90 mmol), sodium carbonate (146 mg, 1.38 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100 ° C. for reaction for 3 h. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=1:1) to obtain 180 mg of a light yellow solid. 1 H NMR(500MHz,DMSO-d6)δ9.64(s,1H),8.80(d,J=2.7Hz,1H),8.30(d,J=1.8Hz,1H),8.04–7.98(m ,1H),7.95(d,J=1.6Hz,1H),6.68(dd,J=2.7,1.6Hz,1H),2.55(s,3H).ESI-MS:m / z277.56[M+H] + .

[0125] Example 19 2-(Difluoromethoxy)-6-methyl-8-(naphthalen-1-yl)quinazoline (Compound 19)

[0126]

[0127] Compound 14-2 (200 mg, 0.69 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 1-naphthaleneboric acid (100 mg, 0.90 mmol), sodium carbonate (146 mg, 1.38 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100 ° C for reaction for 3 h. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=5:1) to obtain 240 mg of a light yellow solid. 1 H NMR (500MHz, DMSO-d6) δ9.65(s,1H),8.11(s,1H),8.05(t,J=7.3Hz,2H),7.95(d,J=2.0Hz,1H),7.64(t,J=7.6Hz,1H),7. 53(q,J=7.2Hz,2H),7.47-7.18(t,J=75.0Hz,1H),7.38(t,J=7.5Hz,1H),7.34(d,J=8.5Hz,1H),2.61(s,3H).ESI-MS:m / z 337.11[M+H] + .

[0128] Example 20 2-(2-(Difluoromethoxy)-6-methylquinazolin-8-yl)-5-fluoro-6-methoxybenzo[d]thiazole (Compound 20)

[0129]

[0130] Compound 16-1 (232 mg, 0.69 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 2-bromo-5-fluoro-6-methoxybenzo[d]thiazole (180 mg, 0.69 mmol), sodium carbonate (146 mg, 1.38 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100°C for reaction for 9 hours. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:EA=20:1) to obtain 45 mg of a light yellow solid. 1H NMR(500MHz,Chloroform-d)δ9.39(s,1H),9.09(d,J=2.0Hz,1H),8.02-7.73(m,1H) ,7.87(d,J=2.6Hz,2H),7.56(d,J=7.9Hz,1H),4.07(s,3H),2.71(s,3H).ESI-MS:m / z 392.07[M+H] + .

[0131] Example 21 8-(5-Fluoro-6-methoxybenzo[d]thiazol-2-yl)-N,N,6-trimethylquinazolin-2-amine (Compound 21)

[0132]

[0133] Compound 1-6 (4.50 g, 17.47 mmol) was dissolved in tetrahydrofuran (20 mL), 2M dimethylamine (6.17 g, 34.94 mmol) was added, and the temperature was raised to 60°C for reaction for 10 h. After the reaction was completed, the reaction mixture was poured into water (100 mL), ethyl acetate (60 mL) was added, and the mixture was stirred for separation. The aqueous phase was extracted with ethyl acetate twice (50 mL*2), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 1.30 g of a light yellow solid. 1 H NMR (500MHz, DMSO-d6) δ9.09 (s, 1H), 8.02–7.82 (m, 1H), 7.59 (dd, J = 1.9, 1.0Hz, 1H), 3.26 (s, 6H), 2.39 (s, 3H).

[0134] Compound 21-1 (100 mg, 0.40 mmol) was dissolved in 1,4-dioxane (5 mL), and diboric acid pinacol ester (200 mg, 0.79 mmol), potassium acetate (77 mg, 0.80 mmol), and Pd(dppf)Cl2 (20 mg, 0.027 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 110 ° C for 10 h. The reaction was completed by TLC monitoring. The reaction solution was cooled to room temperature, and ice water (30 mL) and ethyl acetate (20 mL) were added to the reaction solution. Stir and separate the liquids. The aqueous phase was extracted twice with ethyl acetate (20 mL*2), and the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 120 mg of a brown solid, which was directly used in the next step without purification. ESI-MS: m / z 314.17 [M+H] + .

[0135] Compound 21-2 (235 mg, 0.69 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 2-bromo-5-fluoro-6-methoxybenzo[d]thiazole (188 mg, 0.69 mmol), sodium carbonate (158 mg, 1.50 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100°C for reaction for 11 h. After the reaction was completed, water (10 mL) and ethyl acetate (20 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:EA=20:1) to obtain 45 mg of a light yellow solid. 1 H NMR(500MHz,Chloroform-d)δ9.02(s,1H),8.87(d,J=2.0Hz,1H),7.83(d,J=11.6Hz,1 H),7.65–7.40(m,2H),4.03(s,3H),3.48(s,6H),2.57(s,3H).ESI-MS:m / z369.12[M+H] + .

[0136] Example 22 8-(4-Chloro-6-methoxybenzo[d]thiazol-2-yl)-N,N,6-trimethylquinazolin-2-amine (Compound 22)

[0137]

[0138] Compound 21-2 (235 mg, 0.40 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 2-bromo-4-chloro-6-methoxybenzo[d]thiazole (219 mg, 0.44 mmol), sodium carbonate (159 mg, 0.80 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100°C for reaction for 3 h. After the reaction was completed, water (10 mL) and ethyl acetate (20 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:EA=20:1) to obtain 40 mg of a light yellow solid. 1H NMR (500MHz, DMSO-d6) δ9.21 (s, 1H), 8.73 (s, 1H), 7.73 (d, J = 47.2Hz, 2H), 7.25 (d ,J=2.4Hz,1H),3.89(s,3H),3.38(s,6H),2.47(s,3H).ESI-MS:m / z407.79[M+Na] + .

[0139] Example 23 4-Chloro-6-methoxy-2-(2-methoxy-6-methylquinazolin-8-yl)benzo[d]thiazole (Compound 23)

[0140]

[0141] Compound 1-6 (4.00 g, 22.39 mmol) was dissolved in methanol (60 mL), sodium methoxide (6.17 g, 114.21 mmol) was added, and the temperature was raised to 60 ° C for reaction for 10 h. After the reaction was completed, the reaction was poured into water (50 mL), ethyl acetate (60 mL) was added, stirred and separated, the aqueous phase was extracted with ethyl acetate twice (50 mL*2), the organic phase was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to obtain 1.20 g of a light yellow solid. 1 H NMR (500MHz, DMSO-d6) δ9.37 (s, 1H), 8.13 (d, J = 1.8Hz, 1H), 7.93–7.76 (m, 1H), 4.08 (s, 3H), 2.47 (s, 3H).

[0142] Compound 23-1 (100 mg, 0.40 mmol) was dissolved in 1,4-dioxane (5 mL), and diboric acid pinacol ester (200 mg, 0.80 mmol), potassium acetate (77 mg, 0.80 mmol), and Pd(dppf)Cl2 (20 mg, 0.027 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 110 ° C for 10 h. The reaction was completed by TLC monitoring. The reaction solution was cooled to room temperature, and ice water (30 mL) and ethyl acetate (20 mL) were added to the reaction solution. Stir and separate the liquids. The aqueous phase was extracted with ethyl acetate twice (20 mL*2), and the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 130 mg of brown solid, which was directly used for the next step without purification. ESI-MS: m / z 301.19 [M+H] + .

[0143] Compound 23-2 (120 mg, 0.40 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 2-bromo-4-chloro-6-methoxybenzo[d]thiazole (122 mg, 0.44 mmol), sodium carbonate (85 mg, 0.80 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100°C for reaction for 5 h. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:EA=20:1) to obtain 40 mg of a light yellow solid. 1 H NMR(500MHz,Chloroform-d)δ9.25(s,1H),9.09(d,J=2.0Hz,1H),7.77(dd,J=2.0,1.0Hz,1H),7 .37(d,J=2.4Hz,1H),7.22(d,J=2.4Hz,1H),4.37(s,3H),3.94(s,3H),2.66(s,3H).ESI-MS:m / z 394.04[M+Na] + .

[0144] Example 24 5-Fluoro-6-methoxy-2-(2-methoxy-6-methylquinazolin-8-yl)benzo[d]thiazole (Compound 24)

[0145]

[0146] Compound 23-2 (177 mg, 0.59 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 2-bromo-5-fluoro-6-methoxybenzo[d]thiazole (170 mg, 0.65 mmol), sodium carbonate (146 mg, 1.18 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100°C for reaction for 5 h. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:EA=20:1) to obtain 50 mg of a light yellow solid. 1H NMR(500MHz,Chloroform-d)δ9.26(s,1H),9.00(s,1H),7.84(d,J=11.4Hz,1H),7.7 7(s,1H),7.51(d,J=7.9Hz,1H),4.38(s,3H),4.04(s,3H),2.66(s,3H).ESI-MS:m / z 378.07[M+Na] + .

[0147] Example 25 6-methoxy-2-(2-methoxy-6-methylquinazolin-8-yl)benzo[d]thiazole (Compound 25)

[0148]

[0149] Compound 23-2 (232 mg, 0.69 mmol) was dissolved in toluene (10 mL) and water (5 mL), and 2-bromo-6-methoxybenzo[d]thiazole (168 mg, 0.69 mmol), sodium carbonate (146 mg, 1.38 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The gas was replaced three times under nitrogen protection, and the temperature was raised to 100°C for reaction for 7 hours. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL*2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:EA=20:1) to obtain 60 mg of a light yellow solid. 1 H NMR(500MHz,Chloroform-d)δ9.28(s,1H),9.06(d,J=2.0Hz,1H),8.08(d,J=8.9Hz,1H),7.88–7.73(m,1H ),7.49(d,J=2.5Hz,1H),7.18(dd,J=9.0,2.6Hz,1H),4.40(s,3H),3.97(s,3H),2.67(s,3H).ESI-MS:m / z 338.10[M+H] + .

[0150] Evaluation of antiplatelet aggregation activity in vitro

[0151] Test principle: AYPGKF-NH2 is a PAR4-specific agonist peptide that can selectively activate PAR4 expression and cause platelet aggregation. The compound of the present invention can antagonize platelet PAR4, thereby inhibiting platelet aggregation. The test uses washed platelets taken from mouse arterial plasma.

[0152] Pipette 300μL Tyrode's buffer into a clean test cup, place it in the platelet aggregation test area and adjust to zero. The instrument reading board displays PRP mode. Then accurately pipette 270μL of washed platelet suspension into the preheating tank, add 20μL of saline or different concentrations of the test sample, incubate at 37℃ for 5min and place it in the test area. After adding magnetic beads to the test cup in turn, immediately press the buttons of each channel, and then add 10μL AYPGKF-NH2 inducer to start testing its aggregation rate. Finally, the aggregation meter displays the maximum aggregation rate of platelets within 5min. The platelet aggregation inhibition rate is calculated by the following formula. Calculation formula: Platelet aggregation inhibition rate = [(XY) / X]*100%, where X is the maximum aggregation rate of platelets in the saline group, and Y is the maximum aggregation rate of compound platelets. BMS-986120 is a PAR4 antagonist developed by BMS and is in Phase II clinical research. This experiment measured IC 50 =9.7nM, which is basically consistent with the experimental data in the literature (9.5nM). The experimental results of some compounds are shown in Table 1 below:

[0153] Table 1 Inhibition of AYP-induced platelet aggregation by compounds

[0154]

[0155] (Note: A: 0.1-20nM; B: 20-100nM; C: >100nM)

[0156] The results show that the above compounds of the present invention have significant antiplatelet aggregation activity.

[0157] Example 26 Tablets

[0158] Compound 1 (10 g) prepared in Example 1, carboxypropyl methylcellulose E (30 g), starch (40 g), appropriate amount of povidone K30 and magnesium stearate (0.3 g) were mixed, granulated and tableted.

Claims

1. A compound represented by the following structure, or a pharmaceutically acceptable salt thereof:

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The pharmaceutically acceptable salt refers to a salt formed by a compound and an organic acid or an inorganic acid, wherein the organic acid and the inorganic acid are selected from: acetylsalicylic acid, fumaric acid, methanesulfonic acid, ethanesulfonic acid, sulfuric acid, hydrochloric acid, formic acid, acetic acid, benzenesulfonic acid, hydrobromic acid, lactic acid, phosphoric acid, oxalic acid, 2-hydroxyethanesulfonic acid, gentisic acid, tartaric acid, succinic acid, maleic acid, lauric acid, citric acid, camphoric acid, n-dodecylsulfonic acid, adipic acid, ascorbic acid, trifluoroacetic acid, formic acid, tannic acid, and picric acid.

3. A pharmaceutical composition comprising the compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

4. Use of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a PAR4 antagonist.

5. Use of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating thromboembolic disorders.

6. The use according to claim 5, characterized in that: Thromboembolic disorders include: acute coronary syndrome, transient ischemic attack, atherosclerosis, stroke, myocardial infarction, cerebral arterial thrombosis, peripheral arterial occlusive disease, deep vein thrombosis, arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders.

7. A method for preparing the compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The method is selected from the following scheme 1, scheme 2 or scheme 3: Solution 1 Solution 2 Solution 3 Wherein, R1, R2 and R3 are as shown in the structure of claim 1.

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