PYRIDOPYRIMIDINONE DERIVATIVE, PREPARATION METHOD THEREFOR, AND USE THEREOF

Abstract

A pyridopyrimidinone derivative as represented by formula I, and a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof or a prodrug thereof. The pyridopyrimidinone derivative has a good SOS1 inhibitory effect.

##STR00001##

Claims

1. A pyridopyrimidinone derivative as represented by formula I, a tautomer thereof, a stereoisomer thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof: ##STR00181## wherein ring A is a 6- to 10-membered aromatic ring or a 9- to 11-membered heteroaromatic ring; R.sub.1 is 3- to 10-membered cycloalkyl or 4- to 10-membered heterocycloalkyl, the R.sub.1 is optionally substituted by one or more than one R.sub.11, the R.sub.11 is a substituent selected from: halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, ##STR00182## when there is more than one substituent R.sub.11, the substituents R.sub.11 are the same or different; the R.sub.11 is optionally substituted by a substituent selected from: C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, hydroxyl; R.sub.12 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl substituted by one or more than one F, or 3- to 6-membered cycloalkyl; R.sub.13 is hydrogen, C.sub.1-C.sub.6 alkyl or cyano; R.sub.14 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; R.sub.2 is hydrogen or a substituent selected from: halogen, C.sub.1-C.sub.6 alkyl, 3- to 6-membered cycloalkyl, C.sub.1-C.sub.6 alkoxy; the C.sub.1-C.sub.6 alkyl, 3- to 6-membered cycloalkyl, C.sub.1-C.sub.6 alkoxy are each independently substituted by one or more than one R.sub.21; the R.sub.21 is a substituent selected from: hydroxyl, halogen, C.sub.1-C.sub.3 alkoxy; when there is more than one substituent, the R.sub.21 are the same or different; R.sub.3 is hydrogen or a substituent selected from: halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; R.sub.4 is C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 haloalkyl; R.sub.5 is hydrogen or a substituent selected from: halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; R.sub.6 is SF.sub.5, ##STR00183## the R.sub.61 and the R.sub.62 are each independently C.sub.1-C.sub.6 alkyl substituted by halogen, or 3- to 6-membered cycloalkyl; or, the ring A together with R.sub.6 and R.sub.5 forms a group moiety ##STR00184## wherein Z is ##STR00185## R.sub.63 is hydrogen or a substituent selected from: halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl substituted by halogen; when there is more than one substituent R.sub.63, the R.sub.63 are the same or different; m is 1 or 2; p is 1, 2, or 3; and n is 1, 2, or 3.

2. The pyridopyrimidinone derivative as represented by formula I, the tautomer thereof, the stereoisomer thereof, the hydrate thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein, ##STR00186## wherein ring A is a 6- to 10-membered aromatic ring or a 9- to 11-membered heteroaromatic ring; R.sub.1 is 3- to 10-membered cycloalkyl or 4- to 10-membered heterocycloalkyl, the cycloalkyl is optionally substituted by one or more than one R.sub.11, the R.sub.11 is a substituent selected from: halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, ##STR00187## when there is more than one substituent R.sub.11, the substituents R.sub.11 are the same or different; R.sub.12 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl substituted by one or more than one F, or 3- to 6-membered cycloalkyl; R.sub.13 is hydrogen, C.sub.1-C.sub.6 alkyl or cyano; R.sub.2 is hydrogen or a substituent selected from: halogen, C.sub.1-C.sub.6 alkyl, 3- to 6-membered cycloalkyl, C.sub.1-C.sub.6 alkoxy; the C.sub.1-C.sub.6 alkyl, 3- to 6-membered cycloalkyl, C.sub.1-C.sub.6 alkoxy are each independently substituted by one or more than one R.sub.21; the R.sub.21 is a substituent selected from: hydroxyl, halogen, C.sub.1-C.sub.3 alkoxy; when there is more than one substituent, the R.sub.21 are the same or different; R.sub.3 is hydrogen or a substituent selected from: halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; R.sub.4 is C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 haloalkyl; R.sub.5 is hydrogen or a substituent selected from: halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; R.sub.6 is SF.sub.5, ##STR00188## the R.sub.61 and the R.sub.62 are each independently C.sub.1-C.sub.6 alkyl substituted by halogen, or 3- to 6-membered cycloalkyl; or, the ring A together with R.sub.6 and R.sub.5 forms a group moiety ##STR00189## wherein Z is ##STR00190## R.sub.63 is hydrogen or a substituent selected from: halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl substituted by halogen; when there is more than one substituent R.sub.63, the R.sub.63 are the same or different; m is 1 or 2; p is 1, 2, or 3; and n is 1, 2, or 3.

3. The pyridopyrimidinone derivative as represented by formula I, the tautomer thereof, the stereoisomer thereof, the hydrate thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the pyridopyrimidinone derivative as represented by formula I has a structure of I-1, ##STR00191## or, the pyridopyrimidinone derivative as represented by formula I has a structure of I-2, ##STR00192## wherein R.sub.4 is methyl or CH.sub.2F.

4. The pyridopyrimidinone derivative as represented by formula I, the tautomer thereof, the stereoisomer thereof, the hydrate thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.5 is hydrogen, fluorine or methyl; m is 1 or 2; R.sub.6 is SF.sub.5, ##STR00193## the R.sub.61 and the R.sub.62 are each independently C.sub.1-C.sub.6 alkyl substituted by one or more than one F, or 3- to 6-membered cycloalkyl; or, R.sub.61 is CH.sub.2F, CHF.sub.2, CF.sub.3, CF.sub.2CH.sub.3 or cyclopropyl; or, R.sub.62 is CH.sub.2F, CHF.sub.2, CF.sub.3; or, R.sub.62 is CHF.sub.2; or ##STR00194## or, the ring A together with R.sub.6 and R.sub.5 forms a group moiety ##STR00195## wherein Z is ##STR00196## p is 1, n is 2 or 3, R.sub.63 is fluorine or hydroxyl, and when there is more than one, R.sub.63, the R.sub.63 are the same or different; or, the group moiety ##STR00197## has a structure of ##STR00198## or, the group moiety ##STR00199## has a structure of ##STR00200##

5.-6. (canceled)

7. The pyridopyrimidinone derivative as represented by formula I, the tautomer thereof, the stereoisomer thereof, the hydrate thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the pyridopyrimidinone derivative as represented by formula I meets one or more than one of the following conditions: (1) R.sub.5 is hydrogen; R.sub.6 is SF.sub.5, ##STR00201## (2) R.sub.4 is C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl; (3) the halogen is fluorine, chlorine, bromine; (4) in the R.sub.1, the 3- to 10-membered cycloalkyl comprises a monocyclic, bicyclic, tricyclic, spiro or bridged ring; the 4- to 10-membered heterocycloalkyl has one or more than one heteroatom, the heteroatom is N, O or S; (5) 3- to 10-membered cycloalkyl is: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl (octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthalene), bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcaranyl), bicyclo[3.1.1]heptyl (pinanyl), spiro[2.5]octyl, spiro[3.3]heptyl; (6) the 4- to 10-membered heterocycloalkyl is: tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl, 1,4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, 1,3-dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, [1.4]-oxazepanyl, tetrahydrothienyl, homothiomorpholinyl-S,S-dioxide, oxazolidonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuranyl, dihydropyranyl, tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-S-oxide, 2,3-dihydroazetidinyl, 2H-pyrrolyl, 4H-pyranyl, 1,4-dihydropyridinyl, 8-aza-bicyclo[3.2.1]octyl, 8-aza-bicyclo[5.1.0]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 2,5-diaza-bicyclo-[2.2.1]heptyl, 1-aza-bicyclo[2.2.2]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 3,9-diaza-bicyclo[4.2.1]nonyl, 2,6-diaza-bicyclo[3.2.2]nonyl; (7) R.sub.1 is 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl, the cycloalkyl is optionally substituted by one or more than one R.sub.11, the R.sub.11 is a substituent selected from: halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; when there is more than one substituent R.sub.11, the substituents R.sub.11 are the same or different; (8) R.sub.1 is ##STR00202## wherein the R.sub.11 is a substituent selected from: halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; (9) R.sub.11 is C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkyl substituted by fluorine; (9) R.sub.2 is hydrogen or a substituent selected from: halogen, C.sub.1-C.sub.6 alkyl, 3- to 6-membered cycloalkyl; (10) R.sub.3 is hydrogen, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 haloalkyl.

8. The pyridopyrimidinone derivative as represented by formula I, the tautomer thereof, the stereoisomer thereof, the hydrate thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the pyridopyrimidinone derivative as represented by formula I meets one or more than one of the following conditions: (1) R.sub.4 is methyl or CH.sub.2F; (2) the halogen is fluorine; (3) the 3- to 10-membered cycloalkyl is: ##STR00203## (4) the 4- to 10-membered heterocycloalkyl is: ##STR00204## or, the 4- to 10-membered heterocycloalkyl is: ##STR00205## (5) R.sub.11 is methyl, CH.sub.2F or CH.sub.2.

9.-11. (canceled)

12. The pyridopyrimidinone derivative as represented by formula I, the tautomer thereof, the stereoisomer thereof, the hydrate thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the pyridopyrimidinone derivative as represented by formula I meets one or more than one of the following conditions: (1) R.sub.1 is 3- to 10-membered cycloalkyl or 4- to 10-membered heterocycloalkyl, the heterocycloalkyl is optionally substituted by one or more than one R.sub.11, and the R.sub.11 is hydroxyl or ##STR00206## when there is more than one substituent R.sub.11, the substituents R.sub.11 are the same or different; the R.sub.11 is optionally substituted by a substituent selected from: C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, hydroxyl; R.sub.14 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; (2) R.sub.1 is 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl, the R.sub.1 is optionally substituted by one or more than one R.sub.11, the R.sub.11 is a substituent selected from: halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, ##STR00207## R.sub.14 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl; the R.sub.11 is optionally substituted by a substituent selected from: C.sub.1-C.sub.3 alkoxy, halogen; (3) R.sub.5 is hydrogen; R.sub.6 is SF.sub.5; R.sub.4 is methyl; R.sub.3 is methyl; and R.sub.2 is hydrogen; (4) R.sub.2 is hydrogen or a substituent selected from: halogen, C.sub.1-C.sub.6 alkyl, 3- to 6-membered cycloalkyl; (5) R.sub.3 is hydrogen, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 haloalkyl.

13. The pyridopyrimidinone derivative as represented by formula I, the tautomer thereof, the stereoisomer thereof, the hydrate thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the pyridopyrimidinone derivative as represented by formula I meets one or more than one of the following conditions: (1) R.sub.1 is 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl, the R.sub.1 is optionally substituted by one or more than one R.sub.11, the R.sub.11 is a substituent selected from: halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, ##STR00208## R.sub.14 is hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl; the R.sub.11 is optionally substituted by a substituent selected from: C.sub.1-C.sub.3 alkoxy, halogen; the halogen is fluorine; (2) R.sub.1 is 3- to 10-membered cycloalkyl or 4- to 10-membered heterocycloalkyl, the heterocycloalkyl is optionally substituted by one or more than one R.sub.11, the R.sub.11 is hydroxyl or ##STR00209## when there is more than one substituent R.sub.11, the substituents R.sub.11 are the same or different; the R.sub.11 is optionally substituted by a substituent selected from: C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, halogen, hydroxyl; R.sub.14 is hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl.

14. The pyridopyrimidinone derivative as represented by formula I, the tautomer thereof, the stereoisomer thereof, the hydrate thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.1 is selected from cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, epoxypropanyl, pyrrolidinyl or piperidinyl; the R.sub.1 is optionally substituted by one or more than one R.sub.11, and the R.sub.11 is a substituent selected from: fluorine, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl substituted by C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.6 alkoxy, ##STR00210## R.sub.14 is C.sub.1-C.sub.6 alkyl; R.sub.1 is selected from: ##STR00211##

15.-17. (canceled)

18. The pyridopyrimidinone derivative as represented by formula I, the tautomer thereof, the stereoisomer thereof, the hydrate thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the pyridopyrimidinone derivative comprises: ##STR00212## ##STR00213## ##STR00214## ##STR00215## ##STR00216##

19.-23. (canceled)

24. A method for preparing the pyridopyrimidinone derivative as represented by formula I, the tautomer thereof, the stereoisomer thereof, the hydrate thereof or the pharmaceutically acceptable salt thereof according to claim 1, comprising: 1) reacting an intermediate B-1 with an intermediate B-2 to obtain the pyridopyrimidinone derivative as represented by formula I, ##STR00217## wherein R.sub.7 is hydroxyl, chlorine, bromine, iodine or sulfonate.

25. The method according to claim 24, wherein the method meets one or more of the following conditions: (1) ring A is phenyl; (2) the group moiety ##STR00218## has a structure of ##STR00219## (3) R.sup.7 is hydroxyl; (4) the sulfonate is SO.sub.3R.sup.71, wherein R.sup.71 is methyl, CF.sub.3, phenyl or 2,4,6-trimethylphenyl; (5) R.sup.5 is hydrogen, fluorine or methyl; m is 1 or 2; (6) m is 1; (7) R.sup.6 is SF.sub.5, ##STR00220## the R.sup.61 and the R.sup.62 are each independently C.sub.1-C.sub.6 alkyl substituted b y one or more than one F, or 3- to 6-membered cycloalkyl; or, the ring A together with R.sup.6 and R.sup.5 forms a group moiety; wherein Z is ##STR00221## p is 1, n is 2 or 3, R.sup.63 is fluorine or hydroxyl, and when there is more than one R.sup.63, the R.sup.63 are the same or different; (8) the group moiety ##STR00222## has a structure of ##STR00223## (9) the group moiety ##STR00224## has a structure of ##STR00225## (10) R.sup.61 is CH.sub.2F, CHF.sub.2, CF.sub.3, CF.sub.2CH.sub.3 or cyclopropyl; (11) R.sup.62 is CH.sub.2F, CHF.sub.2, CF.sub.3; (12) the method further comprises: 2) converting the intermediate B-1 to an amine salt of B-1 and then reacting with the intermediate B-2 to obtain the pyridopyrimidinone derivative as represented by formula I.

26.-27. (canceled)

28. A pharmaceutical composition comprising: the pyridopyrimidinone derivative as represented by formula I, the tautomer thereof, the stereoisomer thereof, the hydrate thereof or the pharmaceutically acceptable salt thereof according to claim 1; and a pharmaceutically acceptable carrier.

29. A pharmaceutical composition comprising: the pyridopyrimidinone derivative as represented by formula I, the tautomer thereof, the stereoisomer thereof, the hydrate thereof or the pharmaceutically acceptable salt thereof according to claim 1; and at least one other pharmacologically active inhibitor.

30. The pharmaceutical composition according to claim 29, wherein the other pharmacologically active inhibitor is an inhibitor of MEK and/or a mutant thereof; or the other pharmacologically active inhibitor is trametinib.

31. A method of preventing and/or treating cancer and RASopathies in a subject in need thereof, comprising administering a therapeutically effective amount of the compound represented by the pyridopyrimidinone derivative as represented by formula I, the tautomer thereof, the stereoisomer thereof, the hydrate thereof or the pharmaceutically acceptable salt thereof according to claim 1.

32. The method se according to claim 31, wherein the RASopathies comprise Noonan syndrome, cardio-facio-cutaneous syndrome, hereditary gingival fibromatosis type 1, neurofibromatosis type 1, capillary malformation-arteriovenous malformation syndrome, Costello syndrome and Legius syndrome; and/or, the cancer is selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder carcinoma, cholangiocarcinoma, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric tumor, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial carcinoma, ureteral tumor, prostate cancer, seminoma, testicular cancer, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and glioma; and/or, the pyridopyrimidinone derivative as represented by formula I, the tautomer thereof, the stereoisomer thereof, the hydrate thereof or the pharmaceutically acceptable salt thereof are used in combination with trametinib.

33. (canceled)

34. The method according to claim 32, wherein the liver cancer is hepatocellular carcinoma; the head and neck tumor is head and neck squamous cell carcinoma; the sarcoma is osteosarcoma; and the colorectal cancer is colon cancer or rectal cancer.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0159] FIG. 1 shows the tumor inhibitory ability of representative compounds at the tumor volume level (tumor volume (mm.sup.3) at the end of treatment) tested in Mia Paca-2 pancreatic cancer in vivo efficacy experiment.

[0160] FIG. 2 shows the tumor inhibitory ability of representative compounds at the tumor weight level (tumor volume (mm.sup.3) at the end of treatment) tested in LOVO colorectal cancer in vivo efficacy experiment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0161] The present disclosure is further illustrated below in conjunction with specific embodiments. It should be understood that the following description is only the most preferred embodiment of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. On the basis of a full understanding of the present disclosure, the experimental methods without indication of specific conditions in the following embodiments shall be implemented usually in accordance with conventional conditions or the conditions suggested by the manufacturer. Those skilled in the art can make non-essential modifications to the technical solutions of the present disclosure, and such modifications should be considered to be included in the scope of protection of the present disclosure.

[0162] The abbreviations in the present disclosure are defined as follows:

[0163] Symbols or units: [0164] IC.sub.50: half inhibitory concentration, which refers to a concentration at which half of the maximum inhibitory effect is reached. [0165] M: mol/L, for example, n-butyllithium (14.56 mL, 29.1 mmol, 2.5 M n-hexane) means a solution of n-butyllithium in n-hexane with a molar concentration of 2.5 mol/L. [0166] N: equivalent concentration, for example, 2 N hydrochloric acid means 2 mol/L hydrochloric acid solution. [0167] Reagents: [0168] DCM: dichloromethane. [0169] DIPEA: also referred to as DIEA, diisopropylethylamine, i.e., N,N-diisopropylethylamine. [0170] DMF: N,N-dimethylformamide. [0171] DMSO: dimethyl sulfoxide. [0172] EA: ethyl acetate. [0173] Et.sub.3N: triethylamine. [0174] MeOH: methanol. [0175] PE: petroleum ether. [0176] THF: tetrahydrofuran. [0177] Test or detection methods: [0178] HPLC: high performance liquid chromatography. [0179] SFC: supercritical fluid chromatography. [0180] Acidic preparation condition B: [0181] Welch, Ultimate C18 column, 10 ?m, 21.2 mm?250 mm. Mobile phase A is a 1%.sub.0 solution of formic acid in pure water, and mobile phase B is an acetonitrile solution. Gradient conditions: mobile phase A was kept at 90% (0 to 3 min), then reduced from 90% to 5% by gradient elution (3 to 18 min) and kept at 5% (18 to 22 min).

Intermediate A1: Preparation of Intermediate A1

[0182] The synthetic route is as follows:

##STR00066##

Step 1: Methyl (Z)-2-((dimethylamino)methylene)-3-oxoglutarate (A1-2)

[0183] ##STR00067##

[0184] To 2-methyltetrahydrofuran (100 mL) was added compound dimethyl 3-oxoglutarate (10.0 g, 57.4 mmol) at room temperature, then DMF-DMA (6.8 g, 57.1 mmol) was added thereto, and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:1) to obtain a crude product of the title compound methyl (Z)-2-((dimethylamino)methylene)-3-oxoglutarate (A1-2) (12 g, yield: 91.1%) as a yellow liquid.

[0185] LC-MS, M/Z (ESI): 230.2 [M+H].sup.+.

Step 2: Methyl 1-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-6-oxo-1,6-dihydroxypyridine-3-carboxylate (A1-4)

[0186] ##STR00068##

[0187] To 2-methyltetrahydrofuran (30 mL) was added compound methyl (Z)-2-((dimethylamino)methylene)-3-oxoglutarate (2.4 g, 10.4 mmol) at room temperature, then 4 N hydrochloric acid (10 mL) was added thereto, and the reaction mixture was stirred for 3 h. The liquid was separated, and the aqueous phase was extracted with ethyl acetate (100 mL?3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, added with methanol (30 mL), then added with 1-(fluoromethyl)cyclopropane-1-amine hydrochloride (1.0 g, 8.0 mmol), and the mixture was stirred at room temperature for 16 h. The system was added with sodium methoxide (1.3 g, 24.0 mmol), and stirred for 2 h. The reaction mixture was added with concentrated hydrochloric acid to adjust the pH to 2, and filtered to obtain a crude product of the title compound methyl 1-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-6-oxo-1,6-dihydroxypyridine-3-carboxylate (A1-4) (2.0 g, yield: 79.1%) as a brown solid.

[0188] LC-MS, M/Z (ESI): 242.2 [M+H].sup.+.

Step 3: Methyl 1-(1-(fluoromethyl)cyclopropyl)-6-oxo-4-(p-toluenesulfonyloxy)-1,6-dihydroxypyridine-3-carboxylate (A1-5)

[0189] ##STR00069##

[0190] To acetonitrile (20 mL) was added raw material methyl 1-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-6-oxo-1,6-dihydroxypyridine-3-carboxylate (2.0 g, 8.3 mmol) at room temperature, the reaction mixture was cooled to 0? C., added with triethylamine (1.68 g, 16.6 mmol) and TsCl (1.58 g, 8.3 mmol), heated to room temperature, and stirred for 2 h. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=5:1 to 1:1) to obtain the title compound methyl 1-(1-(fluoromethyl)cyclopropyl)-6-oxo-4-(p-toluenesulfonyloxy)-1,6-dihydroxypyridine-3-carboxylate (A1-5) (1.2 g, yield: 36.6%) as a white solid.

[0191] LC-MS, M/Z (ESI): 396.3 [M+H].sup.+.

Step 4: Methyl 4-acetamido-1-(1-(fluoromethyl)cyclopropyl)-6-oxo-1,6-dihydroxypyridine-3-carboxylate (A1-6)

[0192] ##STR00070##

[0193] To dioxane (50 mL) was added raw material methyl 1-(1-(fluoromethyl)cyclopropyl)-6-oxo-4-(p-toluenesulfonyloxy)-1,6-dihydroxypyridine-3-carboxylate (1.2 g, 3.0 mmol) at room temperature, the reaction mixture was added with potassium phosphate (700 mg, 3.3 mmol), Xantphos (173 mg, 0.3 mmol) and palladium (II) (?-cinnamyl) chloride dimer (212 mg, 0.3 mmol), heated and stirred at reflux for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=3:1 to 1:1) to obtain the title compound methyl 4-acetamido-1-(1-(fluoromethyl)cyclopropyl)-6-oxo-1,6-dihydroxypyridine-3-carboxylate (A1-6) (680 mg, yield: 79.3%) as a white solid.

[0194] LC-MS, M/Z (ESI): 283.2 [M+H].sup.+.

Step 5: 6-(1-(Fluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (A1)

[0195] ##STR00071##

[0196] To a 7 mol/L solution of ammonia in methanol (10 mL) was added raw material methyl 4-acetamido-1-(1-(fluoromethyl)cyclopropyl)-6-oxo-1,6-dihydroxypyridine-3-carboxylate (680 mg, 2.41 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 5 d. The reaction mixture was concentrated to 3 mL and filtered to obtain the title compound 6-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (460 mg, yield: 16.4%) as a white solid.

[0197] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.8 (s, 1H), 8.36 (s, 1H), 6.17 (s, 1H), 4.62 (d, 2H), 2.24 (s, 3H), 1.27 (s, 4H).

[0198] LC-MS, M/Z (ESI): 250.2 [M+H].sup.+.

Intermediate A2: Preparation of Intermediate A2

[0199] The synthetic route is as follows:

##STR00072##

Step 1: Synthesis of 4,6-dichloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidine (A2-2)

[0200] ##STR00073##

[0201] To toluene (200 mL) was added 4,6-dichloro-2-methylpyrimidine-5-carbaldehyde (20 g, 105 mmol), the reaction mixture was added with ethylene glycol (5.84 mL) and p-toluenesulfonic acid (2 g, 10.5 mmol), and refluxed at 120? C. for 12 h. After the reaction was completed, the reaction mixture was concentrated, added with dichloromethane (200 mL), and washed with saturated sodium bicarbonate solution (200 mL?3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=10:1) to obtain the title compound 4,6-dichloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidine (A2-2) (11 g, yield: 44.6%).

[0202] LC-MS, M/Z (ESI): 235.0 [M+H].sup.+.

Step 2: Synthesis of dimethyl 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)malonate (A2-3)

[0203] ##STR00074##

[0204] To dimethyl sulfoxide (50 mL) was added 4,6-dichloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidine (10 g, 42.5 mmol), the reaction mixture was added with cesium carbonate (27.7 g, 85 mmol) and dimethyl malonate (6.18 g, 46.8 mmol), and stirred at 80? C. for 12 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (200 mL?3) and saturated brine (200 mL?3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=3:1) to obtain the title compound dimethyl 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)malonate (A2-3) (10 g, yield: 71%).

[0205] LC-MS, M/Z (ESI): 331.1 [M+H].sup.+.

Step 3: Synthesis of methyl 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)acetate (A2-4)

[0206] ##STR00075##

[0207] To dimethyl sulfoxide (30 mL) was added dimethyl 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)malonate (10.2 g, 30.8 mmol), the reaction mixture was added with lithium chloride (5.23 g, 123 mmol), and stirred at 120? C. for 12 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (200 mL?3) and saturated brine (200 mL?3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=3:1) to obtain the title compound methyl 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)acetate (A2-4) (6 g, yield: 71.3%).

[0208] LC-MS, M/Z (ESI): 273.1 [M+H].sup.+.

Step 4: Synthesis of methyl (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluoro-4.SUP.6.-sulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate (A2-5)

[0209] ##STR00076##

[0210] To dimethyl sulfoxide (25 mL) was added methyl 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)acetate (2.5 g, 9.17 mmol), the reaction mixture was added with N,N-diisopropylethylamine (4.8 mL, 27.5 mmol) and (R)-1-(3-(pentafluorosulfanyl)phenyl)ethan-1-amine hydrochloride (3.12 g, 11 mmol), and stirred at 80? C. for 6 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (100 mL?3) and saturated brine (100 mL?3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:1) to obtain the title compound methyl (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate (A2-5) (2.3 g, yield: 51.9%).

[0211] LC-MS, M/Z (ESI): 484.1 [M+H].sup.+.

Step 5: Synthesis of (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetic acid (A2)

[0212] ##STR00077##

[0213] To a mixed solution of dimethyl sulfoxide (25 mL) and acetonitrile (1 mL) was added methyl (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetate (250 mg, 0.52 mmol), the reaction mixture was added with sodium hydroxide (83 mg, 2.07 mmol), and stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was directly concentrated and dried to obtain methyl (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetic acid (A2) (243 mg, yield: 100%).

[0214] LC-MS, M/Z (ESI): 470.1 [M+H].sup.+.

Embodiment 1: Synthesis of Compound I-1

[0215] The synthetic route is as follows:

##STR00078## ##STR00079##

Step 1: Synthesis of S-(3-bromo-2-methylphenyl)acetylmercaptoester (B1-2)

[0216] ##STR00080##

[0217] To anhydrous toluene (20 mL) was added 1-bromo-3-iodo-2-toluene (2.0 g, 6.7 mmol) at room temperature, the reaction mixture was added with potassium thioacetate (1.2 g, 10.5 mmol), 1,10-phenanthroline (120 mg, 0.67 mmol) and cuprous iodide (260 mg, 1.4 mmol), heated to 100? C. under nitrogen atmosphere, and stirred for 3 h. The reaction mixture was cooled to room temperature, added with water (50 mL), extracted with EA (80 mL?3), and the liquid was separated. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain S-(3-bromo-2-methylphenyl)acetylmercaptoester (B1-2, a crude product as colorless liquid, 1.0 g, yield: 42.0%).

[0218] LC-MS, M/Z (ESI): 245.0 [M+H].sup.+.

Step 2: Synthesis of 3-bromo-2-methylbenzenethiol (B1-3)

[0219] ##STR00081##

[0220] To methanol (20 mL) and THF (20 mL) were added S-(3-bromo-2-methylphenyl)acetylmercaptoester (2.44 g, 10.0 mmol) at room temperature, the reaction mixture was added with potassium hydroxide (670 mg, 12.0 mmol), and stirred at room temperature for 0.5 h. The reaction mixture was concentrated to obtain 3-bromo-2-methylbenzenethiol (B1-3, a crude product as yellow solid, 2.10 g).

[0221] LC-MS, M/Z (ESI): 202.9 [M+H].sup.+.

Step 3: Synthesis of (3-bromo-2-methylphenyl)(difluoromethyl)sulfide (B1-4)

[0222] ##STR00082##

[0223] To acetonitrile (20 mL) was added 3-bromo-2-methylbenzenethiol (2.1 g, 10.0 mmol) at room temperature, the reaction mixture was added with potassium carbonate (2.8 g, 20.0 mmol) and sodium bromodifluoroacetate (3.0 g, 15.0 mmol), heated to 100? C. and stirred for 1 h. The reaction mixture was cooled to room temperature and filtered to obtain a solution of compound B1-4.

[0224] .sup.19F NMR (400 MHz, CDCl.sub.3) ? ?92.36.

[0225] LC-MS, M/Z (ESI): 252.9 [M+H].sup.+.

Step 4: Synthesis of 1-bromo-3-((difluoromethyl)sulfonyl)-2-methylbenzene (B1-5)

[0226] ##STR00083##

[0227] To acetonitrile (40 mL), carbon tetrachloride (40 mL) and water (80 mL) were added the solution of compound B1-4 at room temperature, the reaction mixture was added with ruthenium trichloride (2.1 g, 10.0 mmol) and sodium periodate (6.5 g, 30.0 mmol), and stirred for 16 h. The reaction mixture was diluted with water (400 mL), extracted with DCM (100 mL?3), and the liquid was separated. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=10:1) to obtain 1-bromo-3-((difluoromethyl)sulfonyl)-2-methylbenzene (B1-5, colorless liquid, 710 mg, yield: 24.9%).

[0228] LC-MS, M/Z (ESI): 284.9 [M+H].sup.+.

Step 5: Synthesis of 1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethan-1-one (B1-6)

[0229] ##STR00084##

[0230] To dioxane (50 mL) was added compound 1-bromo-3-((difluoromethyl)sulfonyl)-2-methylbenzene (700 mg, 3.07 mmol) at room temperature, the reaction mixture was added with bis(triphenylphosphine)palladium(II) chloride (431 mg, 0.61 mmol) and tributyl(1-ethoxyvinyl)tin (2.21 g, 6.14 mmol), heated to 90? C. under nitrogen atmosphere, and stirred for 14 h. The reaction mixture was cooled to room temperature, added with 2 N hydrochloric acid (30 mL), and stirred for 4 h. The reaction mixture was extracted with ethyl acetate (50 mL?3), and the liquid was separated. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=10:1) to obtain 1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethan-1-one (B1-6, colorless liquid, 450 mg, yield: 74.6%).

[0231] LC-MS, M/Z (ESI): 249.0 [M+H].sup.+.

Step 6: Synthesis of (S,E)-N-(1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (B1-7)

[0232] ##STR00085##

[0233] To THF (100 mL) was added compound 1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethan-1-one (650 mg, 2.60 mmol) at room temperature, the reaction mixture was added with (S)-tert-butylsulfinamide (475 mg, 3.93 mmol) and tetraethyl titanate (1.18 g, 5.20 mmol), heated to 70? C. and stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with water (200 mL), extracted with ethyl acetate (100 mL?3), and the liquid was separated. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=4:1) to obtain (S,E)-N-(1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (B1-7, white solid, 900 mg, yield: 100%).

[0234] LC-MS, M/Z (ESI): 352.3 [M+H].sup.+.

Step 7: Synthesis of (S)-N-((R)-1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (B1-8)

[0235] ##STR00086##

[0236] To methanol (20 mL) was added raw material (S,E)-N-(1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (900 mg, 2.56 mmol) at room temperature, and the reaction mixture was cooled to 0? C. The NaBH.sub.4 (474 mg, 12.8 mmol) was added into methanol in batches, and the reaction mixture was heated to room temperature and stirred for 3 h. The reaction mixture was concentrated and purified by preparative thin-layer chromatography to obtain (S)-N-((R)-1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (B1-8, white solid, 500 mg, yield: 55.3%).

[0237] LC-MS, M/Z (ESI): 354.1 [M+H].sup.+.

Step 8: Synthesis of (R)-1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethan-1-amine hydrochloride (B1-9)

[0238] ##STR00087##

[0239] To a 4 mol/L solution of hydrochloric acid in dioxane (1 mL) was added raw material (S)-N-((R)-1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (350 mg, 1.0 mmol) at room temperature, and the reaction mixture was stirred for 4 h. The reaction mixture was concentrated, added with methyl tert-butyl ether (20 mL), stirred for 1 h, and filtered to obtain (R)-1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethan-1-amine hydrochloride (B1-9, white solid, 260 mg, yield: 100%).

[0240] LC-MS, M/Z (ESI): 250.2 [M+H].sup.+.

Step 9: Synthesis of (R)-4-((1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (I-1)

[0241] ##STR00088##

[0242] To acetonitrile (20 mL) was added raw material 6-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (A1) (200 mg, 0.80 mmol) at room temperature, the reaction mixture was added with potassium phosphate (678 mg, 3.20 mmol) and phosphonitrilic chloride trimer (416 mg, 1.20 mmol), and stirred at room temperature for 16 h. To DCM (10 mL) was added raw material (R)-1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethan-1-amine hydrochloride (200 mg, 0.87 mmol), the reaction mixture was added with DIPEA (2 mL), and stirred for 0.5 h. The above system was added with the reaction mixture and stirred at room temperature for 6 h. The reaction mixture was concentrated and prepared under acidic preparation condition B to obtain (R)-4-((1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (I-1, white solid, 26 mg, yield: 6.7%).

[0243] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.17 (s, 1H), 9.03 (d, 1H), 7.92 (t, 2H), 7.59 (t, 1H), 7.46 (t, 1H), 6.05 (s, 1H), 5.67 (q, 1H), 4.73 (t, 2H), 2.83 (s, 3H), 2.14 (s, 3H), 1.56 (d, 3H), 1.33 (s, 4H).

[0244] LC-MS, M/Z (ESI): 481.2 [M+H].sup.+.

Embodiment 2: Synthesis of Compound I-2

[0245] The synthetic route is as follows:

##STR00089## ##STR00090##

Step 1: Synthesis of 3-bromo-2-fluorobenzene-1-diazonium tetrafluoroborate (B2-2)

[0246] ##STR00091##

[0247] To 50% tetrafluoroboric acid aqueous solution (21 mL) was added 3-bromo-2-fluoroaniline (10.3 g, 54.2 mmol) at room temperature, the reaction mixture was cooled to 0? C., and stirred for 1 h. A solution of sodium nitrite (3.8 g, 55 mmol) dissolved in water (6 mL) was added dropwise thereto at 0? C., and the reaction mixture was stirred continuously at low temperature for 1 h. The reaction mixture was filtered and dried to obtain 3-bromo-2-fluorobenzene-1-diazonium tetrafluoroborate (B2-2, a crude product as yellow solid, 13.0 g, yield: 83.2%).

Step 2: Synthesis of (3-bromo-2-fluorophenyl)(trifluoromethyl)sulfide (B2-3)

[0248] ##STR00092##

[0249] To acetonitrile (130 mL) was added 3-bromo-2-fluorobenzene-1-diazonium tetrafluoroborate (13 g, 45.1 mmol) at room temperature, the reaction mixture was added with cesium carbonate (30 g, 91.0 mmol), sodium thiocyanate (5.5 g, 67.9 mmol) and cuprous thiocyanate (2.8 g, 23.0 mmol), stirred for 0.5 h, then added with trifluoromethyltrimethylsilane (12.8 g, 90 mmol), and stirred for 16 h. The reaction mixture was filtered to obtain a solution of compound B2-3.

[0250] LC-MS, M/Z (ESI): 274.9 [M+H].sup.+.

Step 3: Synthesis of 1-bromo-2-fluoro-3-((trifluoromethyl)sulfonyl)benzene (B2-4)

[0251] ##STR00093##

[0252] To acetonitrile (200 mL), carbon tetrachloride (200 mL) and water (400 mL) were added the solution of compound B2-3 from the previous step at room temperature, the reaction mixture was added with ruthenium trichloride (9.3 g, 45.0 mmol) and sodium periodate (28.8 g, 134.5 mmol), and stirred for 16 h. The reaction mixture was diluted with water (800 mL), extracted with DCM (400 mL?3), and the liquid was separated. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=10:1) to obtain 1-bromo-2-fluoro-3-((trifluoromethyl)sulfonyl)benzene (B2-4, colorless liquid, 6.5 g, yield: 46.9%).

[0253] LC-MS, M/Z (ESI): 306.9 [M+H].sup.+.

Step 4: Synthesis of 1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethan-1-one (B2-5)

[0254] ##STR00094##

[0255] To dioxane (150 mL) was added compound 1-bromo-2-fluoro-3-((trifluoromethyl)sulfonyl)benzene (6.5 g, 21.2 mmol) at room temperature, the reaction mixture was added with bis(triphenylphosphine)palladium(II) chloride (1.5 g, 2.12 mmol) and tributyl(1-ethoxyvinyl)tin (11.5 g, 31.7 mmol), heated to 90? C. under nitrogen atmosphere, and stirred for 14 h. The reaction mixture was cooled to room temperature, added with 2 N hydrochloric acid (100 mL), and stirred for 4 h. The reaction mixture was extracted with ethyl acetate (200 mL?3), and the liquid was separated. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=10:1) to obtain 1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethan-1-one (B2-5, colorless liquid, 5.0 g, yield: 87.7%).

[0256] LC-MS, M/Z (ESI): 271.0 [M+H].sup.+.

Step 5: Synthesis of (S,E)-N-(1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (B2-6)

[0257] ##STR00095##

[0258] To THF (150 mL) was added compound 1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethan-1-one (2.7 g, 10.0 mmol) at room temperature, the reaction mixture was added with (S)-tert-butylsulfinamide (1.82 g, 15.0 mmol) and tetraethyl titanate (4.56 g, 20.0 mmol), heated to 70? C. and stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with water (300 mL), extracted with ethyl acetate (200 mL?3), and the liquid was separated. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=4:1) to obtain (S,E)-N-(1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (B2-6, white solid, 4.0 g, yield: 100%).

[0259] LC-MS, M/Z (ESI): 374.1 [M+H].sup.+.

Step 6: Synthesis of (S)-N-((R)-1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (B2-7)

[0260] ##STR00096##

[0261] To methanol (30 mL) was added raw material (S,E)-N-(1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.5 g, 4.0 mmol) at room temperature, and the reaction mixture was cooled to 0? C. NaBH.sub.4 (744 mg, 20.1 mmol) was added to methanol in batches, and the reaction mixture was heated to room temperature and stirred for 3 h. The reaction mixture was concentrated and purified by preparative thin-layer chromatography to obtain (S)-N-((R)-1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (B2-7, white solid, 600 mg, yield: 40.0%).

[0262] LC-MS, M/Z (ESI): 376.1 [M+H].sup.+.

Step 7: Synthesis of (R)-1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethan-1-amine hydrochloride (B2-8)

[0263] ##STR00097##

[0264] To a 4 mol/L solution of hydrochloric acid in dioxane (1 mL) was added raw material (S)-N-((R)-1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (250 mg, 0.67 mmol) at room temperature, and the reaction mixture was stirred for 4 h. The reaction mixture was concentrated, added with methyl tert-butyl ether (20 mL), stirred for 1 h, and filtered to obtain (R)-1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethan-1-amine hydrochloride (B2-8, white solid, 163 mg, yield: 79.6%).

[0265] LC-MS, M/Z (ESI): 272.2 [M+H].sup.+.

Step 8: Synthesis of (R)-4-((1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (I-2)

[0266] ##STR00098##

[0267] To acetonitrile (20 mL) was added raw material 6-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (A1) (200 mg, 0.80 mmol) at room temperature, the reaction mixture was added with potassium phosphate (678 mg, 3.20 mmol) and phosphonitrilic chloride trimer (416 mg, 1.20 mmol), and stirred at room temperature for 16 h. To DCM (10 mL) was added raw material (R)-1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethan-1-amine hydrochloride (163 mg, 0.53 mmol), the reaction mixture was added with DIPEA (2 mL), and stirred for 0.5 h. The above system was added with the reaction mixture, and stirred at room temperature for 6 h. The reaction mixture was concentrated and prepared under acidic preparation condition B to obtain (R)-4-((1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (I-2, white solid, 25 mg, yield: 6.2%).

[0268] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.18 (s, 1H), 9.06 (d, 1H), 8.10 (t, 1H), 7.98 (t, 1H), 7.62 (t, 1H), 6.08 (s, 1H), 5.64 (q, 1H), 4.64 (t, 2H), 2.11 (s, 3H), 1.62 (d, 3H), 1.33 (s, 4H).

[0269] LC-MS, M/Z (ESI): 503.4 [M+H].sup.+.

Embodiment 3: Synthesis of Compound I-3

[0270] The synthetic route is as follows:

##STR00099##

Step 1: Synthesis of 1-(3-(pentafluorosulfanyl)phenyl)ethan-1-one (B3-2)

[0271] ##STR00100##

[0272] To dioxane (100 mL) was added compound 3-bromo-(pentafluorosulfanyl)benzene (3.00 g, 10.6 mmol) at room temperature, the reaction mixture was added with bis(triphenylphosphine)palladium(II) chloride (744 mg, 1.06 mmol) and tributyl(1-ethoxyvinyl)tin (4.20 g, 11.7 mmol), heated to 90? C. under nitrogen atmosphere, and stirred for 14 h. The reaction mixture was cooled to room temperature, added with 2 N hydrochloric acid (100 mL), and stirred for 4 h. The reaction mixture was extracted with ethyl acetate (200 mL?3), and the liquid was separated. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=8:1) to obtain 1-(3-(pentafluorosulfanyl)phenyl)ethan-1-one (B3-2, yellow liquid, 2.4 g, yield: 89%).

[0273] LC-MS, M/Z (ESI): 247.0 [M+H].sup.+.

Step 2: Synthesis of (S,E)-2-methyl-N-(1-(3-(pentafluorosulfanyl)phenyl)ethylidene)propane-2-sulfinamide (B3-3)

[0274] ##STR00101##

[0275] To THF (150 mL) was added compound 1-(3-(pentafluorosulfanyl)phenyl)ethan-1-one (1.0 g, 4.06 mmol) at room temperature, the reaction mixture was added with (S)-tert-butylsulfinamide (492 mg, 4.06 mmol) and tetraethyl titanate (1.14 g, 5.0 mmol), heated to 70? C. and stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (100 mL?3), and the liquid was separated. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=4:1) to obtain (S,E)-2-methyl-N-(1-(3-(pentafluorosulfanyl)phenyl)ethylidene)propane-2-sulfinamide (B3-3, white solid, 1.42 g, yield: 100%).

[0276] LC-MS, M/Z (ESI): 350.2 [M+H].sup.+.

Step 3: Synthesis of (S)-2-methyl-N-((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)propane-2-sulfinamide (B3-4)

[0277] ##STR00102##

[0278] To methanol (30 mL) was added raw material (S,E)-2-methyl-N-(1-(3-(pentafluorosulfanyl)phenyl)ethylidene)propane-2-sulfinamide (1.5 g, 4.3 mmol) at room temperature, and the reaction mixture was cooled to 0? C. NaBH.sub.4 (744 mg, 20.1 mmol) was added to methanol in batches, and the reaction mixture was heated to room temperature and stirred for 3 h. The reaction mixture was concentrated and purified by preparative thin-layer chromatography to obtain (S)-2-methyl-N-((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)propane-2-sulfinamide (B3-4, white solid, 600 mg, yield: 40.0%).

[0279] LC-MS, M/Z (ESI): 352.1 [M+H].sup.+.

Step 4: Synthesis of (R)-1-(3-(pentafluorosulfanyl)phenyl)ethan-1-amine hydrochloride (B3-5)

[0280] ##STR00103##

[0281] To a 4 mol/L solution of hydrochloric acid in dioxane (10 mL) was added raw material (R)-2-methyl-N-((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)propane-2-sulfinamide (600 mg, 1.70 mmol) at room temperature, and the reaction mixture was stirred for 4 h. The reaction mixture was concentrated, added with methyl tert-butyl ether (20 mL), stirred for 1 h, and filtered to obtain (R)-1-(3-(pentafluorosulfanyl)phenyl)ethan-1-amine hydrochloride (B3-5, white solid, 350 mg, yield: 72.7%).

[0282] LC-MS, M/Z (ESI): 248.2 [M+H].sup.+.

Step 5: Synthesis of (R)-6-(1-(fluoromethyl)cyclopropyl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-3)

[0283] ##STR00104##

[0284] To acetonitrile (20 mL) was added raw material 6-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (A1) (200 mg, 0.80 mmol) at room temperature, the reaction mixture was added with potassium phosphate (678 mg, 3.20 mmol) and phosphonitrilic chloride trimer (416 mg, 1.20 mmol), and stirred at room temperature for 16 h. To DCM (10 mL) was added raw material (R)-1-(3-(pentafluorosulfanyl)phenyl)ethan-1-amine hydrochloride (160 mg, 0.56 mmol), the reaction mixture was added with DIPEA (2 mL), and stirred for 0.5 h. The above system was added into the reaction mixture and stirred at room temperature for 6 h. The reaction mixture was concentrated and prepared under acidic preparation condition B to obtain (R)-6-(1-(fluoromethyl)cyclopropyl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-3, white solid, 44 mg, yield: 16.4%).

[0285] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.18 (s, 1H), 8.87 (d, 1H), 7.96 (s, 1H), 7.78 (d, 1H), 7.71 (d, 1H), 7.60 (t, 1H), 6.08 (s, 1H), 5.60 (q, 1H), 4.68-4.56 (m, 2H), 2.21 (s, 3H), 1.61 (d, 3H), 1.32-1.28 (m, 4H).

[0286] LC-MS, M/Z (ESI): 479.4 [M+H].sup.+.

Embodiment 4: Synthesis of Compound I-4

[0287] Compound I-4 was synthesized with reference to the synthetic method of compound I-1 by replacing sodium bromodifluoroacetate with iodotrifluoromethane in step 3 to obtain (R)-6-(1-(fluoromethyl)cyclopropyl)-2-methyl-4-((1-(2-methyl-3-((trifluoromethyl)sulfonyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-4).

[0288] LC-MS, M/Z (ESI): 499.1 [M+H].sup.+.

##STR00105##

Embodiment 5: Synthesis of Compound I-5

[0289] Compound I-5 was synthesized with reference to the synthetic method of compound I-1 with the starting material replaced by 1-bromo-2-fluoro-3-iodobenzene to obtain (R)-4-((1-(3-((difluoromethyl)sulfonyl)-2-fluorophenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (I-5). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.17 (s, 1H), 8.94 (d, 1H), 7.98 (t, 1H), 7.83 (t, 1H), 7.53 (d, 1H), 7.41 (t, 1H), 6.08 (s, 1H), 5.65-5.68 (m, 1H), 4.55-4.60 (m, 2H), 2.15 (s, 3H), 1.60 (d, 3H), 1.78 (d, 3H), 1.23-1.34 (m, 4H).

[0290] LC-MS, M/Z (ESI): 485.0 [M+H].sup.+.

##STR00106##

Embodiment 6: Synthesis of Compound I-6

[0291] The synthetic route is as follows:

##STR00107## ##STR00108##

[0292] Compound 4-(((R)-1-((R)-2,2-difluoro-3-hydroxy-1,1-dioxo-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (I-6) was obtained. LC-MS, M/Z (ESI): 495.2 [M+H].sup.+.

Embodiment 7: Synthesis of Compound I-7

[0293] The synthetic route is as follows:

##STR00109##

[0294] Compound (R)-4-((1-(3-(cyclopropylsulfonyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (I-7) was obtained.

[0295] LC-MS, M/Z (ESI): 493.2 [M+H].sup.+.

Embodiment 8: Synthesis of Compound I-8

[0296] The synthetic route is as follows:

##STR00110##

Step 1: ((3-Bromo-2-fluorophenyl)imino)dimethylsulfanone (B8-2)

[0297] ##STR00111##

[0298] To dioxane (50 mL) was added compound 1-bromo-2-fluoro-3-iodobenzene (1.00 g, 3.32 mmol) at room temperature, and the reaction mixture was added with iminodimethylsulfanone (370 mg, 4.00 mmol), cesium carbonate (3.25 g, 11.7 mmol), tris(dibenzylideneacetone)dipalladium (607 mg, 0.664 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (384 mg, 0.664 mmol). The reaction mixture was heated to 105? C. under nitrogen atmosphere and stirred for 3 h. The reaction mixture was cooled to room temperature, added with water (100 mL), extracted with ethyl acetate (200 mL?3), and the liquid was separated. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=5:1) to obtain the title compound ((3-bromo-2-fluorophenyl)imino)dimethylsulfanone (B8-2) (500 mg, yield: 56.6%) as a yellow solid.

Step 2: ((3-Acetyl-2-fluorophenyl)imino)dimethylsulfanone (B8-3)

[0299] ##STR00112##

[0300] To dioxane (30 mL) was added compound ((3-bromo-2-fluorophenyl)imino)dimethylsulfanone (460 mg, 1.73 mmol) at room temperature, the reaction mixture was added with bis(triphenylphosphine)palladium(II) chloride (122 mg, 0.173 mmol) and tributyl(1-ethoxyvinyl)tin (628 g, 1.73 mmol), heated to 90? C. under nitrogen atmosphere, and stirred for 14 h. The reaction mixture was cooled to room temperature, added with 2 N hydrochloric acid (10 mL), and stirred for 4 h. The reaction mixture was extracted with ethyl acetate (50 mL?3), and the liquid was separated. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=5:1) to obtain the title compound ((3-acetyl-2-fluorophenyl)imino)dimethylsulfanone (B8-3) (340 mg, yield: 85%) as a yellow liquid.

Step 3: (S,E)-N-(1-(3-((dimethyl(oxo)sulfonyl)amino)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (B8-4)

[0301] ##STR00113##

[0302] To THF (15 mL) was added compound ((3-acetyl-2-fluorophenyl)imino)dimethylsulfanone (340 mg, 1.50 mmol) at room temperature, the reaction mixture was added with (S)-tert-butylsulfinamide (856 mg, 2.25 mmol) and tetraethyl titanate (273 mg, 3.75 mmol), heated to 70? C. and stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (50 mL?3), and the liquid was separated. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:1) to obtain the title compound (S,E)-N-(1-(3-((dimethyl(oxo)sulfonyl)amino)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (B8-4) (600 mg, yield >100%) as a yellow solid.

[0303] LC-MS, M/Z (ESI): 333.4 [M+H].sup.+.

Step 4: (S)-N-((R)-1-(3-((dimethyl(oxo)sulfonyl)amino)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (B8-5)

[0304] ##STR00114##

[0305] To methanol (30 mL) was added raw material (S,E)-N-(1-(3-((dimethyl(oxo)sulfonyl)amino)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (600 mg, 1.8 mmol) at room temperature, and the reaction mixture was cooled to 0? C. Sodium borohydride (96 mg, 2.5 mmol) was added to methanol in batches, and the reaction mixture was heated to room temperature and stirred for 3 h. The reaction mixture was concentrated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate (V/V)=1:1) to obtain the title compound (S)-N-((R)-1-(3-((dimethyl(oxo)sulfonyl)amino)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (B8-5) (200 mg, yield: 33.0%) as a white solid.

Step 5: (R)-((3-(1-aminoethyl)-2-fluorophenyl)imino)dimethylsulfanone hydrochloride (B8-6)

[0306] ##STR00115##

[0307] To a 4 mol/L solution of hydrochloric acid in dioxane (10 mL) was added raw material (S)-N-((R)-1-(3-((dimethyl(oxo)sulfonyl)amino)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (200 mg, 0.60 mmol) at room temperature, and the reaction mixture was stirred for 4 h. The reaction mixture was concentrated, added with methyl tert-butyl ether (20 mL), stirred for 1 h, and filtered to obtain the title compound (R)-((3-(1-aminoethyl)-2-fluorophenyl)imino)dimethylsulfanone hydrochloride (B8-6) (100 mg, yield: 62.9%) as a white solid.

[0308] LC-MS, M/Z (ESI): 231.2 [M+H].sup.+.

Step 6: (R)-6-(1-(difluoromethyl)cyclopropyl)-4-((1-(3-((dimethyl(oxo)sulfonyl)amino)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one

[0309] ##STR00116##

[0310] To acetonitrile (20 mL) was added raw material 6-(1-(difluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (200 mg, 0.80 mmol) at room temperature, the reaction mixture was added with potassium phosphate (678 mg, 3.20 mmol) and phosphonitrilic chloride trimer (416 mg, 1.20 mmol), and stirred at room temperature for 16 h. To DCM (10 mL) was added raw material (R)-((3-(1-aminoethyl)-2-fluorophenyl)imino)dimethylsulfanone hydrochloride (149 mg, 0.56 mmol), the reaction mixture was added with DIPEA (2 mL), and stirred for 0.5 h. The above system was added with the reaction mixture, and stirred at room temperature for 6 h. The reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane:methanol (V/V)=10:1) to obtain the title compound (R)-6-(1-(difluoromethyl)cyclopropyl)-4-((1-(3-((dimethyl(oxo)sulfonyl)amino)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (9 mg, yield: 3.35%) as a white solid.

[0311] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.17 (s, 1H), 8.79 (d, 1H), 7.04-7.01 (m, 1H), 6.97-6.95 (m, 1H), 6.33 (t, 1H), 6.08 (s, 1H), 5.79-5.75 (m, 1H), 3.32 (s, 3H), 3.21 (s, 3H), 2.20 (s, 3H), 1.53 (d, 3H), 1.37-1.23 (m, 4H).

[0312] LC-MS, M/Z (ESI): 480.4 [M+H].sup.+.

Embodiment 9: Synthesis of Compound I-9

[0313] The synthetic route is as follows:

##STR00117## ##STR00118##

[0314] Compound (R)-4-((1-(3-((1,1-difluoroethyl)sulfonyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (I-9) was obtained. LC-MS, M/Z (ESI): 517.2 [M+H].sup.+.

Embodiment 10: Synthesis of Compound I-10

[0315] ##STR00119##

[0316] Compound I-10 was synthesized with reference to the synthetic method of compound I-9 to obtain compound (R)-6-(1-(difluoromethyl)cyclopropyl)-4-((1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethyl)amino)-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (I-10). LC-MS, M/Z (ESI): 521.2 [M+H].sup.+.

Embodiment 11: Synthesis of Compound I-11

[0317] The synthetic route is as follows:

##STR00120##

[0318] Intermediate B11-1 was synthesized with reference to the synthesis of intermediate A1 by replacing 1-(fluoromethyl)cyclopropane-1-amine hydrochloride with raw material 1-methylcyclopropylamine hydrochloride.

[0319] To acetonitrile (10 mL) was added raw material 4-hydroxy-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one (B11-1) (100 mg, 0.43 mmol), the reaction mixture was added with compound (R)-1-(2-fluoro-3((trifluoromethyl)sulfonyl)phenyl)ethane-1-ethylamine hydrochloride (B2-8) (146 mg, 0.48 mmol) and anhydrous potassium phosphate (229 mg, 1.08 mmol), stirred at room temperature for 24 h, then added with phosphonitrilic chloride trimer (150 mg, 0.43 mmol) and triethylamine (137 mg, 1.29 mmol), and stirred continuously at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 1:1) to obtain (R)-4-((1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethyl)amino)-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidin-7(6H)-one (I-11) (48 mg, yield: 22.9%) as a white solid.

[0320] .sup.1H NMR (400 MHz, DMSO) ? 9.40 (s, 1H), 9.24 (s, 1H), 8.18 (s, 2H), 7.91-8.07 (s, 1H), 7.58 (m, 1H), 5.49-5.77 (m, 1H), 1.93-2.25 (m, 3H), 1.61 (d, J=7.1 Hz, 3H), 1.38-1.55 (m, 3H), 1.19 (s, 2H), 0.88-1.08 (m, 2H).

[0321] LC-MS, M/Z (ESI): 485.5 [M+H].sup.+.

Embodiment 12: Synthesis of Compound I-12

[0322] The synthetic route is as follows:

##STR00121##

Step 1: 1-Bromo-3-(difluoromethoxy)-2-fluorobenzene (B12-2)

[0323] ##STR00122##

[0324] To DMF (100 mL) was added compound 3-bromo-2-fluorophenol (7.20 g, 37.6 mmol) at room temperature, the reaction mixture was added with cesium carbonate (26.7 g, 75.2 mmol) and sodium bromodifluoroacetate (8.89 g, 45.1 mmol), heated to 100? C. and stirred for 2 h. The reaction mixture was cooled to room temperature, added with water (300 mL), extracted with ethyl acetate (200 mL?3), and the liquid was separated. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=8:1) to obtain the title compound 1-bromo-3-(difluoromethoxy)-2-fluorobenzene (035B) (5.0 g, yield: 55.2%) as a yellow liquid.

Step 2: 1-(3-(Difluoromethoxy)-2-fluorophenyl)ethan-1-one (B12-3)

[0325] ##STR00123##

[0326] To dioxane (100 mL) was added compound 1-bromo-3-(difluoromethoxy)-2-fluorobenzene (4.60 g, 19.0 mmol) at room temperature, the reaction mixture was added with bis(triphenylphosphine)palladium(II) chloride (2.13 g, 1.52 mmol) and tributyl(1-ethoxyvinyl)tin (6.85 g, 19.0 mmol), heated to 90? C. under nitrogen atmosphere, and stirred for 14 h. The reaction mixture was cooled to room temperature, added with 2 N hydrochloric acid (100 mL), and stirred for 4 h. The reaction mixture was extracted with ethyl acetate (200 mL?3), and the liquid was separated. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=5:1) to obtain the title compound 1-(3-(difluoromethoxy)-2-fluorophenyl)ethan-1-one (2.40 g, yield: 72%) as a yellow liquid.

Step 3: (S,E)-N-(1-(3-(difluoromethoxy)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide

[0327] ##STR00124##

[0328] To THF (150 mL) was added compound 1-(3-(difluoromethoxy)-2-fluorophenyl)ethan-1-one (5.0 g, 25.0 mmol) at room temperature, the reaction mixture was added with (S)-tert-butylsulfinamide (4.55 g, 37.5 mmol) and tetraethyl titanate (14.3 g, 62.5 mmol), heated to 70? C. and stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with water (300 mL), extracted with ethyl acetate (200 mL?3), and the liquid was separated. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:1) to obtain the title compound (S,E)-N-(1-(3-(difluoromethoxy)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (8.50 g, yield: 100%) as a yellow solid.

[0329] LC-MS, M/Z (ESI): 308.2 [M+H].sup.+.

Step 4: (S)-N-((R)-1-(3-(difluoromethoxy)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (B12-5)

[0330] ##STR00125##

[0331] To methanol (100 mL) was added raw material (S,E)-N-(1-(3-(difluoromethoxy)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (8.5 g, 27.6 mmol) at room temperature, and the reaction mixture was cooled to 0? C. Sodium borohydride (1.50 g, 39.3 mmol) was added to methanol in batches, and the reaction mixture was heated to room temperature and stirred for 3 h. The reaction mixture was concentrated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate (V/V)=1:1) to obtain the title compound (S)-N-((R)-1-(3-(difluoromethoxy)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (2.0 g, yield: 23.5%) as a colorless solid.

[0332] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.38-7.20 (m, 3H), 7.25 (t, 1H), 5.53 (d, 1H), 4.71-4.68 (m, 1H), 1.49 (d, 3H), 1.09 (s, 9H).

[0333] LC-MS, M/Z (ESI): 310.1 [M+H].sup.+.

Step 5: (R)-1-(3-(difluoromethoxy)-2-fluorophenyl)ethan-1-amine hydrochloride

[0334] ##STR00126##

[0335] To a 4 mol/L solution of hydrochloric acid in dioxane (50 mL) was added raw material (S)-N-((R)-1-(3-(difluoromethoxy)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (2.0 g, 6.45 mmol) at room temperature, and the reaction mixture was stirred for 4 h. The reaction mixture was concentrated, added with methyl tert-butyl ether (50 mL), stirred for 1 h, and filtered to obtain the title compound (R)-1-(3-(difluoromethoxy)-2-fluorophenyl)ethan-1-amine hydrochloride (1.0 g, yield: 64.1%) as a white solid.

[0336] LC-MS, M/Z (ESI): 206.2 [M+H].sup.+.

Step 6: (R)-4-((1-(3-(difluoromethoxy)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one

[0337] ##STR00127##

[0338] To acetonitrile (20 mL) was added raw material 6-(1-(difluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (200 mg, 0.80 mmol) at room temperature, the reaction mixture was added with potassium phosphate (678 mg, 3.20 mmol) and phosphonitrilic chloride trimer (416 mg, 1.20 mmol), and stirred at room temperature for 16 h. To DCM (10 mL) was added raw material (R)-1-(3-(difluoromethoxy)-2-fluorophenyl)ethan-1-amine hydrochloride (181 mg, 0.75 mmol), the reaction mixture was added with DIPEA (2 mL), and stirred for 0.5 h. The above system was added with the reaction mixture and stirred at room temperature for 6 h. The reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane:methanol=50:1 to 10:1) to obtain the title compound (R)-4-((1-(3-(difluoromethoxy)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (15 mg, yield: 4.4%) as a white solid.

[0339] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.16 (s, 1H), 8.88 (d, 1H), 7.36-7.19 (m, 4H), 7.27 (t, 1H), 6.33 (t, 1H), 6.09 (s, 1H), 5.75-5.72 (m, 1H), 2.18 (s, 3H), 1.58 (d, 3H), 1.48-1.32 (m, 4H).

[0340] LC-MS, M/Z (ESI): 455.3 [M+H].sup.+.

Embodiment 13: Synthesis of Compound I-13

[0341] The synthetic route is as follows:

##STR00128##

Step 1: Synthesis of (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)-N-(1-(methoxymethyl)cyclopropyl)acetamide (B13-1)

[0342] ##STR00129##

[0343] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetic acid (243 mg, 0.52 mmol) was dissolved in a mixed solution of dimethyl sulfoxide (2 mL) and acetonitrile (1 mL), the reaction mixture was added with triethylamine (0.14 mL, 1.03 mmol), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (295 mg, 0.78 mmol) and 1-(methoxymethyl)cyclopropanamine hydrochloride (107 mg, 0.78 mmol), and stirred at room temperature for 12 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (10 mL?3) and saturated brine (10 mL?3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:3) to obtain the title compound (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)-N-(1-(methoxymethyl)cyclopropyl)acetamide (B13-1) (70 mg, yield: 24.5%).

[0344] LC-MS, M/Z (ESI): 553.2 [M+H].sup.+.

Step 2: Synthesis of (R)-6-(1-(methoxymethyl)cyclopropyl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-13)

[0345] ##STR00130##

[0346] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)-N-(1-(methoxymethyl)cyclopropyl)acetamide (70 mg, 0.13 mmol) was dissolved in isopropanol (2 mL), the reaction mixture was added with 2 M hydrochloric acid (1 mL), and stirred at 50? C. for 4 h. After the reaction was completed, the reaction mixture was directly concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (V/V)=10:1) to obtain the title compound (R)-6-(1-(methoxymethyl)cyclopropyl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-13, 40 mg, yield: 56.3%).

[0347] .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.28 (s, 1H), 7.85 (s, 1H), 7.65-7.68 (m, 1H), 7.57 (d, 1H), 7.26-7.47 (m, 1H), 6.51 (s, 1H), 6.16 (d, 1H), 5.60-5.68 (m, 2H), 3.61 (s, 2H), 3.26 (s, 3H), 1.68 (d, 3H), 1.20 (d, 4H).

[0348] LC-MS, M/Z (ESI): 491.2 [M+H].sup.+.

Embodiment 14: Synthesis of Compound I-14

[0349] The synthetic route is as follows:

##STR00131##

Step 1: Synthesis of (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)-N-(3-methyloxetan-3-yl)acetamide (B14-1)

[0350] ##STR00132##

[0351] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetic acid (583 mg, 1.24 mmol) was dissolved in a mixed solution of dimethyl sulfoxide (2 mL) and acetonitrile (1 mL), the reaction mixture was added with triethylamine (0.35 mL, 2.48 mmol), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (708 mg, 1.86 mmol) and 3-trimethoprim-3-amine hydrochloride (199 mg, 1.61 mmol), and stirred at room temperature for 12 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (10 mL?3) and saturated brine (10 mL?3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:3) to obtain the title compound (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)-N-(3-methyloxetan-3-yl)acetamide (B14-1) (300 mg, yield: 44.9%).

[0352] LC-MS, M/Z (ESI): 539.1 [M+H].sup.+.

Step 2: (R)-2-methyl-6-(3-methyloxetan-3-yl)-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-14)

[0353] ##STR00133##

[0354] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)-N-(3-methyloxetan-3-yl)acetamide (300 mg, 0.56 mmol) was dissolved in isopropanol (2 mL), the reaction mixture was added with 2 M hydrochloric acid (1 mL), and stirred at 50? C. for 4 h. After the reaction was completed, the reaction mixture was directly concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (V/V)=10:1) to obtain the title compound (R)-2-methyl-6-(3-methyloxetan-3-yl)-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-14, 150 mg, yield: 56.6%).

[0355] .sup.1H NMR (400 MHz, CDCl.sub.3) ? 11.01 (d, 1H), 10.25 (d, 1H), 8.75 (s, 1H), 7.96 (d, 1H), 7.79 (d, 1H), 7.62-7.75 (m, 2H), 7.41-7.49 (m, 1H), 6.99 (s, 1H), 5.59-5.64 (m, 1H), 5.03-5.05 (m, 1H), 4.64 (d, 1H), 4.42-4.45 (m, 1H), 3.73-3.76 (m, 1H), 2.54 (d, 3H), 1.73-1.81 (m, 6H).

[0356] LC-MS, M/Z (ESI): 477.1 [M+H].sup.+.

Embodiment 15: Synthesis of Compound I-15

[0357] The synthetic route is as follows:

##STR00134##

Step 1: Synthesis of 2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)-N-((1r,3R)-3-hydroxy-3-methylcyclobutyl)acetamide (B15-1)

[0358] ##STR00135##

[0359] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetic acid (400 mg, 0.83 mmol) was dissolved in a mixed solution of dimethyl sulfoxide (2 mL) and acetonitrile (1 mL), the reaction mixture was added with triethylamine (0.23 mL, 1.65 mmol), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (472 mg, 1.24 mmol) and (1r,3r)-3-amino-1-methylcyclobutanol (148 mg, 1.07 mmol), and stirred at room temperature for 12 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (10 mL?3) and saturated brine (10 mL?3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:3) to obtain the title compound 2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)-N-((1r,3R)-3-hydroxy-3-methylcyclobutyl)acetamide (B15-1) (300 mg, yield: 65.6%).

[0360] LC-MS, M/Z (ESI): 553.1 [M+H].sup.+.

Step 2: Synthesis of 6-((1r,3R)-3-hydroxy-3-methylcyclobutyl)-2-methyl-4-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-15)

[0361] ##STR00136##

[0362] 2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)-N-((1r,3R)-3-hydroxy-3-methylcyclobutyl)acetamide (300 mg, 0.54 mmol) was dissolved in isopropanol (2 mL), the reaction mixture was added with 2 M hydrochloric acid (1 mL), and stirred at 50? C. for 4 h. After the reaction was completed, the reaction mixture was directly concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (V/V)=10:1) to obtain the title compound 6-((1r,3R)-3-hydroxy-3-methylcyclobutyl)-2-methyl-4-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-15, 140 mg, yield: 52.6%).

[0363] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.94 (s, 1H), 8.87 (d, 1H), 7.93 (s, 1H), 7.77 (d, 1H), 7.73 (d, 1H), 7.56-7.60 (m, 1H), 6.05 (s, 1H), 5.59-5.62 (m, 1H), 5.23 (s, 1H), 4.55-4.63 (m, 1H), 2.52-2.55 (m, 2H), 2.47-2.49 (m, 2H), 2.19 (s, 3H), 1.60 (d, 3H), 1.36 (s, 3H).

[0364] LC-MS, M/Z (ESI): 491.1 [M+H].sup.+.

Embodiment 16: Synthesis of Compound I-16

[0365] The synthetic route is as follows:

##STR00137##

Step 1: Synthesis of (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)-N-(3,3-difluorocyclobutyl)acetamide (B16-1)

[0366] ##STR00138##

[0367] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetic acid (291 mg, 0.62 mmol) was dissolved in a mixed solution of dimethyl sulfoxide (2 mL) and acetonitrile (1 mL), the reaction mixture was added with triethylamine (0.17 mL, 1.24 mmol), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (354 mg, 0.93 mmol) and 3,3-difluorocyclobutanamine hydrochloride (116 mg, 0.80 mmol), and stirred at room temperature for 12 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (10 mL?3) and saturated brine (10 mL?3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:3) to obtain the title compound (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)-N-(3,3-difluorocyclobutyl)acetamide (B16-1) (300 mg, yield: 86.4%).

[0368] LC-MS, M/Z (ESI): 559.1 [M+H].sup.+.

Step 2: Synthesis of (R)-6-(3,3-difluorocyclobutyl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-16)

[0369] ##STR00139##

[0370] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)-N-(3,3-difluorocyclobutyl)acetamide (300 mg, 0.54 mmol) was dissolved in isopropanol (2 mL), the reaction mixture was added with 2 M hydrochloric acid (1 mL), and stirred at 50? C. for 4 h. After the reaction was completed, the reaction mixture was directly concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (V/V)=10:1) to obtain the title compound (R)-6-(3,3-difluorocyclobutyl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-16, 150 mg, yield: 56.2%).

[0371] .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.89 (s, 1H), 8.10 (s, 1H), 7.77 (s, 1H), 7.55-7.77 (m, 2H), 7.26-7.39 (m, 1H), 6.40 (s, 1H), 5.73 (t, 1H), 5.11-5.16 (m, 1H), 3.00-3.13 (m, 2H), 2.81-2.90 (m, 2H), 2.42 (s, 3H), 1.61 (d, 3H).

[0372] LC-MS, M/Z (ESI): 497.1 [M+H].sup.+.

Embodiment 17: Synthesis of Compound I-17

[0373] The synthetic route is as follows:

##STR00140##

Step 1: Synthesis of tert-butyl 4-(((benzyloxy)carbonyl)amino)-4-methylpiperidine-1-carboxylate (B17-2)

[0374] ##STR00141##

[0375] tert-Butyl 4-amino-4-methylpiperidine-1-carboxylate (4 g, 18.67 mmol) was dissolved in a mixed solution of dioxane (20 mL) and water (20 mL), the reaction mixture was added with sodium bicarbonate (4.7 g, 56.0 mmol) and benzyl(2,5-dioxopyrrolidin-1-yl)carbonate (9.3 g, 37.3 mmol), and stirred at room temperature for 3 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (100 mL?3) and saturated brine (100 mL?3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=10:1) to obtain the title compound tert-butyl 4-(((benzyloxy)carbonyl)amino)-4-methylpiperidine-1-carboxylate (B17-2) (6.4 g, yield: 98%).

[0376] LC-MS, M/Z (ESI): 349.2 [M+H].sup.+.

Step 2: Synthesis of benzyl(4-methylpiperidin-4-yl)carbamate (B17-3)

[0377] ##STR00142##

[0378] tert-Butyl 4-(((benzyloxy)carbonyl)amino)-4-methylpiperidine-1-carboxylate (6.4 g, 18.37 mmol) was dissolved in a 4 M solution of hydrogen chloride in dioxane (9.18 mL), and the reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction mixture was concentrated to obtain the title compound benzyl(4-methylpiperidin-4-yl)carbamate (B17-3) (5.23 g, yield: 100%).

[0379] LC-MS, M/Z (ESI): 249.1 [M+H].sup.+.

Step 3: Synthesis of benzyl(1-acetyl-4-methylpiperidin-4-yl)carbamate (B17-4)

[0380] ##STR00143##

[0381] Benzyl(4-methylpiperidin-4-yl)carbamate (5.23 g, 21.06 mmol) was dissolved in dichloromethane (50 mL), the reaction mixture was added with triethylamine (8.81 mL, 63.2 mmol) and acetic anhydride (3.23 g, 31.6 mmol), and stirred at room temperature for 3 h. After the reaction was completed, the reaction mixture was diluted with dichloromethane (50 mL), and washed with water (100 mL?3) and saturated brine (100 mL?3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=5:1) to obtain the title compound benzyl(1-acetyl-4-methylpiperidin-4-yl)carbamate (B17-4) (4 g, yield: 65.3%).

[0382] LC-MS, M/Z (ESI): 291.2 [M+H].sup.+.

Step 4: Synthesis of 1-(4-amino-4-methylpiperidin-1-yl)ethan-1-one (B17-5)

[0383] ##STR00144##

[0384] Benzyl(1-acetyl-4-methylpiperidin-4-yl)carbamate (4 g, 13.78 mmol) was dissolved in methanol (40 mL), the reaction mixture was added with wet palladium on carbon (1 g, 10%), and stirred at room temperature under hydrogen atmosphere for 12 h. After the reaction was completed, the reaction mixture was filtered to obtain the title compound 1-(4-amino-4-methylpiperidin-1-yl)ethan-1-one (B17-5) (1.46 g, yield: 100%).

[0385] LC-MS, M/Z (ESI): 157.1 [M+H].sup.+.

Step 5: Synthesis of (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)-N-(1-acetyl-4-methylpiperidin-4-yl)acetamide (B17-6)

[0386] ##STR00145##

[0387] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetic acid (583 mg, 1.24 mmol) was dissolved in a mixed solution of dimethyl sulfoxide (2 mL) and acetonitrile (1 mL), the reaction mixture was added with triethylamine (0.35 mL, 2.48 mmol), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (708 mg, 1.86 mmol) and 1-(4-amino-4-methylpiperidin-1-yl)ethan-1-one (291 mg, 1.86 mmol), and stirred at room temperature for 12 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (10 mL), and washed with water (10 mL?3) and saturated brine (10 mL?3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:3) to obtain the title compound (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)-N-(1-acetyl-4-methylpiperidin-4-yl)acetamide (B17-6) (150 mg, yield: 20.0%).

[0388] LC-MS, M/Z (ESI): 608.2 [M+H].sup.+.

Step 6: Synthesis of (R)-6-(1-acetyl-4-methylpiperidin-4-yl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-17)

[0389] ##STR00146##

[0390] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)-N-(1-acetyl-4-methylpiperidin-4-yl)acetamide (150 mg, 0.25 mmol) was dissolved in isopropanol (2 mL), the reaction mixture was added with 2 M hydrochloric acid (1 mL), and stirred at 50? C. for 4 h. After the reaction was completed, the reaction mixture was directly concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (V/V)=10:1) to obtain the title compound (R)-6-(1-acetyl-4-methylpiperidin-4-yl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-17, 100 mg, yield: 74.0%).

[0391] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.79 (d, 1H), 8.72 (s, 1H), 7.94 (s, 1H), 7.70-7.77 (m, 2H), 7.55-7.59 (m, 1H), 6.04 (s, 1H), 5.59-5.64 (m, 1H), 3.87-3.97 (m, 1H), 3.40-3.41 (m, 1H), 3.39-3.41 (m, 1H), 3.31-3.37 (m, 1H), 2.48-2.50 (m, 1H), 2.19-2.25 (m, 3H), 2.18 (s, 3H), 1.98 (s, 3H), 1.72 (s, 3H), 1.59 (d, 3H).

[0392] LC-MS, M/Z (ESI): 546.1 [M+H].sup.+.

Embodiment 18: Synthesis of Compound I-18

[0393] The synthetic route is as follows:

##STR00147##

Step 1: Synthesis of tert-butyl 3-(((benzyloxy)carbonyl)amino)-3-methylpyrrolidine-1-carboxylate (B18-2)

[0394] ##STR00148##

[0395] tert-Butyl 3-amino-3-methylpyrrolidine-1-carboxylate (2 g, 9.99 mmol) was dissolved in a mixed solution of dioxane (10 mL) and water (10 mL), the reaction mixture was added with sodium bicarbonate (2.52 g, 30.0 mmol) and benzyl(2,5-dioxopyrrolidin-1-yl)carbonate (4.98 g, 19.97 mmol), and stirred at room temperature for 3 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (50 mL), and washed with water (50 mL?3) and saturated brine (50 mL?3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=10:1) to obtain the title compound tert-butyl 3-(((benzyloxy)carbonyl)amino)-3-methylpyrrolidine-1-carboxylate (B18-2) (3.3 g, yield: 98.8%).

[0396] LC-MS, M/Z (ESI): 335.2 [M+H].sup.+.

Step 2: Synthesis of benzyl(3-methylpyrrolidin-3-yl)carbamate (B18-3)

[0397] ##STR00149##

[0398] tert-Butyl 3-(((benzyloxy)carbonyl)amino)-3-methylpyrrolidine-1-carboxylate (3.3 g, 9.87 mmol) was dissolved in a 4 M solution of hydrogen chloride in dioxane (8 mL), and the reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction mixture was concentrated to obtain the title compound benzyl(3-methylpyrrolidin-3-yl)carbamate (B18-3) (2.6 g, yield: 97%).

[0399] LC-MS, M/Z (ESI): 235.1 [M+H].sup.+.

Step 3: Synthesis of benzyl(1-acetyl-3-methylpyrrolidin-3-yl)carbamate (B18-4)

[0400] ##STR00150##

[0401] Benzyl(3-methylpyrrolidin-3-yl)carbamate (2.6 g, 11.10 mmol) was dissolved in dichloromethane (50 mL), the reaction mixture was added with triethylamine (4.64 mL, 33.3 mmol) and acetic anhydride (2.27 g, 22.19 mmol), and stirred at room temperature for 3 h. After the reaction was completed, the reaction mixture was diluted with dichloromethane (50 mL) and washed with water (100 mL?3) and saturated brine (100 mL?3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=5:1) to obtain the title compound benzyl(1-acetyl-3-methylpyrrolidin-3-yl)carbamate (B18-4) (2.4 g, yield: 78.2%).

[0402] LC-MS, M/Z (ESI): 277.1 [M+H].sup.+.

Step 4: Synthesis of 1-(3-amino-3-methylpyrrolidin-1-yl)ethan-1-one (B18-5)

[0403] ##STR00151##

[0404] Benzyl(1-acetyl-3-methylpyrrolidin-3-yl)carbamate (2.4 g, 8.69 mmol) was dissolved in methanol (24 mL), the reaction mixture was added with wet palladium on carbon (240 mg, 10%), and stirred at room temperature under hydrogen atmosphere for 12 h. After the reaction was completed, the reaction mixture was filtered and concentrated to obtain the title compound 1-(3-amino-3-methylpyrrolidin-1-yl)ethan-1-one (B18-5) (1.23 g, yield: 100%).

[0405] LC-MS, M/Z (ESI): 143.1 [M+H].sup.+.

Step 5: Synthesis of 2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)-N-(1-acetyl-3-methylpyrrolidin-3-yl)acetamide (B18-6)

[0406] ##STR00152##

[0407] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)acetic acid (583 mg, 1.24 mmol) was dissolved in a mixed solution of dimethyl sulfoxide (2 mL) and acetonitrile (1 mL), the reaction mixture was added with triethylamine (0.35 mL, 2.48 mmol), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (708 mg, 1.86 mmol) and 1-(3-amino-3-methylpyrrolidin-1-yl)ethan-1-one (176 mg, 1.24 mmol), and stirred at room temperature for 12 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (10 mL), and washed with water (10 mL?3) and saturated brine (10 mL?3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:3) to obtain the title compound 2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)-N-(1-acetyl-3-methylpyrrolidin-3-yl)acetamide (B18-6) (100 mg, yield: 13.6%).

[0408] LC-MS, M/Z (ESI): 594.2 [M+H].sup.+.

Step 6: Synthesis of 6-(1-acetyl-3-methylpyrrolidin-3-yl)-2-methyl-4-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-18)

[0409] ##STR00153##

[0410] 2-(5-(1,3-Dioxolan-2-yl)-2-methyl-6-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidin-4-yl)-N-(1-acetyl-3-methylpyrrolidin-3-yl)acetamide (100 mg, 0.17 mmol) was dissolved in isopropanol (2 mL), the reaction mixture was added with 2 M hydrochloric acid (1 mL), and stirred at 50? C. for 4 h. After the reaction was completed, the reaction mixture was directly concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (V/V)=10:1) to obtain the title compound 6-(1-acetyl-3-methylpyrrolidin-3-yl)-2-methyl-4-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-18, 80 mg, yield: 88.9.0%).

[0411] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.83 (s, 1H), 7.93 (s, 1H), 7.76 (d, 1H), 7.70 (d, 1H), 7.55-7.59 (m, 1H), 6.06 (d, 1H), 5.57-5.64 (m, 1H), 4.39-4.44 (m, 1H), 3.59-3.67 (m, 2H), 3.32-3.3.33 (m, 1H), 2.70-2.73 (m, 1H), 2.48-2.52 (m, 1H), 2.20 (d, 3H), 1.94 (q, 3H), 1.60 (d, 3H), 1.54 (q, 3H).

[0412] LC-MS, M/Z (ESI): 532.1 [M+H].sup.+.

Embodiment 19: Synthesis of Compound I-19

[0413] The synthetic route is as follows:

##STR00154##

Step 1: Synthesis of methyl 1-((1R,3R)-3-fluorocyclobutyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (B19-1)

[0414] ##STR00155##

[0415] To 2-methyltetrahydrofuran (30 mL) was added dimethyl (Z)-2-((dimethylamino)methylene)-3-oxoglutarate (1.95 g, 9.65 mmol) at room temperature, the reaction mixture was added with 4 N hydrochloric acid (10 mL) and stirred for 3 h. The reaction mixture was separated, and the aqueous phase was extracted with ethyl acetate (100 mL?3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The reaction mixture was added with methanol (30 mL), then added with (1R,3R)-3-fluorocyclobutanamine hydrochloride (1.21 g, 9.65 mmol), and stirred at room temperature for 16 h. The system was added with sodium methoxide (1.04 g, 19.29 mmol), and stirred for 2 h. The reaction mixture was added with concentrated hydrochloric acid to adjust the pH to 2 and filtered to obtain a crude product of the title compound methyl 1-((1R,3R)-3-fluorocyclobutyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (B19-1) (1.35 g, yield: 58.2%) as a white solid.

[0416] LC-MS, M/Z (ESI): 242.1 [M+H].sup.+.

Step 2: Synthesis of methyl 1-((1R,3R)-3-fluorocyclobutyl)-6-oxo-4-(toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylate (B19-2)

[0417] ##STR00156##

[0418] To acetonitrile (20 mL) was added methyl 1-((1R,3R)-3-fluorocyclobutyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (1.35 g, 5.60 mmol) at room temperature, the reaction mixture was cooled to 0? C., added with triethylamine (1.56 mL, 11.19 mmol) and p-toluenesulfonyl chloride (1.28 g, 6.72 mmol), heated to room temperature, and stirred for 2 h. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=5:1 to 1:1) to obtain the title compound methyl 1-((1R,3R)-3-fluorocyclobutyl)-6-oxo-4-(toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylate (B19-2) (2.2 g, yield: 99%) as a white solid.

[0419] LC-MS, M/Z (ESI): 396.1 [M+H].sup.+.

Step 3: Synthesis of methyl 4-acetamido-1-((1R,3R)-3-fluorocyclobutyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (B19-3)

[0420] ##STR00157##

[0421] To dioxane (50 mL) was added methyl 1-((1R,3R)-3-fluorocyclobutyl)-6-oxo-4-(toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylate (1.2 g, 3.0 mmol) at room temperature, the reaction mixture was added with potassium phosphate (700 mg, 3.3 mmol), Xantphos (173 mg, 0.3 mmol) and palladium (7r-cinnamyl) chloride dimer (212 mg, 0.3 mmol), heated and stirred at reflux for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=3:1 to 1:1) to obtain the title compound methyl 4-acetamido-1-((1R,3R)-3-fluorocyclobutyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (B19-3) (1.4 g, yield: 87%) as a white solid.

[0422] LC-MS, M/Z (ESI): 283.1 [M+H].sup.+.

Step 4: Synthesis of 6-((1R,3R)-3-fluorocyclobutyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one

[0423] ##STR00158##

[0424] To a 7 M solution of ammonia in methanol (10 mL) was added methyl 4-acetamido-1-((1R,3R)-3-fluorocyclobutyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (1.4 g, 4.96 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 5 d. The reaction mixture was concentrated to 3 mL and filtered to obtain the title compound 6-((1R,3R)-3-fluorocyclobutyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (1 g, yield: 81%) as a white solid.

[0425] LC-MS, M/Z (ESI): 250.1 [M+H].sup.+.

Step 5: Synthesis of 6-((1R,3R)-3-fluorocyclobutyl)-2-methyl-4-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-19)

[0426] ##STR00159##

[0427] To acetonitrile (10 mL) was added 6-((1R,3R)-3-fluorocyclobutyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (200 mg, 0.80 mmol), the reaction mixture was added with compound (R)-1-(3-(pentafluorosulfanyl)phenyl)ethan-1-amine hydrochloride (250 mg, 0.88 mmol) and anhydrous potassium phosphate (426 mg, 2.0 mmol), stirred at room temperature for 24 h, then added with phosphonitrilic chloride trimer (418 mg, 1.20 mmol) and triethylamine (0.28 mL, 1.60 mmol), and stirred continuously at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol=50:1 to 10:1) to obtain 6-((1R,3R)-3-fluorocyclobutyl)-2-methyl-4-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-19, 150 mg, yield: 39.1%) as a white solid.

[0428] .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.89 (s, 1H), 7.82 (s, 1H), 7.59-7.62 (m, 3H), 7.36-7.40 (m, 1H), 6.40 (s, 1H), 5.70-5.72 (m, 1H), 5.33-5.37 (m, 1H), 5.23 (s, 1H), 5.09 (s, 1H), 2.72-2.78 (m, 4H), 2.43 (s, 3H), 1.66 (d, 3H).

[0429] LC-MS, M/Z (ESI): 479.1 [M+H].sup.+.

Embodiment 20: Synthesis of Compound I-20

[0430] The compound synthetic route is as follows:

##STR00160##

Step 1: Synthesis of methyl 4-hydroxy-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (B20-1)

[0431] ##STR00161##

[0432] To 2-methyltetrahydrofuran (30 mL) was added dimethyl (Z)-2-((dimethylamino)methylene)-3-oxoglutarate (1.3 g, 5.67 mmol) at room temperature, the reaction mixture was added with 4 N hydrochloric acid (10 mL), and stirred for 3 h. The liquid was separated, and the aqueous phase was extracted with ethyl acetate (100 mL?3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, added with methanol (30 mL), then added with 3-methyltetrahydrofuran-3-amine (0.57 g, 5.67 mmol), and stirred at room temperature for 16 h. The system was added with sodium methoxide (0.61 g, 11.34 mmol), and stirred for 2 h. The reaction mixture was added with concentrated hydrochloric acid to adjust the pH to 2 and filtered to obtain a crude product of the title compound methyl 4-hydroxy-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (B20-1) (0.7 g, yield: 48.7%) as a white solid.

[0433] LC-MS, M/Z (ESI): 254.1 [M+H].sup.+.

Step 2: Synthesis of methyl 1-(3-methyltetrahydrofuran-3-yl)-6-oxo-4-(p-toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylate (B20-2)

[0434] ##STR00162##

[0435] To acetonitrile (20 mL) was added methyl 4-hydroxy-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (0.7 g, 2.76 mmol) at room temperature, the reaction mixture was cooled to 0? C., added with triethylamine (0.77 mL, 5.53 mmol) and p-toluenesulfonyl chloride (553 mg, 2.90 mmol), heated to room temperature, and stirred for 2 h. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=5:1 to 1:1) to obtain the title compound methyl 1-(3-methyltetrahydrofuran-3-yl)-6-oxo-4-(p-toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylate (B20-2) (1 g, yield: 89%) as a white solid.

[0436] LC-MS, M/Z (ESI): 408.1 [M+H].sup.+.

Step 3: Synthesis of methyl 4-acetamido-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (B20-3)

[0437] ##STR00163##

[0438] To dioxane (50 mL) was added methyl 1-(3-methyltetrahydrofuran-3-yl)-6-oxo-4-(p-toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylate (1 g, 2.45 mmol) at room temperature, the reaction mixture was added with potassium phosphate (0.78 g, 3.68 mmol), Xantphos (142 mg, 0.25 mmol) and palladium (7r-cinnamyl) chloride dimer (225 mg, 0.25 mmol), heated at reflux for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=3:1 to 1:1) to obtain the title compound methyl 4-acetamido-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (B20-3) (0.56 g, yield: 78%) as a white solid.

[0439] LC-MS, M/Z (ESI): 295.1 [M+H].sup.+.

Step 4: Synthesis of 4-hydroxy-2-methyl-6-(3-methyltetrahydrofuran-3-yl)pyrido[4,3-d]pyrimidin-7(6H)-one

[0440] ##STR00164##

[0441] To a 7 M solution of ammonia in methanol (10 mL) was added methyl 4-acetamido-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (560 mg, 1.90 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated to 3 mL and filtered to obtain the title compound 4-hydroxy-2-methyl-6-(3-methyltetrahydrofuran-3-yl)pyrido[4,3-d]pyrimidin-7(6H)-one (350 mg, yield: 70.4%) as a white solid.

[0442] LC-MS, M/Z (ESI): 262.1 [M+H].sup.+.

Step 5: Synthesis of 2-methyl-6-(3-methyltetrahydrofuran-3-yl)-4-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-20)

[0443] ##STR00165##

[0444] To acetonitrile (10 mL) was added 4-hydroxy-2-methyl-6-(3-methyltetrahydrofuran-3-yl)pyrido[4,3-d]pyrimidin-7(6H)-one (350 mg, 1.34 mmol), the reaction mixture was added with compound (R)-1-(3-(pentafluorosulfanyl)phenyl)ethan-1-amine hydrochloride (418 mg, 1.47 mmol) and anhydrous potassium phosphate (711 mg, 3.35 mmol), stirred at room temperature for 24 h, then added with phosphonitrilic chloride trimer (699 mg, 2.01 mmol) and triethylamine (0.47 mL, 2.68 mmol), and stirred continuously at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol=50:1 to 10:1) to obtain 2-methyl-6-(3-methyltetrahydrofuran-3-yl)-4-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-20, 200 mg, yield: 30.4%) as a white solid.

[0445] .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.60 (s, 1H), 7.86 (s, 1H), 7.62-7.65 (m, 2H), 7.42-7.45 (m, 1H), 6.40 (d, 1H), 5.68-5.72 (m, 1H), 4.38-4.42 (m, 1H), 4.02-4.06 (m, 1H), 3.95-3.97 (m, 2H), 2.51-2.57 (m, 2H), 2.43 (s, 3H), 1.68-1.74 (m, 6H).

[0446] LC-MS, M/Z (ESI): 491.1 [M+H].sup.+.

Embodiment 21: Synthesis of Compound I-21

[0447] The synthetic route is as follows:

##STR00166##

Step 1: Synthesis of methyl 4-hydroxy-1-(4-methyltetrahydro-2H-pyran-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (B21-1)

[0448] ##STR00167##

[0449] To methanol (60 mL) was added compound dimethyl (Z)-2-((dimethylamino)methylene)-3-oxoglutarate (12 g, 52.3 mmol) at room temperature, the reaction mixture was added with 4-methyltetrahydro-2H-pyran-4-amine hydrochloride (7.9 g, 52.3 mmol), and stirred at room temperature for 16 h. The system was added with sodium methoxide (6.5 g, 120.0 mmol), and stirred for 2 h. The reaction mixture was added with concentrated hydrochloric acid to adjust the pH to 2 and filtered to obtain a crude product of the title compound methyl 4-hydroxy-1-(4-methyltetrahydro-2H-pyran-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (2.2 g, yield: 15.9%) as a brown solid.

[0450] LC-MS, M/Z (ESI): 268.1 [M+H].sup.+.

Step 2: Synthesis of methyl 1-(4-methyltetrahydro-2H-pyran-4-yl)-6-oxo-4-(tolyloxy)-1,6-dihydropyridine-3-carboxylate (B21-2)

[0451] ##STR00168##

[0452] To acetonitrile (20 mL) was added raw material methyl 4-hydroxy-1-(4-methyltetrahydro-2H-pyran-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (2.2 g, 8.3 mmol) at room temperature, the reaction mixture was cooled to 0? C., added with triethylamine (1.68 g, 16.6 mmol) and p-toluenesulfonyl chloride (1.58 g, 8.3 mmol), heated to room temperature, and stirred for 2 h. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=5:1 to 1:1) to obtain the title compound methyl 1-(4-methyltetrahydro-2H-pyran-4-yl)-6-oxo-4-(tolyloxy)-1,6-dihydropyridine-3-carboxylate (1.26 g, yield: 57.2%) as a white solid.

[0453] LC-MS, M/Z (ESI): 422.1 [M+H].sup.+.

Step 3: Synthesis of methyl 4-acetamido-1-(4-methyltetrahydro-2H-pyran-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (B21-3)

[0454] ##STR00169##

[0455] To dioxane (50 mL) was added raw material methyl 1-(4-methyltetrahydro-2H-pyran-4-yl)-6-oxo-4-(tolyloxy)-1,6-dihydropyridine-3-carboxylate (1.26 g, 3.0 mmol) at room temperature, the reaction mixture was added with potassium phosphate (700 mg, 3.3 mmol), Xantphos (173 mg, 0.3 mmol) and palladium (7r-cinnamyl) chloride dimer (212 mg, 0.3 mmol), heated and stirred at reflux for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=3:1 to 1:1) to obtain the title compound methyl 4-acetamido-1-(4-methyltetrahydro-2H-pyran-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (742 mg, yield: 79.3%) as a white solid.

[0456] LC-MS, M/Z (ESI): 309.1 [M+H].sup.+.

Step 4: Synthesis of 4-hydroxy-2-methyl-6-(4-methyltetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-7(6H)-one (B21-4)

[0457] ##STR00170##

[0458] To a 7 mol/L solution of ammonia in methanol (10 mL) was added raw material methyl 4-acetamido-1-(4-methyltetrahydro-2H-pyran-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (742 mg, 2.41 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 5 d. The reaction mixture was concentrated to 3 mL and filtered to obtain the title compound 4-hydroxy-2-methyl-6-(4-methyltetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-7(6H)-one (220 mg, yield: 33.5%) as a white solid.

[0459] LC-MS, M/Z (ESI): 276.1 [M+H].sup.+.

Step 5: Synthesis of (R)-2-methyl-6-(4-methyltetrahydro-2H-pyran-4-yl)-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-21)

[0460] ##STR00171##

[0461] To acetonitrile (20 mL) was added raw material 4-hydroxy-2-methyl-6-(4-methyltetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-7(6H)-one (220 mg, 0.80 mmol) at room temperature, the reaction mixture was added with potassium phosphate (678 mg, 3.20 mmol) and phosphonitrilic chloride trimer (416 mg, 1.20 mmol), and stirred at room temperature for 16 h. To DCM (10 mL) was added raw material (R)-1-(3-(pentafluorosulfanyl)phenyl)ethan-1-amine hydrochloride (246 mg, 0.87 mmol), the reaction mixture was added with DIPEA (2 mL), and stirred for 0.5 h. The above system was added with the reaction mixture, and stirred at room temperature for 6 h. The reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane:methanol=50:1 to 10:1) to obtain (R)-2-methyl-6-(4-methyltetrahydro-2H-pyran-4-yl)-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-21, 40 mg, yield: 9.9%) as a white solid.

[0462] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.90 (s, 1H), 8.75 (s, 1H), 7.94 (s, 1H), 7.77-7.71 (m, 2H), 7.57 (t, 1H), 6.04 (s, 1H), 5.63 (m, 1H), 3.75-3.62 (m, 4H), 2.48-2.41 (m, 2H), 2.30-2.23 (m, 2H), 2.20 (s, 3H), 1.72 (s, 3H), 1.60 (d, 3H).

[0463] LC-MS, M/Z (ESI): 505.1 [M+H].sup.+.

Embodiment 22: Synthesis of Compound I-22

[0464] The synthetic route is as follows:

##STR00172##

[0465] To acetonitrile (10 mL) was added raw material 6-(1-(methyl)cyclopropyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (B22-4) (100 mg, 0.43 mmol), the reaction mixture was then added with compound (R)-1-(3-(pentafluorosulfanyl)phenyl)ethan-1-amine hydrochloride (135 mg, 0.48 mmol) and anhydrous potassium phosphate (229 mg, 1.08 mmol), stirred at room temperature for 24 h, then added with phosphonitrilic chloride trimer (150 mg, 0.43 mmol) and triethylamine (137 mg, 1.29 mmol), and stirred continuously at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol=50:1 to 10:1) to obtain (R)-2-methyl-6-(1-methylcyclopropyl)-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-22, 42 mg, yield: 22.1%) as a white solid.

##STR00173##

[0466] .sup.1H NMR (400 MHz, DMSO) ? 9.23 (s, 1H), 8.90 (s, 1H), 7.95 (s, 1H), 7.74 (t, J=9.0 Hz, 2H), 7.49-7.63 (m, 2H), 5.48-5.66 (m, 1H), 2.11-2.25 (m, 3H), 1.59 (d, J=7.1 Hz, 3H), 1.49 (d, J=14.2 Hz, 3H), 1.27-1.37 (m, 1H), 1.21 (s, 1H), 1.09 (t, J=13.0 Hz, 1H), 0.94-1.05 (m, 1H).

[0467] LC-MS, M/Z (ESI): 461.5 [M+H].sup.+.

Embodiment 23: Synthesis of Target Compound I-23

[0468] The synthetic route is as follows:

##STR00174##

Step 1: Synthesis of methyl 1-(1-(difluoromethyl)cyclopropyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (B23-1)

[0469] ##STR00175##

[0470] Compound dimethyl (Z)-2-((dimethylamino)methylene)-3-oxoglutarate (5.0 g, 21.81 mmol) and 1-(difluoromethyl)cyclopropane-1-amine hydrochloride (3.44 g, 23.99 mmol) were dissolved in methanol (50.0 mL), and the reaction system was stirred at room temperature for 16 h. The reaction mixture was then added with sodium methoxide (1.76 g, 32.58 mmol), and the reaction system was stirred at 25? C. for 0.5 h. The reaction system was added with HCl (1.0 N, 15.0 mL) to adjust the pH to 1 to 2, at which time a white solid was precipitated. The reaction mixture was filtered, and the filter cake was washed with 10.0 mL of methanol and dried to obtain compound methyl 1-(1-(difluoromethyl)cyclopropyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (B23-1) (2.4 g, yield: 42.5%) as a white solid.

[0471] LC-MS, M/Z (ESI): 260.3 [M+H].sup.+.

Step 2: Synthesis of methyl 1-(1-(difluoromethyl)cyclopropyl)-6-oxo-4-(toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylate (B23-2)

[0472] ##STR00176##

[0473] Methyl 1-(1-(difluoromethyl)cyclopropyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (2.4 g, 9.26 mmol) was dissolved in acetonitrile (24.0 mL), the reaction system was then added with triethylamine (1.41 g, 13.89 mmol), slowly added with p-toluenesulfonyl chloride (1.77 g, 9.26 mmol) in batches, and the reaction system was stirred at 25? C. for 2 h. The reaction mixture was diluted with dichloromethane (20.0 mL), and added with 1 N HCl (10.0 mL) to adjust the pH to 2 to 3. The reaction mixture was extracted, and the organic phase was evaporated to dryness by rotary evaporation to obtain methyl 1-(1-(difluoromethyl)cyclopropyl)-6-oxo-4-(toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylate (B23-2) (3.4 g, yield: 89%) as a light yellow solid.

[0474] LC-MS, M/Z (ESI): 414.5 [M+H].sup.+.

Step 3: Synthesis of methyl 4-acetamido-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (B23-3)

[0475] ##STR00177##

[0476] To a 100 mL single-necked flask was successively added compound 5 (3.3 g, 7.98 mmol), acetamide (707.0 mg, 11.97 mmol), Xantphos (924.0 mg, 1.60 mmol), potassium phosphate (3.39 g, 15.97 mmol) and palladium (7r-cinnamyl) chloride dimer (1.46 g, 1.60 mmol), which were dissolved in dioxane (30.0 mL). The reaction system was replaced with nitrogen three times, heated to 115? C., and stirred for 16 h. The reaction mixture was cooled, and then filtered. The resulting mother liquor was evaporated to dryness by rotary evaporation, then the sample was mixed, and the mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=10:1 to 1:1) to obtain methyl 4-acetamido-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (B23-3) (1.6 g, yield: 67%) as a white solid.

Step 4: 6-(1-(Difluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (B23-4)

[0477] ##STR00178##

[0478] To a 50.0 mL sealed tank was added methyl 4-acetamido-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (1.6 g, 5.33 mmol) which was dissolved in a solution of ammonia in methanol (7 N, 15.0 mL), and the reaction system was heated to 50? C. and stirred for 12 h. The reaction mixture was cooled and then filtered, and the filter cake was washed with methanol (15.0 mL) to obtain 6-(1-(difluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (B23-4) (900 mg, yield: 63%) as a light yellow solid.

[0479] LC-MS, M/Z (ESI): 268.2 [M+H].sup.+.

Step 5: (R)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-23)

[0480] ##STR00179##

[0481] 6-(1-(Difluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one (300.0 mg, 1.12 mmol) was dissolved in acetonitrile (15.0 mL), the reaction mixture was added with potassium phosphate (596.0 mg, 2.81 mmol) and then phosphonitrilic chloride trimer (585.0 mg, 1.68 mmol), stirred at room temperature for 2 h, then added with (R)-1-(3-(pentafluorosulfanyl)phenyl)ethan-1-amine hydrochloride (318.0 mg, 1.12 mmol), and reacted and stirred overnight at room temperature. The reaction mixture was first filtered, the filter cake was washed with acetonitrile (15.0 mL), and the filtrate was evaporated to dryness by rotary evaporation to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 1:1) to obtain (R)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (I-23, 166.0 mg, yield: 30%) as a light yellow solid.

[0482] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.11 (s, 1H), 8.91 (d, J=7.1 Hz, 1H), 7.95 (s, 1H), 7.77 (dd, J=8.2, 2.1 Hz, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.59 (t, J=8.0 Hz, 1H), 6.31 (t, J=57.1 Hz, 1H), 6.10 (s, 1H), 5.60 (t, J=6.9 Hz, 1H), 2.18 (d, J=26.4 Hz, 3H), 1.60 (d, J=7.1 Hz, 3H), 1.48 (s, 2H), 1.37 (s, 2H).

[0483] LC-MS, M/Z (ESI): 497.2 [M+H].sup.+.

[0484] In the test examples of the present disclosure, control compound I was prepared with reference to patent WO2019122129A1, and control compound II was prepared with reference to patent WO2019122129A1. Their structures are as follows:

##STR00180##

Test Example 1: Inhibition Test of Compounds on KRAS G12C::SOS1 Binding

[0485] The compound to be tested was prepared into a 10 mM stock solution with DMSO, and the compound was serially diluted using 1? test buffer. 0.1 ?L of the compound solution with different concentrations was transferred to a 384-well plate. 5 ?L of GST-KRAS G12C was added to the 384-well plate, and centrifuged at 1000 rpm for 1 min. 5 ?L of His-SOS1 was added to the 384-well plate, centrifuged at 1000 rpm for 1 min, and incubated at room temperature for 15 min.

[0486] After incubation, 10 ?L of a mixed solution of anti-6his-Tb monoclonal antibody (Cisbio, Cat. No. 61HI2TLA) and anti-GST-XL665 monoclonal antibody (Cisbio, Cat. No. 61GSTXLA) was added to the test well, centrifuged at 1000 rpm for 1 min, and incubated at room temperature for 1 h.

[0487] After incubation, the fluorescence signal ratios at 665 nm and 615 nm were read on a multifunctional microplate reader (Perkin Elmer, Envision 2104), and the IC.sub.50 values were calculated using Graphpad 5 software.

TABLE-US-00001 TABLE 1 Inhibition results of test compounds on KRAS G12C::SOS1 binding Test compound IC.sub.50 (nM) Control compound I 8.58 Control compound II 8.15 I-1 6.87 I-2 7.73 I-3 3.94 I-5 10.0 I-12 22.2 I-15 14.4 I-16 16.1 I-19 9.5 I-21 6.9 I-22 21.7 I-23 4.9

[0488] The experimental results indicate that the compounds of the present disclosure have a significant inhibitory effect on KRAS G12C::SOS1 binding.

Test Example 2: Inhibition Test of Compounds on KRAS G12C-SOS1 Activity

[0489] The inhibitory effect of compounds on KRAS G12C-SOS1 was detected using Transcreener?GDP-FI (BellBrook, Cat. No. 3014-1K).

[0490] The compound to be tested was prepared into a 10 mM stock solution with DMSO, and serially diluted using 1? test buffer (modified Tris buffer). The resulting compound solution was transferred to a 384-well plate, and the final content of DMSO was 0.25%, and an additional DMSO well without compound was set up as a high signal control.

[0491] 1? test buffer (modified Tris buffer) was prepared. KRAS G12C (SignalChem, Cat. No. R06-32DH-BULK), SOS1 (Cytoskeleton, Inc., Cat. No. GE02-XL) and GTP solution (BellBrook, Cat. No. 3014-1K) were prepared respectively using the test buffer. 10 ?L of KRAS G12C was transferred to the 384-well plate, and another 10 ?L of the buffer was transferred to an empty well as a low signal control. 5 ?L of SOS1 and 5 ?L of GTP were transferred to the 384-well plate, respectively.

[0492] GDP detection reagent was prepared using the test buffer. 10 ?L of the detection reagent solution was transferred to the 384-well plate and incubated at room temperature for 2 h. After incubation, the plate was read on a multifunctional microplate reader (SpectraMax Paradigm) with an excitation wavelength of 580 nm and an emission wavelength of 620 nm. The fluorescence signal was read, and the inhibition rate was calculated as:

inhibition percentage=(high signal control?sample signal)/(high signal control?low signal control)?100, and IC.sub.50 values were calculated using Graphpad 5 software.

TABLE-US-00002 TABLE 2 Inhibition results of test compounds on KRAS G12C-SOS1 activity Test compound IC.sub.50 (nM) Control compound I 45 I-1 59 I-2 102

[0493] The experimental results indicate that the compounds of the present disclosure have a significant inhibitory effect on KRAS G12C-SOS1.

Test Example 3: Inhibition Test of Compounds on ERK Phosphorylation Level in DLD-1 Cells

[0494] Intracellular western blot quantitative analysis was used to detect the inhibitory level of compounds on ERK phosphorylation in DLD-1 cells.

[0495] DLD-1 cells (ATCC, CCL-221) were seeded in a T75 culture flask at 2.5?10.sup.6 cells/flask and cultured in a RPMI 1640 medium containing 10% FBS for 2 days. On day 3, the cells were seeded on a 384-well plate, and cultured overnight at 37? C., 5% CO.sub.2. After overnight culture, the plate was added with serially diluted compounds (the final content of DMSO was 0.5%), the negative group was added with DMSO, and incubated in a 37? C., 5% CO.sub.2 incubator.

[0496] The cells were fixed, washed once with PBS, treated to disrupt membranes, and blocked at room temperature for 1 h. The blocking solution was removed. The plate was added with primary antibody (CST, Cat. No. #4370S), and incubated overnight at 4? C. The plate was washed 3 times with PBST (PBS solution added with 0.05% Tween-20) and soaked for 2 min each time. The plate was added with secondary antibody (LI-COR, Cat. No. 926-32211) and incubated at room temperature in the dark. The plate was washed 3 times with PBST and soaked for 2 min each time. The plate was centrifuged at 1000 rpm for 1 min, scanned on a two-color infrared laser imaging system (Odyssey? CLX) to read the signal.

Relative signal=800-channel signal values/700-channel signal values.

Relative expression level of ERK phosphorylation=(test compound?control compound I)/(DMSO group?control compound I)

[0497] IC.sub.50 values were calculated using Graphpad 5 software.

TABLE-US-00003 TABLE 3 Inhibition results of test compounds on ERK phosphorylation level in DLD-1 cells Test compound IC.sub.50 (nM) Control compound I 72 I-1 102 I-2 58 I-3 56 I-12 196 I-13 109 I-17 119 I-18 115 I-19 131 I-20 92 I-21 141 I-23 159

[0498] The experimental results indicate that the compounds of the present disclosure have a significant inhibitory effect on the ERK phosphorylation level in DLD-1 cells.

Test Example 4: Inhibition Test of Compounds on 3D Cell Proliferation

[0499] H358 cells were seeded in a T75 culture flask and cultured in a RPMI 1640 medium containing 10% FBS for 2 days for subsequent experiments in which the cells would be cultured or seeded on a 384-well plate.

[0500] On day 1, the cells were seeded on the 384-well plate, with 40 ?L of medium added per well and serially diluted compounds or DMSO added per well, and an additional well without seeded cells but with medium was set up as a blank control. After culture at 37? C., 5% CO.sub.2 for 7 days, the plate was added with 3D CellTiter-Glo reagent (Promega, Cat. No. G9683) on day 8, shaken at 320 rpm for 20 min, and left at room temperature for 2 h. Luminescence signals were read on a multifunctional microplate reader. Cell viability inhibition rate was calculated as:

Cell viability inhibition rate=(DMSO group?test compound)/(DMSO group?blank control group)?100%

[0501] IC.sub.50 values were calculated using Graphpad 5 software.

TABLE-US-00004 TABLE 4 Inhibition results of test compounds on 3D proliferation of H358 cells Test compound IC.sub.50 (nM) Control compound I 13 I-1 26 I-2 13.9 I-3 11.5 I-13 15.7 I-17 12.1 I-18 9.2 I-19 137.3 I-20 31.0 I-21 85.1 I-22 10.7 I-23 12.0

[0502] The experimental results indicate that the compounds of the present disclosure have a strong inhibitory effect on the 3D proliferation of H358 cells.

Test Example 5: Human Liver Microsome Stability Test

[0503] The human liver microsome stability test was performed by incubating the compound and human liver microsomes in vitro. First, the compound to be tested was prepared into a 10 mM stock solution in DMSO solvent, and then the compound was diluted to 0.5 mM with acetonitrile. Human liver microsomes (Corning) were diluted with PBS into a microsome/buffer solution, and the solution was used to dilute 0.5 mM compound into a working solution, in which the concentration of the compound was 1.5 ?M, and the concentration of human liver microsomes was 0.75 mg/mL. A deep-well plate was taken, 30 ?L of the working solution was added per well, and then 15 ?L of pre-heated 6 mM NADPH solution was added thereto to initiate a reaction, and the reaction was incubated at 37? C. At 0, 5, 15, 30 and 45 min of the incubation, 135 ?L of acetonitrile was added to the corresponding wells to terminate the reaction. After the reaction was terminated with acetonitrile at the last time point of 45 min, the deep-well plate was vortexed and vibrated for 10 min (600 rpm/min), and then centrifuged for 15 min. After centrifugation, the supernatant was collected, and added with purified water in a ratio of 1:1 to perform LC-MS/MS detection. A ratio of a peak area of compound to a peak area of internal standard at each time point was obtained, and the peak area ratios of the compound at 5, 15, 30 and 45 min were compared with the peak area ratio at 0 min to calculate the remaining percentage of the compound at each time point. T.sub.1/2 was calculated by using GraphPad 5 software.

TABLE-US-00005 TABLE 5 Results of human liver microsome stability test Remaining percentage (%) of compound after Compound incubation for 30 min T.sub.1/2 (min) Control compound I 70.2 64.2 I-1 76.4 87.5 I-2 96.5 475 I-3 98.7 765

[0504] The experimental results indicate that, compared with the control compound I, the compounds of the present disclosure exhibit better hepatic metabolic stability, slower metabolism in the human body, and higher exposure.

Test Example 6: Inhibition Test of Compounds on Cytochrome P450

[0505] The inhibitory potential of compounds on cytochrome P450 (CYP450) subtype CYP3A4 (two substrates of midazolam and testosterone) was detected. First, the compound to be tested was prepared into a 10 mM stock solution in DMSO solvent, and the CYP3A4 inhibitor ketoconazole was prepared as 10 mM, 2.5 mM and 2.5 mM stock solutions in DMSO solvent. The test compound and ketoconazole were diluted to 400-fold final concentration (compound: 10 ?M, ketoconazole: 2.5 ?M) with acetonitrile.

[0506] NADPH cofactor (10 mL of potassium phosphate buffer added with 66.7 mg NADPH) at 4-fold final concentration and substrates were prepared with potassium phosphate buffer (0.1 M, pH=7.4), with CYP3A4 substrate midazolam at a final concentration of 320 ?M and CYP3A4 substrate testosterone at a final concentration of 20 ?M.

[0507] A human liver microsome solution at a concentration of 0.2 mg/mL was prepared with potassium phosphate buffer on ice. A solution of the compound to be tested and a control inhibitor (control compound) solution at 2-fold final concentration were prepared with the human liver microsome solution on ice. The test wells were added with 30 mL of the test compound solution and the control inhibitor solution respectively, and then added with 15 mL of the substrate for duplication. A 96-well assay plate and a NADPH solution were incubated at 37? C. for 5 min, and 15 ?L of pre-heated 8 mM NADPH solution was added to the assay plate to initiate the reaction. A CYP3A4 assay plate was pre-incubated at 37? C. for 5 min. The plate was added with 120 ?L of acetonitrile to terminate the reaction, and after quenching, the plate was shaken on a shaker (IKA, MTS 2/4) for 10 min (600 rpm/min), and then centrifuged for 15 min. After centrifugation, the supernatant was collected, and added with purified water in a ratio of 1:1 to perform LC-MS/MS detection. A ratio of a peak area of compound to a peak area of internal standard was obtained, and the peak area ratio of the compound was compared with the peak area ratio of the control inhibitor to calculate the inhibition rate.

TABLE-US-00006 TABLE 6 Inhibition results of test compounds on CYP450 enzyme CYP inhibition rate (%) Compound CYP3A4 CYP3A4 (10 ?M) (midazolam) (testosterone) Control compound I 33.52 8.5 I-1 17.8 0 I-2 10.8 0 I-3 0 0

[0508] The experimental results indicate that, compared with the control compound I, the compounds of the present disclosure have a weak or no inhibitory effect on CYP3A4 enzymes at 10 ?M, and have a low risk of potential drug-drug interactions. Herein, compound I-3 has a more significant inhibitory effect on CYP3A4 enzymes.

Test Example 7: Plasma Protein Binding Rate of Compounds

[0509] Plasma protein binding rate of compounds was detected by equilibrium dialysis (HTDialysis, HTD 96b). The compound was prepared into a 0.5 nM stock solution with DMSO, and then 25-fold diluted with 0.05 M sodium phosphate buffer as a working solution. A blank 96-well plate was taken and preloaded with 380 ?L of plasma per well. The plasma was then added with the working solution at 20 ?L/well and mixed well, with the compound at a final concentration of 1 ?M, containing 0.2% DMSO per well.

[0510] 100 ?L of 0.05 M sodium phosphate buffer was added to the reception-side of each dialysis chamber (HTD 96b), and then 100 ?L of plasma containing the compound was added to the supply-side. The dialysis chamber was covered with a plastic lid, shaken and incubated at 37? C. for 5 h.

[0511] After incubation, 25 ?L of samples were taken from each of the supply-side and the reception-side of the dialysis chamber and placed in the blank 96-well plate. An equal volume of plasma was added to each of the supply-side samples while an equal volume of 0.05 M sodium phosphate buffer was added to each of the reception-side samples and mixed well. The 96-well plate was added with an acetonitrile solution containing internal standard at 200 ?L per well, vortexed and shaken at 600 rpm for 10 min, and centrifuged at 5594 g for 15 min (Thermo Multifuge?3R). 50 ?L of the supernatant was then transferred to a new 96-well plate, and the samples were mixed with 50 ?L of ultra-pure water for LC-MS/MS analysis.

[0512] Plasma protein binding rate and free fraction were calculated using the following formulas: % binding rate=100?([supply-side concentration].sub.5h?[reception-side concentration].sub.5h)/[supply-side concentration].sub.5h. % free fraction=100?% binding rate.

TABLE-US-00007 TABLE 7 Free fraction of test compounds in plasma Compound Human (%) Mouse (%) Control compound I 0.9 0.5 I-1 4.2 5.4 I-2 1.5 2.8 I-3 1.7 1.1 I-5 7.7 11.4

[0513] The experimental results indicate that the compounds of the present disclosure have a higher ratio of free drug in both human and mouse plasma relative to the control drug and have good druggability.

Test Example 8: Pharmacokinetic Test in Mice

[0514] Male ICR mice (20 to 25 g) were used and fasted overnight. Three mice were taken and orally administered by gavage (10 mg/kg). Blood was collected before the administration, and at 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h after the administration. 6,800 g of the blood samples were centrifuged at 2 to 8? C. for 6 min, and plasma was collected and stored at ?80? C. The plasma at each time point was taken and added with an acetonitrile solution containing internal standard in 3 to 5 times the amount, vortexed and mixed for 1 min, and centrifuged at 13,000 rpm/min at 4? C. for 10 min. The supernatant was collected, added with water in 3 times the amount, and mixed. An appropriate amount of the mixture was taken for LC-MS/MS analysis. The main pharmacokinetic parameters were analyzed using WinNonlin 7.0 software with non-compartmental model.

TABLE-US-00008 TABLE 8 Results of pharmacokinetic test in mice of the test compounds Pharmacokinetic parameters of mice (oral administration by gavage) Cmax Tmax AUC.sub.0-t T.sub.1/2 Compound (ng/mL) (hr) (h * ng/mL) (hr) Control compound I 176 0.25 365 1.35 Control compound II 669 0.50 1002 0.96 I-2 256 0.50 517 0.99 I-3 1442 1.00 3080 0.97 I-23 4244 2.00 44126 2.33

[0515] The experimental results of pharmacokinetic test in mice indicate that the compounds of the present disclosure have high oral exposure, good pharmacokinetic properties and good druggability.

Test Example 9: Mia Paca-2 Pancreatic Cancer In Vivo Efficacy Test

[0516] After one week of adaptive feeding of mice, Mia Paca-2 cells in a log phase were resuspended in serum-free DMEM, and then mixed with Matrigel in a ratio of 1:1.1?10.sup.7 Mia Paca-2 cells were inoculated subcutaneously at the right flank at 100 ?L per mouse, and tumor growth was observed regularly. When the tumor grew to an average volume of 150 to 200 mm.sup.3, the mice were randomly divided into a model group and an administration group (single drug, in combination with trametinib) based on the tumor size and body weight. The tumor size and body weight were measured and recorded before and during the administration. After the treatment, the tumor size in the model group was compared with that in the administration group to determine the efficacy.

TABLE-US-00009 TABLE 9 Tumor inhibitory ability of the test compounds at the level of tumor weight Average tumor Tumor weight weight at the end inhibition rate of the treatment (relative to the Drug Dose (mg/kg) (g) vehicle group) Vehicle 1.14 Control compound II 50, BID 0.46 59% I-3 25, BID 0.35 70% I-3 50, BID 0.27 76% I-23 25, BID 0.45 61% I-23 50, BID 0.38 67% I-3 + I-3: 25, BID 0.13 89% Trametinib Trametinib: 0.125, BID I-23 + I-23: 25, BID 0.16 86% Trametinib Trametinib: 0.125, BID Trametinib 0.125, BID 0.22 80% in the table means no testing.

[0517] The experimental results indicate (see FIG. 1 for details) that the compounds of the present disclosure, alone or in combination with trametinib, have a significant inhibitory effect on Mia Paca-2 tumor growth, and the combined use is more effective than the single use.

Test Example 10: LOVO Colorectal Cancer In Vivo Efficacy Test

[0518] After one week of adaptive feeding of mice, LOVO cells in a log phase were resuspended in serum-free F12K, 5?10.sup.6 LOVO cells were inoculated subcutaneously at the right flank at 100 ?L per mouse, and tumor growth was observed regularly. When the tumor grew to an average volume of 150 to 200 mm.sup.3, the mice were randomly divided into a model group and an administration group based on the tumor size and body weight. The tumor size and body weight were measured and recorded before and during the administration. After the treatment, the tumor size in the model group was compared with that in the administration group to determine the efficacy.

TABLE-US-00010 TABLE 10 Tumor inhibitory ability of the test compounds at the level of tumor weight Average tumor Tumor weight weight at inhibition rate the end of the (relative to the Drug Dose (mg/kg) treatment (g) vehicle group) Vehicle 1.39 Control compound II 50, BID 1.08 23% I-3 50, BID 0.75 46% I-23 25, BID 0.65 53% in the table means no testing.

[0519] The experimental results indicate (see FIG. 2 for details) that the compounds of the present disclosure have a significant inhibitory effect on LOVO tumor tissue growth, which is better than that of the control compound II.

[0520] Although the embodiments of the present disclosure are illustrated and described above, it can be understood that the above-mentioned embodiments are illustrative and should not be construed as limiting the present disclosure. Those skilled in the art can make changes, modifications, substitutions and variations based on the above-mentioned embodiments within the scope of the present disclosure.