Pyridopyrimidinone derivatives, methods for producing the same, and their use

Abstract

The present invention provides a pyridopyrimidinone derivative represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug, which has a better SOS1 inhibitory effect. [Formula 1] JPEG2024505732000245.jpg53170

Description

Detailed description of the invention

[0001] This application claims priority to Chinese patent application 2021101723722, filed on February 8, 2021, and Chinese patent application 2021113158687, filed on November 8, 2021. This application incorporates the full text of the aforementioned Chinese patent applications.

[0002] [Technical field] This invention belongs to the field of pharmaceuticals, and more specifically, it relates to pyridopyrimidinone derivatives, methods for producing the same, and uses thereof.

[0003] [Background technology] RAS proteins are membrane-bound proteins with intrinsic GTPase activity that are activated by many extracellular stimuli and cycle between GDP-bound (off) and GTP-bound (on) states. When in the GTP-bound (on) state, they can activate downstream pathways and promote a series of processes such as cell proliferation, differentiation, migration, and immunity.

[0004] The RAS protein family includes three highly homologous isomers: KRAS (Kirsten rat sarcoma virus oncogene), HRAS (Harvey rat sarcoma virus oncogene), and NRAS (Neuroblastoma ras oncogene). KRAS also includes two alternative splicing variants: KRAS4A and KRAS4B. RAS family proteins have weak endogenous GTPase activity and slow nucleotide exchange rates (Hunter et al. Mol. Cancer Res., 2015, 13(9):1325-1335).

[0005] Activation of mutations in the RAS gene is a significant cause of tumorigenesis, with RAS mutations occurring in 27% of all tumor patients (Hobbs GA, et al. J Cell Sci., 2016, 129(7):1287-1292). Among these, KRAS mutations are the most frequent, accounting for 86% (Cox, Adrienne D., et al. Nat Rev Drug Discov., 2014, 13(11): 828-851). KRAS-4B mutations are present in approximately 90% of pancreatic cancers, 30-40% of colon cancers, and 15-20% of lung cancers. This mutation is also present in cholangiocarcinomas, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, and breast cancer (Liu P, et al. Acta Pharm Sin B., 2019, 9(5):871-879). The most common type of mutation in the KRAS gene is point mutation, with the most common being KRAS-G12D (41%), KRAS-G12V (28%), and KRAS-G12C (14%) mutations. Mutant KRAS affects its ability to bind to GTPase activating protein (GAP), thereby inhibiting GAP-induced GTP hydrolysis. As GTPase hydrolysis capacity decreases, GTP gradually accumulates, making it easier for KRAS to bind to GTP, activating most of the KRAS gene and inducing the development and formation of malignant tumors.

[0006] The transition from the inactive to the activated state of RAS proteins involves the release of GDP and the binding of GTP, and the release of GDP requires the involvement of guanine nucleotide exchange factors (GEFs) such as the SOS (Son of Sevenless) protein. The SOS protein was first discovered in Drosophila in 1992 and is a GEF for RAS and Rac proteins, playing an important role in the RAS and Rac signaling pathways. Humans have two SOS homologs, SOS1 and SOS2, which are very similar in structure and sequence with 70% homology, but have predetermined differences in biological function. The SOS1 protein consists of 1300 amino acid residues and has a proline-rich domain at its C-terminus that can interact with growth factor receptor-bound protein 2 (Grb2) in the RAS pathway. After binding to Grb2 and forming a complex, SOS1 can be transported to the vicinity of the cell membrane RAS protein. The interaction between SOS1 and RAS involves two domains of SOS1: the CDC25 domain and the REM domain. The CDC25 domain contains an active site for nucleotide exchange, while the REM domain contains a site that can bind to RAS-GTP and induce allosteric activation of the CDC25 domain (Pierre S, et al. BiochemPharmacol., 2011, 82(9):1049-1056). SOS1 can convert GDP to GTP by catalytic exchange, and GTP is then hydrolyzed by RAS, subsequently activating downstream signals and triggering a corresponding series of biological effects.

[0007] Specific SOS1 inhibitors can inhibit the interaction between SOS1 and KRAS-GTP, thereby reducing the formation of activated KRAS-GTP. A decrease in KRAS-GTP levels leads to a reduction in downstream MAPK signaling, which plays a role in both wild-type and multiple KRAS mutants. The SOS1 small molecule inhibitor BAY-293 can effectively reduce the activity of both mutant and wild-type KRAS in tumor cells (Hillig, Roman C., et al. Proc Nat Acad Sci USA., 2019, 116(7):2551-2560). Boehringer Ingelheim's SOS1 inhibitors BI-3406 and BI-1701963 can bind to the catalytic domain of SOS1, blocking its interaction with KRAS, reducing KRAS-GTP formation, and inhibiting the proliferation of various KRAS-driven cancer cells. Combining SOS1 inhibitors and MEK inhibitors significantly reduces KRAS signaling and enhances antitumor activity through a complementary mechanism of action (Hofmann, Marco H, et al. Cancer Discov., 2020:CD-20-0142). According to Boehringer Ingelheim (AACR Annual Meeting, April 27, 2020), BI-3406 inhibits cytochrome P450 3A4 (CYP3A4) in a time-dependent manner and carries a potential risk of drug-drug interactions (DDIs). Therefore, developing cytochrome P450-free inhibitors offers a clinically valuable advantage over SOS1 inhibitors that do not inhibit CYP3A4, and combination therapies with BI-1701963 and the MEK inhibitor trametinib are both currently in clinical research.

[0008] In addition to cancer, mutations and abnormal expression of the SOS1 gene are closely associated with the development of several genetic disorders. Noonan syndrome (NS) is an autosomal dominant genetic disorder, and approximately 20% of NS patients have SOS1 mutations, which are distributed across the six domains of SOS1. Patients with SOS1 mutations exhibit phenotypic features such as curly hair and ectodermal abnormalities. Mutations in the CDC25 domain can directly increase the GEF activity of SOS1 and induce hyperactivation of the RAS / ERK pathway (Jose M Rojas, et al. Genes Cancer., 2011, 2(3):298-305). Cardiac-facial-cutaneous syndrome is one of the renin-angiotensin system cardiomyopathy disorders, and SOS1 mutations have been reported to be present in this disease (Narumi, Yoko, et al. J Hum Genet., 2008, 53(9):834-841.). Hereditary gingival fibromatosis type 1 is an autosomal dominant genetic disorder, and its etiology is associated with mutations in the proline-rich domain of SOS1 (Jang SI, et al. J Biol Chem., 2007, 282(28):20245-20255).

[0009] [Overview of the prefecture] The object of the present invention is to provide a pyridopyrimidinone derivative that can be used as an inhibitor of the interaction between the catalytic site of SOS1 and RAS family proteins, is involved in the control of cell proliferation, and can be used to treat diseases of excessive or abnormal cell proliferation.

[0010] The present invention solves the above technical problems through the following technical solutions. A first aspect of the present invention provides pyridopyrimidinone derivatives (compounds) represented by formula I, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs thereof.

[0011] [ka]

[0012] Here, ring A is an aromatic ring of 6 to 10 members or a heteroaromatic ring of 9 to 11 members, R1 is a cycloalkyl of 3 to 10 members or a heterocycloalkyl of 4 to 10 members, and the R1 is optionally substituted by one or more R 11 wherein the R 11 is a substituent selected from halogen, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy,

[0013]

Chemical formula

[0014] substituent R 11 when there are a plurality of them, the substituents R 11 are the same or different, the R 11 is optionally substituted by a substituent selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, and R 12 is C1-C6 alkyl, C1-C6 alkyl substituted by one or more F, or cycloalkyl of 3 to 6 members, R 13 is hydrogen, C1-C6 alkyl, or cyano, R 14 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, R2 is hydrogen or a substituent selected from halogen, C1-C6 alkyl, cycloalkyl of 3 to 6 members, and C1-C6 alkoxy, and the C1-C6 alkyl, cycloalkyl of 3 to 6 members, and C1-C6 alkoxy are each independently substituted by one or more R 21 wherein the R 21 is a substituent selected from hydroxyl, halogen, and C1-C3 alkoxy, and when there are a plurality of substituents, the R 21 are the same or different, R3 is hydrogen or a substituent selected from halogen, C1-C6 alkyl, and C1-C6 haloalkyl, R4 is a C1-C6 alkyl or C1-C6 haloalkyl. R5 is either hydrogen or a substituent selected from halogens, C1-C6 alkyl groups, or C1-C6 haloalkyl groups. R6 is -SF5,

[0015] [ka] And the R 61 , the R 62 Each of these is independently a C1-C6 alkyl or 3-6 member cycloalkyl group substituted with a halogen.

[0016] Alternatively, ring A, along with R6 and R5, forms a base fragment.

[0017] [ka] Forms, where Z is

[0018] [ka] And R 63 is hydrogen, or a substituent selected from halogens, hydroxyl, C1-C6 alkyl, or C1-C6 alkyl substituted with a halogen, wherein substituent R 63 If there are multiple instances, the R 63 They are the same or different.

[0019] m is 1 or 2, p is 1, 2 or 3, and n is 1, 2 or 3. In another preferred embodiment, ring A is a 6-10 member aromatic ring or a 9-11 member heteroaromatic ring. R1 is a 3- to 10-membered cycloalkyl or a 4- to 10-membered heterocycloalkyl, and the cycloalkyl is one or more R 11 It is optionally replaced by the R 11 These include halogens, C1-C6 alkyls, C1-C6 haloalkyls, and C1-C6 alkoxys.

[0020] [ka] A substituent selected from, substituent R 11 If there are multiple substituents R 11 They are the same or different.

[0021] R 12 R is a C1-C6 alkyl group, a C1-C6 alkyl group substituted with one or more F atoms, or a 3-6 member cycloalkyl group. 13 These are hydrogen, C1-C6 alkyl, or cyano. R2 is hydrogen, or a substituent selected from halogens, C1-C6 alkyl groups, 3-6 membered cycloalkyl groups, or C1-C6 alkoxy groups, where each of the C1-C6 alkyl groups, 3-6 membered cycloalkyl groups, and C1-C6 alkoxy groups can be one or more R2s independently. 21 Replaced by, the R 21 R is a substituent selected from hydroxyl, halogen, and C1-C3 alkoxy, and if there are multiple substituents, 21 They are the same or different. R3 is either hydrogen or a substituent selected from halogens, C1-C6 alkyl groups, or C1-C6 haloalkyl groups. R4 is a C1-C6 alkyl or C1-C6 haloalkyl. R5 is either hydrogen or a substituent selected from halogens, C1-C6 alkyl groups, or C1-C6 haloalkyl groups. R6 is -SF5,

[0022] [ka] And the R 61 , the R 62 Each of these is independently a C1-C6 alkyl or 3-6 member cycloalkyl group substituted with a halogen.

[0023] Alternatively, ring A, along with R6 and R5, forms a base fragment.

[0024] [ka] Forms, where Z is

[0025] [ka] And R 63 is hydrogen, or a substituent selected from halogens, hydroxyl, C1-C6 alkyl, or C1-C6 alkyl substituted with a halogen, wherein substituent R 63 If there are multiple instances, the R 63 They are the same or different.

[0026] m is 1 or 2, p is 1, 2 or 3, and n is 1, 2 or 3. In the present invention, the definitions of some substituents in the pyridopyrimidinone derivative (compound) represented by formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs may be as described below, and the definitions of substituents not mentioned herein are as described in any embodiment of the present application (hereinafter referred to as "in another preferred embodiment").

[0027] In another preferred embodiment, the 9-11 membered heteroaromatic ring is a 9-11 membered benzoheteroring, where the heteroatoms are selected from O, N, or S, and there are one or two heteroatoms. In another preferred embodiment, ring A is a benzene ring or a nine-membered benzo heteroring, where the heteroatom is selected from O, N, or S, preferably S, and ring A has one or two heteroatoms, preferably one heteroatom.

[0028] In another preferred embodiment, the pyridopyrimidinone derivative (compound) represented by formula I has structure I-1,

[0029] [ka]

[0030] Preferably, the pyridopyrimidinone derivative (compound) represented by formula I has structure I-2,

[0031] [ka]

[0032] Here, the definitions of R1, R2, R3, R5, R6, and m are as described in the first aspect of the present invention, and R4 is methyl or -CH2F. Preferably, R4 is methyl.

[0033] In another preferred embodiment, R5 is hydrogen, fluorine or methyl, m is 1 or 2, preferably m is 1, and R6 is -SF5.

[0034] [ka] And the R 61 , the R 62 Each of these is independently a C1-C6 alkyl or a 3-6 membered cycloalkyl group substituted with one or more F atoms.

[0035] Preferably, R 61 These are -CH2F, -CHF2, -CF3, -CF2CH3, or cyclopropyl. Preferably, R 62 is -CH2F, -CHF2, -CF3, more preferably R 62 It is -CHF2.

[0036] In another preferred embodiment, ring A is a group fragment together with R6 and R5.

[0037] [ka] Forms, where Z is

[0038] [ka] And p is 1, n is 2 or 3, R 63 is fluorine or hydroxyl, and the R 63 If there are multiple, R 63 They are the same or different.

[0039] Preferably, a base fragment

[0040] [ka] teeth,

[0041] [ka] Having a structure, more preferably,

[0042] [ka] teeth

[0043] [ka] That is the case.

[0044] In another preferred embodiment, the benzene ring is a group fragment together with R6 and R5.

[0045] [ka] Forms, where Z is

[0046] [ka] And p is 1, n is 2 or 3, R 63 is fluorine or hydroxyl, and the R 63 If there are multiple, R 63 They are the same or different.

[0047] Preferably, a base fragment

[0048] [ka] teeth,

[0049] [ka] Having a structure, more preferably,

[0050] [ka] teeth

[0051] [ka] That is the case.

[0052] In another preferred embodiment, R5 is hydrogen and R6 is -SF5,

[0053] [ka] Preferably, R6 is -SF5.

[0054] In another preferred embodiment, R4 is a C1-C3 alkyl or C1-C3 haloalkyl, preferably R4 is methyl or -CH2F, and more preferably R4 is methyl. In another preferred embodiment, the halogen is fluorine, chlorine, or bromine, and preferably, the halogen is fluorine.

[0055] In another preferred embodiment, in R1, the 3- to 10-membered cycloalkyl group comprises a monocyclic, dicyclic, tricyclic, spirocyclic, or bridging ring, and the 4- to 10-membered heterocycloalkyl group has one or more heteroatoms, the heteroatoms being N, O, or S.

[0056] In another preferred embodiment, the 3-10 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(norcanphanyl), bicyclo[4.1.0]heptyl(norcarenyl), bicyclo[3.1.1]heptyl(pinyl), spiro[2.5]octyl, spiro[3.3]heptyl, and more preferably the 3-10 membered cycloalkyl is

[0057] [ka] That is the case.

[0058] In another preferred embodiment, the 3- to 10-membered cycloalkyl group in R1 is cyclopropyl or cyclobutyl. In another preferred embodiment, the 4-10 member heterocycloalkyl is tetrahydrofuranil, pyrrolidinil, pyrrolidinil, imidazolidinil, thiazolidinil, imidazolinil, pyrazolidinil, pyrazolidinil, piperidinil, piperazinil, oxyranil, azilidinil, azetidinil, 1,4-dioxanil, azepanil, diazepanil, morpholinil, thiomorpholinil, homomorpholinil, homopiperidinil, homo Piperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, 1,3-dioxolanil, tetrahydropyranil, tetrahydrothiopyranil, [1,4]-oxazepanil, tetrahydrothienyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazineyl, dihydropyridyl, dihydropyrimidinyl Dihydrofuranyl, dihydropyranyl, tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-S-oxide, 2,3-dihydroazetidinyl, 2H-pyrrolyl, 4H-pyranyl, 1,4-dihydropyridyl, 8-azabicyclo[3.2.1]octyl, 8-azabicyclo[5.1.0]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa -3-Azabicyclo[3.2.1]octyl, 3,8-Diazabicyclo[3.2.1]octyl, 2,5-Diazabicyclo-[2.2.1]heptyl, 1-Azabicyclo[2.2.2]octyl, 3,8-Diazabicyclo[3.2.1]octyl, 3,9-Diazabicyclo[4.2.1]nonyl, 2,6-Diazabicyclo[3.2.2]nonyl, and more preferably the 4-10 member heterocycloalkyl is

[0059] [ka] The 4-10 member heterocycloalkyl is,

[0060] [ka] That is the case.

[0061] In another preferred embodiment, in R1, the 4-10 member heterocycloalkyl is a 4-6 member heterocycloalkyl, The aforementioned 4- to 10-membered heterocycloalkyl group has 1, 2, or 3 heteroatoms, and the heteroatoms are N, O, or S. For example, the number of heteroatoms is 1 or 2, and for example, the heteroatoms are N or O. For example, oxetanil, piperidinil, pyrrolidinil, tetrahydrofuranil, and tetrahydropyranil. Also, for example,

[0062] [ka] That is the case.

[0063] In another preferred embodiment, R1 is a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein the cycloalkyl is one or more R 11 It is optionally replaced by the R 11 is a substituent selected from halogens, C1-C6 alkyls, and C1-C6 haloalkyls, and substituent R 11 If there are multiple substituents R 11 They are the same or different. Comfortable, R1

[0064] [ka] And here, R 11 is a substituent selected from halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups, preferably R 11 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted with fluorine, more preferably R 11 It is methyl, -CH2F, or -CHF2.

[0065] In another preferred embodiment, R1 is a 3- to 10-membered cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl is one or more R 11 It is optionally replaced by the R 11 is hydroxyl or

[0066] [ka] and substituent R 11 If there are multiple substituents R 11 They are the same or different.

[0067] The aforementioned R 11 The R is optionally substituted with substituents selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and hydroxyl, preferably the R 11 It is optionally substituted with substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, and hydroxyl. R 14 R is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 14 These are hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl.

[0068] In another preferred embodiment, R1 is a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocycloalkyl, and R1 is one or more R 11 It is optionally replaced by the R 11 These include halogens, hydroxyls, C1-C6 alkyls, C1-C6 alkoxys,

[0069] [ka] A substituent selected from,

[0070] R 14 R is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 14 These are hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl. The aforementioned R 11 It is optionally substituted with substituents selected from C1-C3 alkoxys and halogens. Preferably, the halogen is fluorine.

[0071] In another preferred embodiment, R1 is selected from cyclopropyl, cyclobutyl, tetrahydrofuranil, tetrahydropyranil, propylene oxide, pyrrolidinil, or piperidinil, and R1 is optionally one or more R 11 Replaced by, the R 11 These are C1-C6 alkyl and C1-C6 alkoxy molecules substituted with fluorine, hydroxyl, C1-C6 alkyl, and C1-C3 alkoxy.

[0072] [ka] A substituent selected from R 14 These are C1-C6 alkyl groups,

[0073] Preferably, R1 is

[0074] [ka] Selected from.

[0075] In another preferred embodiment, R5 is hydrogen, R6 is -SF5, R4 is methyl, R3 is methyl, and R2 is hydrogen. In another preferred embodiment, R1 is

[0076] [ka] That is the case.

[0077] In another preferred embodiment,

[0078] [ka] teeth

[0079] [ka] That is the case.

[0080] In another preferred embodiment, R2 is hydrogen or a substituent selected from halogens, C1-C6 alkyls, or 3-6 membered cycloalkyls, preferably R2 is hydrogen or a halogen, and more preferably R2 is hydrogen.

[0081] In another preferred embodiment, R3 is hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group, preferably R3 is a C1-C6 alkyl group, and more preferably R3 is methyl. In another preferred embodiment, the pyridopyrimidinone derivative (compound) includes a compound of the following formula.

[0082] [ka] JPEG0007870776000039.jpg173169

[0083] A second aspect of the present invention provides an intermediate represented by formula B-1, its tautomers, stereoisomers, and salts thereof.

[0084] [ka]

[0085] Here, the definitions of rings A, R4, R5, and R6 are as described in the first embodiment, and m is 1 or 2. In another preferred embodiment, the intermediate represented by formula B-1, its tautomers, stereoisomers, and salts thereof are,

[0086] [ka] Having a structure,

[0087] Here, the definitions of rings A, R4, R5, R6, and m are as described in formula B-1 of the second embodiment, Preferably, R4 is methyl or -CH2F, and more preferably, R4 is methyl. In another preferred embodiment, R5 is hydrogen, fluorine or methyl, m is 1 or 2, preferably m is 1, and R6 is -SF5.

[0088] [ka] And the R 61 , the R 62 Each of these is independently a C1-C6 alkyl or a 3-6 membered cycloalkyl group substituted with one or more F atoms.

[0089] Preferably, R 61 These are -CH2F, -CHF2, -CF3, -CF2CH3, or cyclopropyl. Preferably, R 62 is -CH2F, -CHF2, -CF3, more preferably R 62 It is -CHF2.

[0090] In another preferred embodiment, ring A is a group fragment together with R6 and R5.

[0091] [ka] Forms, where Z is

[0092] [ka] And p is 1, n is 2 or 3, R 63 is fluorine or hydroxyl, and the R 63 If there are multiple, R 63 They are the same or different.

[0093] Preferably, a base fragment

[0094] [ka] teeth,

[0095] [ka] Having a structure, more preferably,

[0096] [ka] teeth

[0097] [ka] That is the case.

[0098] In another preferred embodiment, the intermediate represented by B-1, its tautomers, stereoisomers, and salts thereof include compounds of the following formula.

[0099] [ka]

[0100] In another preferred embodiment, the intermediate represented by B-1, its tautomers, stereoisomers, and salts thereof are,

[0101] [ka] isn't it.

[0102] A third aspect of the present invention provides a method for producing pyridopyrimidinone derivatives (compounds) represented by formula I as described in the first aspect, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, the method being described 1) The process includes the step of reacting intermediate B-1 and intermediate B-2 to obtain a pyridopyrimidinone derivative (compound) represented by formula I,

[0103] [ka]

[0104] Here, the definitions of ring A, R1, R2, R3, R4, R5, R6, m, p, and n are as described in the first embodiment. R7 is a hydroxyl, chlorine, bromine, iodine, or sulfonic acid group, preferably R7 is a hydroxyl group. Preferably, the sulfonic acid group is -SO3R 71 And here, R 71 These are methyl, -CF3, phenyl, or 2,4,6-trimethylbenzene.

[0105] In another preferred embodiment, ring A is phenyl, and preferably a group fragment

[0106] [ka] teeth

[0107] [ka] It has the structure of [the object].

[0108] In another preferred embodiment, R5 is hydrogen, fluorine or methyl, m is 1 or 2, preferably m is 1, and R6 is -SF5.

[0109] [ka] And the R 61 , the R 62 Each of these is independently a C1-C6 alkyl or a 3-6 membered cycloalkyl group substituted with one or more F atoms.

[0110] Alternatively, ring A, along with R6 and R5, forms a base fragment.

[0111] [ka] Forms, where Z is

[0112] [ka] And p is 1, n is 2 or 3, R 63 is fluorine or hydroxyl, and the R 63 If there are multiple, R 63 They are the same or different.

[0113] Preferably, a base fragment

[0114] [ka] teeth,

[0115] [ka] Having a structure, more preferably,

[0116] [ka] teeth

[0117] [ka] And,

[0118] Preferably, R 61 These are -CH2F, -CHF2, -CF3, -CF2CH3, or cyclopropyl. Preferably, R 62 is -CH2F, -CHF2, -CF3, more preferably R 62 It is -CHF2.

[0119] In a preferred embodiment of the present invention, the method further comprises the step of 2) converting the intermediate B-1 to an ammonium salt of B-1, and then reacting it with intermediate B-2 to obtain a pyridopyrimidinone derivative (compound) represented by formula I. The ammonium salt may be an ammonium salt obtained by reacting a pharmaceutically acceptable inorganic or organic acid described in the present invention with -NH2 in intermediate B-1, and includes, but is not limited to, ammonium hydrochloride, ammonium sulfate, ammonium nitrate, and ammonium phosphate.

[0120] In a preferred embodiment of the present invention, the method further comprises the step of 3) reacting intermediate B-1 and intermediate B-2, and then producing a pyridopyrimidinone derivative (compound) represented by formula I through acidic production conditions B. The acidic production conditions B include a Welch, Ultimate C18 column, 10 μm, 21.2 mm × 250 mm, mobile phase A being a 1‰ pure aqueous formic acid solution, and mobile phase B being an acetonitrile solution. The gradient conditions are such that mobile phase A maintains 90% for 0 to 3 minutes, then gradient elutes from 90% to 5% for 3 to 18 minutes, and maintains 5% for 18 to 22 minutes.

[0121] Depending on the differences in each group in the compound of formula I, different synthetic routes and intermediates can be selected. If an active group (e.g., carboxyl, amino, hydroxyl) is present in the substituent, the active group can be protected with a protecting group before participating in the reaction, and the protecting group can be deprotected after the reaction is complete. A compound in which one or more reaction sites are blocked by one or more protecting groups (also called protecting radicals) is a "protected derivative (compound)" of the compound of formula I described in the present invention. For example, suitable carboxyl partial protecting groups include benzyl, tert-butyl, and isotopes. Suitable amino and amide protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl, and benzyloxycarbonyl. Suitable hydroxyl protecting groups include benzyl. Other suitable protecting groups are well known to those skilled in the art.

[0122] In some embodiments, the reaction requires protection by an inert gas, which includes, but is not limited to, nitrogen, helium, neon, and argon. The reactions in each step of the present invention are preferably carried out in an inert solvent, which includes, but is not limited to, toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, trichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or combinations thereof.

[0123] A fourth aspect of the present invention provides a pharmaceutical composition comprising a pyridopyrimidinone derivative (compound) represented by formula I as described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and a pharmaceutically acceptable carrier. Furthermore, the present invention provides a pharmaceutical composition comprising a pyridopyrimidinone derivative (compound) represented by formula I as described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and at least one other pharmacologically active inhibitor. Preferably, the other pharmacologically active inhibitor is an inhibitor of MEK and / or its mutant. Preferably, the other pharmacologically active inhibitor is trametinib.

[0124] A fifth aspect of the present invention provides the use of a pyridopyrimidinone derivative (compound) represented by formula I as described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition as described in the fourth aspect of the present invention, which includes the use of a drug, pharmaceutical composition or formulation used to inhibit the interaction between SOS1 and RAS family proteins; and / or prevent and / or treat diseases related to SOS1 and RAS family proteins; and / or prevent and / or treat diseases related to (or mediated by) SOS1 and RAS family proteins. Preferably, the use includes the use of a pyridopyrimidinone derivative (compound) represented by formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs in combination with trametinib.

[0125] Preferably, diseases associated with (or mediated by) SOS1 and RAS family proteins include, but are not limited to, cancer and RAS diseases. RAS diseases may include Noonan syndrome, cardiac-facial-cutaneous syndrome, hereditary gingival fibromatosis type 1, neurofibromatosis type 1, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, and Regius syndrome.

[0126] A fifth aspect of the present invention further provides the use of a pyridopyrimidinone derivative (compound) represented by formula I as described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the use of a pharmaceutical composition as described in the fourth aspect of the present invention in the manufacture of a drug (pharmaceutical composition or formulation), the drug being a drug for preventing and / or treating diseases mediated by SOS1 and RAS family proteins, or the drug being a drug for preventing and / or treating cancer or RAS disease. The RAS disease or diseases mediated by SOS1 and RAS family proteins include Noonan syndrome, cardiac-facial-skin syndrome, hereditary gingival fibromatosis type 1, neurofibromatosis type 1, capillary malformation-arteriovenous malformation syndrome, Costello syndrome and Regius syndrome. Preferably, the drug comprises a pyridopyrimidinone derivative (compound) represented by formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and trametinib.

[0127] Preferably, the cancer is selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, stomach cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial carcinoma, ureteral tumors, prostate cancer, seminoma, testicular tumors, leukemia, head and neck tumors, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma, and glioma, the liver cancer is preferably hepatocellular carcinoma, the head and neck tumor is preferably squamous cell carcinoma of the head and neck, the sarcoma is preferably osteosarcoma, and the colorectal cancer is preferably colon cancer or rectal cancer.

[0128] The RAS disease is preferably neurofibromatosis type 1 (NF1), the lung cancer is preferably non-small cell lung cancer, more preferably metastatic non-small cell lung cancer, the leukemia is preferably chronic lymphocytic leukemia or acute myeloid leukemia, the lymphoma is preferably diffuse large B-cell lymphoma, the myeloma is preferably multiple myeloma, the osteoma is preferably osteochondroma, the liver cancer is preferably hepatocellular carcinoma, the head and neck tumor is preferably head and neck squamous cell carcinoma, the sarcoma is preferably osteosarcoma, and the colorectal cancer is preferably colon cancer or rectal cancer.

[0129] The RAS family protein may be KRAS, for example, KRAS G12C. A sixth aspect of the present invention provides a method for inhibiting SOS1 and RAS family proteins, or for preventing and / or treating diseases associated with (or mediated by) SOS1 and RAS family proteins, comprising the step of administering a pyridopyrimidinone derivative (compound) represented by formula I as described in the first aspect of the present invention, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug, to a subject requiring such treatment. Preferably, the method comprises a combination of the pyridopyrimidinone derivative (compound) represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug with trametinib.

[0130] Additional aspects and advantages of the present invention are given in part in the following description, and in part may become apparent from the following description or may be understood through the practice of the present invention. Terms and Definitions Unless otherwise specified, the definitions of groups and terms described in the specification and claims of this application include illustrative definitions, exemplary definitions, preferred definitions, definitions listed in tables, and definitions of specific compounds in examples, and can be combined in any way. Such combinations and combined definitions of groups and structures of compounds should fall within the scope described in the specification of this application.

[0131] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as generally understood by those skilled in the art to whom the category of claims belongs. Unless otherwise noted, all patents, patent applications, and published materials cited herein are incorporated herein by whole or in whole by reference. If there are multiple definitions of a term herein, the definition in this chapter shall prevail.

[0132] Please understand that the above brief description and the following detailed description are illustrative and descriptive only and do not limit the categories of the present invention in any way. In this application, unless otherwise specified, the use of the singular includes the plural. Please note that unless otherwise clearly indicated by the context, the singular as used herein and in the claims includes the plural of the object being referred to. Also note that unless otherwise specified, "or" and "or" as used mean "and / or". Furthermore, the term "includes" as used, and other forms such as "contains," "includes," and "contains" are not limited.

[0133] For the definitions of standard chemical terms, reference can be made to the references (such as Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York, etc.). Unless otherwise specified, conventional methods within the technical scope of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy, and pharmacological methods, are used. Unless a specific definition is given, the terms used in this specification in the relevant descriptions of analytical chemistry, synthetic organic chemistry, pharmaceuticals and medicinal chemistry are known in the art. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical manufacture, formulation and delivery, and patient treatment. For example, the instructions of the kit manufacturer can be used, or reactions and purification can be carried out by methods known in the art or according to the descriptions in this specification. The above-mentioned techniques and methods can generally be carried out according to conventional methods well-known in the art, as described in various general and more specific documents cited and discussed in this specification. In this specification, in order to provide stable structural moieties and compounds, bases and their substituents can be selected by those skilled in the art.

[0134] When substituents are represented from left to right in the conventional chemical formula, the chemically equivalent substituents when the structural formula is represented from right to left are also included in the said substituents. For example, CH2O is equivalent to OCH2. As used in this specification,

[0135]

Chem.

[0136] Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described herein. All documents or parts of documents cited herein, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0137] In addition to the above, as used in the specification and claims of this application, the following terms have the meanings set forth below unless otherwise specified. With respect to numerical ranges described in the specification and claims of this application, if such numerical ranges are understood as "integers," they should be understood to include the two endpoints of the range and each integer within that range. For example, "integers from 1 to 6" should be understood to include all integers from 0, 1, 2, 3, 4, 5, and 6.

[0138] In this application, the term "halogen," either alone or as part of another substituent, means fluorine, chlorine, bromine, or iodine, and preferably fluorine. As used herein, the term "amino," either alone or as part of another substituent, means -NH2.

[0139] As used herein, the term “alkyl” means a linear or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without unsaturated bonds, having, for example, 1 to 6 carbon atoms, and connected to the rest of the molecule by single bonds. Examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. Alkyls may be unsubstituted or substituted with one or more suitable substituents. Alkyls may also be naturally abundant isotopic isomers of alkyls, rich in carbon and / or hydrogen isotopes (i.e., deuterium or tritium). As used herein, the term “alkenyl” means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term “alkynyl” means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.

[0140] The term “C1-C6 alkyl” should be understood to mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, either alone or as part of another substituent. The alkyl groups are, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers. In particular, the groups have 1, 2, or 3 carbon atoms (“C1-C3 alkyl”), such as methyl, ethyl, n-propyl, or isopropyl.

[0141] The terms "cycloalkyl" or "carbocyclic group," either alone or as part of another substituent, mean a cyclic alkyl group. m ~C n "Cycloalkyl" should be understood to mean a saturated, unsaturated, or partially saturated carbon ring having m to n atoms. For example, "3 to 15 member cycloalkyl" or "C3 to C 15 "Cycloalkyl" refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 6, or 3 to 5 carbon atoms, and may contain 1 to 4 rings. "3 to 10-membered cycloalkyl" contains 3 to 10 carbon atoms. This includes monocyclic, dicyclic, tricyclic, spirocyclic, or crosslinked rings. Examples of unsubstituted cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or bicyclic hydrocarbon groups such as decahydronaphthalene rings. Cycloalkyls may be substituted with one or more substituents. In some embodiments, cycloalkyls may be condensed to an aryl or heteroaromatic ring group.

[0142] On its own or as part of another substituent, the term “spiro ring” refers to a polycyclic group in which monocyclic rings share a single carbon atom (called a spiro atom), and may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Depending on the number of spiro atoms shared between the rings, spirocycloalkyls are classified as monospirocycloalkyls, bispirocycloalkyls, or polyspirocycloalkyls, preferably monospirocycloalkyls and bispirocycloalkyls. Non-limiting examples of spirocycloalkyls include the following structures:

[0143] [ka]

[0144] Furthermore, this also includes spirocycloalkyls in which a single spirocycloalkyl shares a spiro atom with a heterocycloalkyl, and non-limiting examples include the following structures:

[0145] [ka]

[0146] The term "bridged ring" refers to a cyclic hydrocarbon in a compound where any two rings share two carbon atoms that are not directly bonded. These are classified into bicyclic, tricyclic, and tetracyclic hydrocarbons depending on the number of rings. Non-restrictive examples include the following structures:

[0147] [ka]

[0148] The terms "heterocycloalkyl" or "heterocyclyl" or "heterocycle," either alone or as part of other substituents, mean a cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are substituted by heteroatoms, the heteroatoms being, for example, N, O, S, and P. m ~C n The term "heterocycloalkyl" should be understood to mean a saturated, unsaturated, or partially saturated ring having m to n atoms, where the heterocyclic atoms are selected from N, O, S, and P, preferably from N, O, or S. For example, the term "4-8 membered heterocycloalkyl" or "C4-C8 heterocycloalkyl" should be understood to mean a saturated, unsaturated, or partially saturated ring having 4 to 8 atoms, where 1, 2, 3, or 4 ring atoms are selected from N, O, S, and P, preferably from N, O, or S. "9-11 membered heterocyclic group" means a saturated, unsaturated, or partially saturated ring having 9 to 11 atoms. In some embodiments, the heterocycloalkyl may be a heterocycloalkyl condensed to an aromatic ring group or a heteroaromatic ring group. When prefixes such as 9-11 membered or 9-11 membered are used to indicate a heterocycloalkyl, it means that the carbon number also includes heteroatoms. This includes monocyclic, dicyclic, tricyclic, spirocyclic, or bridging rings.

[0149] 单独地,或者作为其他取代基的一部分,术语“杂芳基”是指单环或多环芳族环系,在一些实施方案中,环系中的1至3个原子是杂原子,即除碳以外的元素,包括但不限于N、O、S或P。例如,呋喃基、咪唑基、二氢吲哚基、四氢吲哚基、吡咯烷基、嘧啶基、四唑基、噻吩基、吡啶基、吡咯基、N-甲基吡咯基、喹啉基和异喹啉基。杂芳基可以任选地与苯环稠合,并且可以包括单环、二环、三环、螺环或桥环。

[0150] 单独地,或者作为其他取代基的一部分,术语“9至11元杂芳基”或“C9 - C 11 杂芳基”应理解为具有9至11个环原子且独立地包含1至3个选自N、O和S的杂原子的一价单环、二环或三环芳基,应理解为具有9、10或11个环原子且独立地包含选自N、O和S的杂原子的一价单环、二环或三环芳基,并且在每种情况下,还可以是苯并稠合的。单独地,或者作为其他取代基的一部分,它可以通过碳或氮连接,其中,-CH 2-The group is optionally substituted with -C(O)-, and unless otherwise specified, the cyclic nitrogen atom or cyclic sulfur atom is optionally oxidized to form an N-oxide or S-oxide, or the cyclic nitrogen atom is optionally quaternized, where the -NH in the ring is optionally substituted with acetyl, formyl, methyl, or methylsulfonyl, and the ring is optionally substituted with one or more halogens. If the total number of S and O atoms in the heterocyclil exceeds 1, it should be understood that these heteroatoms are not adjacent to each other. If the heterocyclil is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic or aromatic ring, provided that at least one ring is nonheteroaromatic. If the heterocyclil is monocyclic, it must not be aromatic.

[0151] On its own or as part of other substituents, “haloalkyl” refers to a branched and linear saturated aliphatic hydrocarbon group (e.g., -CvFw, where v=1 to 3 and w=1 to (2v+1)) substituted with one or more halogens, containing a specific number of carbon atoms. Examples of haloalkyls include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

[0152] The compounds provided herein, including intermediates that can be used to produce the compounds provided herein, contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), and further include their protected derivatives (compounds). A "protected derivative (compound)" is one of those compounds in which one or more reactive sites are blocked by one or more protecting groups (also called protecting groups). Suitable protecting groups for carboxyl moieties include benzyl, tert-butyl, and isotopes, etc. Suitable protecting groups for amino and acylamino groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for hydroxyl groups include benzyl, etc. Other suitable protecting groups are well known to those skilled in the art.

[0153] In the present application, "optional" or "optionally" means that the event or situation described thereafter may or may not occur, and the description includes both the occurrence and non-occurrence of that event or situation. For example, "optionally substituted aryl" means that the aryl is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl.

[0154] In the present application, the terms "salt" or "pharmaceutically acceptable salt" include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" means that for those compounds, materials, compositions and / or dosage forms, they are within the scope of reliable medical judgment, suitable for contact with human and animal tissues, and have little toxicity, irritation, allergic reaction or other problems or complications, and meet a reasonable benefit / risk ratio.

[0155] "Pharmacologically acceptable acid addition salts" mean salts formed with inorganic or organic acids that can retain the biological efficacy of a free base without other side effects. "Pharmacologically acceptable base addition salts" mean salts formed with inorganic or organic bases that can retain the biological efficacy of a free acid without other side effects. In this invention, other salts are also considered in addition to pharmaceutically acceptable salts. These may act as intermediates in the purification of the compound or in the production of other pharmaceutically acceptable salts, or they may be used in the identification, characterization, or purification of the compound of this invention.

[0156] The term "amine salt" refers to a product obtained by neutralizing an alkyl primary, secondary, or tertiary amine with an acid. The acid includes the inorganic or organic acids described in this application. The term "stereoisomer" refers to isomers that arise from differences in the spatial arrangement of atoms within a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0157] Depending on the selection of starting materials and methods, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, for example, as a pure optical isomer, or as a mixture of isomers, for example, as a racemic mixture and a mixture of diastereomers, depending on the number of chiral carbon atoms. When describing optically active compounds, the prefixes D and L, or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) within the molecule. The prefixes D and L, or (+) and (-) are symbols used to specify the rotation of plane polarization by the compound, where (-) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory.

[0158] When the bond with a chiral carbon in the formula of this invention is described as a straight line, it should be understood that both the (R) and (S) configurations of the chiral carbon, and the resulting enantiomerically pure compounds and mixtures, are within the scope of this general formula. The graphical representations of racemates or enantiomerically pure compounds in this specification are from Maehr, J. Chem. Ed. 1985, 62:114-120. The absolute configuration of the stereocenter is indicated by wedge-shaped bonds and dashed-line bonds.

[0159] The term "tautomer" refers to a functional isomer resulting from the rapid movement of atoms between two positions within a molecule. The compounds of the present invention can exhibit the phenomenon of tautomerism. Tautomer compounds can exist as two or more interconvertible species. Prototropic tautomers arise from the movement of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium, and attempting to isolate a single tautomer usually yields a mixture whose physicochemical properties match those of the mixture of compounds. The equilibrium position depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant, while in phenols, the enol form is dominant. The present invention encompasses all tautomer forms of compounds.

[0160] In this application, “pharmaceutical composition” means a formulation of the compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The object of the pharmaceutical composition is to facilitate administration to a living organism, to facilitate the absorption of the active ingredient, and thereby to exert biological activity.

[0161] In this application, “pharmaceutically acceptable carrier” includes, but is not limited to, any adjuvants, carriers, excipients, flow enhancers, sweeteners, diluents, preservatives, dyes / colorants, fragrances, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers approved by the relevant government regulatory body as acceptable for use in humans or livestock.

[0162] The term "solvate" means that the compound or salt thereof of the present invention contains a stoichiometric or non-stoichiometric solvent bonded by intermolecular non-covalent forces, and if the solvent is water, it is a hydrate. The term "prodrug" refers to the compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrug of the present invention is produced by modifying a functional group in the compound, and this modification can be removed by normal procedures or in vivo to obtain the parent compound. Prodrugs include compounds formed by the bonding of a hydroxyl or amino group in the compound of the present invention to any group, and when a prodrug of the compound of the present invention is administered to a mammal, the prodrug is cleaved to form free hydroxyl and free amino groups, respectively.

[0163] The term "excipient" refers to a medicinal, inert component. Examples of types of excipients include, but are not limited to, binders, disintegrants, lubricants, flow enhancers, stabilizers, fillers, and diluents. Excipients can improve the handling properties of pharmaceutical formulations, that is, they can make formulations more suitable for direct compression by increasing their fluidity and / or viscosity.

[0164] The term "treatment" and other similar synonyms as used herein are defined as follows: (i) To prevent the occurrence of diseases or conditions in mammals, in particular in mammals that are susceptible to such diseases or conditions but have not been diagnosed with them. (ii) To inhibit a disease or symptom, that is, to prevent its onset. (iii) To alleviate a disease or symptom, that is, to resolve the state of the disease or symptom, or (iv) This includes the meaning of alleviating the symptoms caused by the disease or condition in question.

[0165] In each step of the reaction, the reaction temperature can be appropriately selected depending on the solvent, starting materials, reagents, etc., and the reaction time can also be appropriately selected depending on the reaction temperature, solvent, starting materials, reagents, etc. After the completion of each step of the reaction, the target compound can be separated and purified from the reaction system by conventional methods such as filtration, extraction, recrystallization, washing, and silica gel column chromatography. Alternatively, the reaction can proceed directly to the next reaction without separating or purifying the target compound, without affecting the next reaction.

[0166] Without violating the ordinary knowledge of the art, each of the above preferred conditions can be arbitrarily combined to obtain each preferred embodiment of the present invention. The reagents and raw materials used in the present invention are commercially available.

[0167] Beneficial effects As a result of extensive and diligent research, the inventors have unexpectedly developed pyridopyrimidinone derivatives (compounds) or pharmaceutically acceptable salts thereof, as well as methods for their production and use.

[0168] The present invention provides pyridopyrimidinone derivatives (compounds) represented by formula I, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, wherein the compounds of formula I have a significant inhibitory effect on the binding of KRAS G12C::SOS1, a significant inhibitory effect on KRAS G12C-SOS1, a significant inhibitory effect on the ERK phosphorylation level of DLD-1 cells, and a strong inhibitory effect on 3D proliferation of H358 cells. The compounds of the present invention exhibit superior hepatic metabolic stability, slower metabolism in the human body, higher exposure, no inhibitory effect on the CYP3A4 enzyme, a lower risk of potential drug interactions, superior pharmacokinetic properties, high safety and pharmaceutical properties, and are more suitable for concomitant administration. Experiments have shown that the compounds described in the present invention, when used alone or in combination with trametinib, have a significant inhibitory effect on the proliferation of Mia Paca-2 cancer, and the concomitant effect is superior to that when used alone.

[0169] The present invention provides a method for producing pyridopyrimidinone derivatives (compounds) represented by formula I, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, and intermediates, wherein the method is easy to operate, yields high yields and high purity, and can be used in the industrial production of pharmaceuticals. [Brief explanation of the drawing]

[0170] [Figure 1] This is a tumor inhibition ability test at the tumor volume level of representative compounds in in vivo drug efficacy experiments for Mia Paca-2 pancreatic cancer (tumor volume at the end of treatment (mm3)). [Figure 2] This is a tumor inhibitory activity test at the tumor weight level of representative compounds in in vivo drug efficacy experiments for LOVO colorectal cancer (tumor volume (mm3) at the end of treatment). [Modes for carrying out the invention]

[0171] [Specific implementation details] The present invention will be further described below based on specific examples. It should be understood that the following description represents only the most preferred embodiments of the present invention and should not be considered as limiting the scope of protection of the present invention. Based on a full understanding of the present invention, experimental methods for which specific conditions are not shown in the following examples can usually be modified by those skilled in the art according to conventional conditions or conditions suggested by the manufacturer, and such modifications should be considered to be within the scope of protection of the present invention.

[0172] This application includes the following definitions: Symbol or unit: I C 50 This refers to the median inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.

[0173] M: mol / L. For example, n-butyllithium (14.56 mL, 29.1 mmol, 2.5 M n-hexane solution) means an n-hexane solution of n-butyllithium with a molar concentration of 2.5 mol / L.

[0174] N stands for normal concentration; for example, 2N hydrochloric acid means a 2 mol / L hydrochloric acid solution. reagent: DCM: Dichloromethane DIPEA: Also known as DIEA, diisopropylethylamine, i.e., N,N-diisopropylethylamine DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide EA: Ethyl acetate Et3N: Triethylamine MeOH: methanol PE: Petroleum ether THF: Tetrahydrofuran Test or detection method: HPLC: High-Performance Liquid Chromatography SFC: Supercritical Fluid Chromatography Acidic production condition B: Welch, Ultimate C18 column, 10 μm, 21.2 mm × 250 mm. Mobile phase A is a 1‰ pure formic acid aqueous solution, and mobile phase B is an acetonitrile solution. Gradient conditions: Mobile phase A maintains 90% at 0-3 minutes, then gradient elutes from 90% to 5% at 3-18 minutes, and maintains 5% at 18-22 minutes.

[0175] Intermediate A1: Production of Intermediate A1 The synthesis route is as follows:

[0176] [ka]

[0177] Step 1: (Z)-2-((dimethylamino)methylene)-3-oxopentadicarboxylate methyl ester (A1-2)

[0178] [ka]

[0179] At room temperature, compound dimethyl 3-oxoglutarate (10.0 g, 57.4 mmol) was added to 2-methyltetrahydrofuran (100 ml), and DMF-DMA (6.8 g, 57.1 mmol) was added. The mixture was stirred at room temperature for 4 hours. The mixture was concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain the crude product of the title compound, (Z)-2-((dimethylamino)methylene)-3-oxopentadicarboxylic acid methyl ester (A1-2), which was a yellow liquid (A1-2) (12 g, yield: 91.1%).

[0180] LC-MS, M / Z (ESI): 230.2[M+H] + . Step 2: 1-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-6-oxo-1,6-dihydroxypyridine-3-carboxylate methyl ester (A1-4)

[0181] [ka]

[0182] At room temperature, compound (Z)-2-((dimethylamino)methylene)-3-oxopentadicarboxylate methyl ester (2.4 g, 10.4 mmol) was added to 2-methyltetrahydrofuran (30 ml), 4N hydrochloric acid (10 ml) was added, and the mixture was stirred for 3 hours. The liquids were separated, the aqueous phase was extracted with ethyl acetate (100 ml x 3), and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, methanol (30 ml) was added, and 1-(fluoromethyl)cyclopropane-1-amino hydrochloride (1.0 g, 8.0 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Sodium methoxide (1.3 g, 24.0 mmol) was added to the reaction system and the mixture was stirred for 2 hours. The pH was adjusted to 2 with concentrated hydrochloric acid, and the mixture was filtered to obtain the brown solid crude product of the title compound, 1-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-6-oxo-1,6-dihydroxypyridine-3-carboxylate methyl ester (A1-4) (2.0 g, yield: 79.1%).

[0183] LC-MS, M / Z (ESI): 242.2[M+H] + . Step 3: 1-(1-(fluoromethyl)cyclopropyl)-6-oxo-4-(p-toluenesulfonyloxy)-1,6-dihydroxypyridine-3-carboxylate methyl ester (A1-5)

[0184] [ka]

[0185] At room temperature, the starting material 1-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-6-oxo-1,6-dihydroxypyridine-3-carboxylate methyl ester (2.0 g, 8.3 mmol) was added to acetonitrile (20 ml), cooled to 0°C, and triethylamine (1.68 g, 16.6 mmol) and TsCl (1.58 g, 8.3 mmol) were added. The mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was concentrated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1 to 1:1) to obtain the title compound, the white solid 1-(1-(fluoromethyl)cyclopropyl)-6-oxo-4-(p-toluenesulfonyloxy)-1,6-dihydroxypyridine-3-carboxylate methyl ester (A1-5) (1.2 g, yield: 36.6%).

[0186] LC-MS, M / Z (ESI): 396.3[M+H] + . Step 4: 4-Acetamido-1-(1-(fluoromethyl)cyclopropyl)-6-oxo-1,6-dihydroxypyridine-3-carboxylate methyl ester (A1-6)

[0187] [ka]

[0188] At room temperature, the starting material 1-(1-(fluoromethyl)cyclopropyl)-6-oxo-4-(p-toluenesulfonyloxy)-1,6-dihydroxypyridine-3-carboxylate methyl ester (1.2 g, 3.0 mmol) was added to dioxane (50 ml), potassium phosphate (700 mg, 3.3 mmol), xanthophos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, Xantphos) (173 mg, 0.3 mmol), and palladium (π-cinnamyl) chloride dimer (212 mg, 0.3 mmol) were added, and the mixture was heated under reflux and stirred under N2 protection for 2 hours. The reaction mixture was cooled to room temperature, concentrated, and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 3:1 to 1:1) to obtain the title compound, a white solid 4-acetamido-1-(1-(fluoromethyl)cyclopropyl)-6-oxo-1,6-dihydroxypyridine-3-carboxylate methyl ester (A1-6) (680 mg, yield: 79.3%).

[0189] LC-MS, M / Z (ESI): 283.2[M+H] + . Step 5: 6-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidine-7(6H)-one(A1)

[0190] [ka]

[0191] At room temperature, the starting material 4-acetamido-1-(1-(fluoromethyl)cyclopropyl)-6-oxo-1,6-dihydroxypyridine-3-carboxylate methyl ester (680 mg, 2.41 mmol) was added to 10 ml of 7 mol / L ammonia-methanol solution and stirred at room temperature for 5 days. The mixture was concentrated (3 ml) and filtered to obtain the title compound, the white solid 6-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidine-7(6H)-one (460 mg, yield: 16.4%).

[0192] 1 1H NMR (400 MHz, DMSO-d6) δ 11.8 (s, 1H), 8.36 (s, 1H), 6.17 (s, 1H), 4.62 (d, 2H), 2.24 (s, 3H), 1.27 (s, 4H). LC-MS, M / Z (ESI): 250.2 [M+H] + 。

[0193] Intermediate A2: Preparation of Intermediate A2 The synthetic route is as follows:

[0194]

Chemical Structure

[0195] Step 1: Synthesis of 4,6-dichloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidine (A2-2)

[0196]

Chemical Structure

[0197] 4,6-Dichloro-2-methylpyrimidine-5-carbaldehyde (20 g, 105 mmol) was added to toluene (200 ml), ethylene glycol (5.84 ml) and p-toluenesulfonic acid (2 g, 10.5 mmol) were added, and the mixture was refluxed at 120 °C for 12 hours. After completion of the reaction, the mixture was concentrated, dichloromethane (200 ml) was added, and the mixture was washed with saturated sodium bicarbonate solution (200 ml × 3). The organic phase was concentrated, and the residue was separated and purified by silica gel column (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%).

[0198] LC-MS, M / Z (ESI): 235.0 [M+H] + 。 Step 2: Synthesis of 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidine-4-yl)dimethyl malonate (A2-3)

[0199] [ka]

[0200] 4,6-Dichloro-5-(1,3-Dioxolan-2-yl)-2-methylpyrimidine (10 g, 42.5 mmol) was added to dimethyl sulfoxide (50 ml), cesium carbonate (27.7 g, 85 mmol) and dimethyl malonate (6.18 g, 46.8 mmol) were added, and the mixture was stirred at 80°C for 12 hours. After the reaction was complete, the mixture was diluted with ethyl acetate (200 ml), washed with water (200 ml x 3), washed with saturated brine (200 ml x 3), the organic phase was concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain the title compound 2-(6-chloro-5-(1,3-Dioxolan-2-yl)-2-methylpyrimidine-4-yl)dimethyl malonate (A2-3) (10 g, yield: 71%).

[0201] LC-MS, M / Z (ESI): 331.1[M+H] + . Step 3: Synthesis of 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidine-4-yl)methyl acetate (A2-4)

[0202] [ka]

[0203] Dimethyl 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidine-4-yl)malonate (10.2 g, 30.8 mmol) was added to dimethyl sulfoxide (30 ml), lithium chloride (5.23 g, 123 mmol) was added, and the mixture was stirred at 120°C for 12 hours. After the reaction was complete, the mixture was diluted with ethyl acetate (100 ml), washed with water (200 ml x 3), washed with saturated brine (200 ml x 3), the organic phase was concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain the title compound 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidine-4-yl)methyl acetate (A2-4) (6 g, yield: 71.3%).

[0204] LC-MS, M / Z (ESI): 273.1[M+H] + . Step 4: (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluoro-λ 6 Synthesis of sulfanyl(phenyl)ethyl(amino)pyrimidine-4-yl)methyl(A2-5) acetate

[0205] [ka]

[0206] 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidine-4-yl)methyl acetate (2.5 g, 9.17 mmol) was added to dimethyl sulfoxide (25 ml), then N,N-diisopropylethylamine (4.8 ml, 27.5 mmol) and (R)-1-(3-(pentafluorosulfanyl)phenyl)ethane-1-amine hydrochloride (3.12 g, 11 mmol) were added, and the mixture was stirred at 80°C for 6 hours. After the reaction was complete, the mixture was diluted with ethyl acetate (100 ml), washed with water (100 ml x 3), washed with saturated brine (100 ml x 3), concentrated the organic phase, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain the title compound (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)methyl acetate (A2-5) (2.3 g, yield: 51.9%).

[0207] LC-MS, M / Z (ESI): 484.1[M+H] + . Step 5: Synthesis of (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)acetic acid (A2)

[0208] [ka]

[0209] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)methyl acetate (250 mg, 0.52 mmol) was added to a mixed solution of dimethyl sulfoxide (25 ml) and acetonitrile (1 ml), and sodium hydroxide (83 mg, 2.07 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated and dried to obtain (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)acetic acid (A2) (243 mg, yield: 100%).

[0210] LC-MS, M / Z (ESI): 470.1[M+H] + . Example 1: Synthesis of Compound I-1 The synthesis route is as follows:

[0211] [ka]

[0212] Step 1: Synthesis of S-(3-bromo-2-methylphenyl)acetyl mercaptoester (B1-2)

[0213] [ka]

[0214] At room temperature, 1-bromo-3-iodo-2-toluene (2.0 g, 6.7 mmol) was added to anhydrous toluene (20 mL), potassium thioacetate (1.2 g, 10.5 mmol), 1,10-phenanthroline (120 mg, 0.67 mmol), and cuprous iodide (260 mg, 1.4 mmol) were added, and the mixture was heated to 100 °C under nitrogen gas protection and stirred for 3 hours. After cooling to room temperature, water (50 mL) was added, and the mixture was extracted with EA (80 mL x 3), the liquid was separated, the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (petroleum ether) to obtain S-(3-bromo-2-methylphenyl)acetyl mercaptoester (B1-2, colorless liquid crude product, 1.0 g, yield: 42.0%).

[0215] LC-MS, M / Z (ESI): 245.0 [M+H] + . Step 2: Synthesis of 3-bromo-2-methylthiophenol (B1-3)

[0216] [ka]

[0217] At room temperature, S-(3-bromo-2-methylphenyl)acetyl mercaptoester (2.44 g, 10.0 mmol) was added to methanol (20 mL) and THF (20 mL), and potassium hydroxide (670 mg, 12.0 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated to obtain 3-bromo-2-methylthiophenol (B1-3, yellow solid crude product, 2.10 g).

[0218] LC-MS, M / Z (ESI): 202.9 [M+H] + . Step 3: Synthesis of (3-bromo-2-methylphenyl)(difluoromethyl) sulfide (B1-4)

[0219] [ka]

[0220] At room temperature, 3-bromo-2-methylthiophenol (2.1 g, 10.0 mmol) was added to acetonitrile (20 mL), potassium carbonate (2.8 g, 20.0 mmol) and sodium bromodifluoroacetate (3.0 g, 15.0 mmol) were added, and the mixture was heated to 100 °C and stirred for 1 hour. After cooling to room temperature, the mixture was filtered to obtain compound B1-4 solution.

[0221] 19 F NMR (400MHz, CDCl3)δ-92.36. LC-MS, M / Z (ESI): 252.9 [M+H] + . Step 4: Synthesis of 1-bromo-3-((difluoromethyl)sulfonyl)-2-methylbenzene (B1-5)

[0222] [ka]

[0223] At room temperature, compound B1-4 solution was added to acetonitrile (40 mL), carbon tetrachloride (40 mL), and water (80 mL). Ruthenium trichloride (2.1 g, 10.0 mmol) and sodium periodate (6.5 g, 30.0 mmol) were added, and the mixture was stirred for 16 hours. The solution was diluted with water (400 mL), extracted with DCM (100 mL x 3), the liquid was separated, the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1), yielding 1-bromo-3-((difluoromethyl)sulfonyl)-2-methylbenzene (B1-5, colorless liquid, 710 mg, yield: 24.9%).

[0224] LC-MS, M / Z (ESI): 284.9 [M+H] + . Step 5: Synthesis of 1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethane-1-one (B1-6)

[0225] [ka]

[0226] At room temperature, compound 1-bromo-3-((difluoromethyl)sulfonyl)-2-methylbenzene (700 mg, 3.07 mmol) was added to dioxane (50 mL), bis(triphenylphosphine)palladium(II) dichloride (431 mg, 0.61 mmol) and tributyl(1-ethoxyvinyl) stannane (2.21 g, 6.14 mmol) were added, and the mixture was heated to 90°C under N2 protection and stirred for 14 hours. After cooling to room temperature, 2N hydrochloric acid (30 mL) was added and the mixture was stirred for 4 hours. Extraction was performed with ethyl acetate (50 mL x 3), the liquid was separated, the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1), obtaining 1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethane-1-one (B1-6, colorless liquid, 450 mg, yield: 74.6%).

[0227] LC-MS, M / Z (ESI): 249.0 [M+H] + . Step 6: Synthesis of (S,E)-N-(1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethylene)-2-methylpropane-2-sulfinamide (B1-7)

[0228] [ka]

[0229] At room temperature, compound 1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethane-1-one (650 mg, 2.60 mmol) was added to THF (100 mL), (S)-tert-butylsulfinamide (475 mg, 3.93 mmol) and tetraethyl titanate (1.18 g, 5.20 mmol) were added, and the mixture was heated to 70°C and stirred for 16 hours. The mixture was cooled to room temperature, diluted with water (200 mL), extracted with ethyl acetate (100 mL x 3), the liquid was separated, the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 4:1), obtaining (S,E)-N-(1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethylene)-2-methylpropane-2-sulfinamide (B1-7, white solid, 900 mg, yield: 100%).

[0230] LC-MS, M / Z (ESI): 352.3 [M+H] + . Step 7: Synthesis of (S)-N-((R)-1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (B1-8)

[0231] [ka]

[0232] At room temperature, the starting material (S,E)-N-(1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethylene)-2-methylpropane-2-sulfinamide (900 mg, 2.56 mmol) was added to methanol (20 mL), cooled to 0°C, and NaBH4 (474 ​​mg, 12.8 mmol) was added to the methanol in batches. The mixture was heated to room temperature and stirred for 3 hours. The reaction mixture was concentrated and purified by TLC plate 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%).

[0233] LC-MS, M / Z (ESI): 354.1 [M+H] + . Step 8: Synthesis of (R)-1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethane-1-amine hydrochloride (B1-9)

[0234] [ka]

[0235] At room temperature, the starting material (S)-N-((R)-1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (350 mg, 1.0 mmol) was added to a 4 mol / L hydrogen chloride-dioxane solution (1 mL) and stirred for 4 hours. The reaction mixture was concentrated, methyl tert-butyl ether (20 mL) was added, and the mixture was stirred for 1 hour. The mixture was then filtered to obtain (R)-1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethane-1-amine hydrochloride (B1-9, white solid, 260 mg, yield: 100%).

[0236] LC-MS, M / Z (ESI): 250.2 [M+H] + . Step 9: Synthesis of (R)-4-((1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyridine[4,3-d]pyrimidine-7(6H)-one(I-1)

[0237] [ka]

[0238] At room temperature, the starting material 6-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyridine[4,3-d]pyrimidine-7(6H)-one (A1) (200 mg, 0.80 mmol) was added to acetonitrile (20 mL), potassium phosphate (678 mg, 3.20 mmol) and phosphonitrile chloride trimer (416 mg, 1.20 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The starting material (R)-1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethane-1-amine hydrochloride (200 mg, 0.87 mmol) was added to DCM (10 mL), DIPEA (2 mL) was added, and the mixture was stirred for 0.5 hours. This solution was then added to the above reaction system, and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated and (R)-4-((1-(3-((difluoromethyl)sulfonyl)-2-methylphenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyridine[4,3-d]pyrimidine-7(6H)-one (I-1, white solid, 26 mg, yield: 6.7%) was obtained under acidic manufacturing conditions B.

[0239] 1 H NMR (400MHz, DMSO-d6) δ9.17 (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).

[0240] LC-MS, M / Z (ESI): 481.2 [M+H] + . Example 2: Synthesis of Compound I-2 The synthesis route is as follows:

[0241] [ka]

[0242] Step 1: Synthesis of 3-bromo-2-fluorobenzene-1-diazotetrafluoroborate (B2-2)

[0243] [ka]

[0244] At room temperature, 10.3 g of 3-bromo-2-fluoroaniline (54.2 mmol) was added to 21 mL of 50% aqueous solution of tetrafluoroboric acid, cooled to 0°C, and stirred for 1 hour. A solution of 3.8 g of sodium nitrite (55 mmol) dissolved in 6 mL of water was added dropwise at 0°C, and stirring was continued at low temperature for 1 hour. The mixture was filtered and dried to obtain 3-bromo-2-fluorobenzene-1-diazotetrafluoroborate (B2-2, yellow solid crude product, 13.0 g, yield: 83.2%).

[0245] Step 2: Synthesis of (3-bromo-2-fluorophenyl)(trifluoromethyl) sulfide (B2-3)

[0246] [ka]

[0247] At room temperature, 3-bromo-2-fluorobenzene-1-diazotetrafluoroborate (13 g, 45.1 mmol) was added to acetonitrile (130 mL), cesium carbonate (30 g, 91.0 mmol), sodium thiocyanate (5.5 g, 67.9 mmol), and cuprous thiocyanate (2.8 g, 23.0 mmol) were added, and the mixture was stirred for 0.5 hours. Then, trifluoromethyltrimethylsilane (12.8 g, 90 mmol) was added, and the mixture was stirred for 16 hours. The mixture was filtered to obtain compound B2-3 solution.

[0248] LC-MS, M / Z (ESI): 274.9 [M+H] + . Step 3: Synthesis of 1-bromo-2-fluoro-3-((trifluoromethyl)sulfonyl)benzene (B2-4)

[0249] [ka]

[0250] At room temperature, the compound B2-3 solution from the previous step was added to acetonitrile (200 mL), carbon tetrachloride (200 mL), and water (400 mL). Ruthenium trichloride (9.3 g, 45.0 mmol) and sodium periodate (28.8 g, 134.5 mmol) were added, and the mixture was stirred for 16 hours. The solution was diluted with water (800 mL), extracted with DCM (400 mL x 3), the liquid was separated, the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1), yielding 1-bromo-2-fluoro-3-((trifluoromethyl)sulfonyl)benzene (B2-4, colorless liquid, 6.5 g, yield: 46.9%).

[0251] LC-MS, M / Z (ESI): 306.9 [M+H] + . Step 4: Synthesis of 1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethane-1-one (B2-5)

[0252] [ka]

[0253] At room temperature, compound 1-bromo-2-fluoro-3-((trifluoromethyl)sulfonyl)benzene (6.5 g, 21.2 mmol) was added to dioxane (150 mL), bis(triphenylphosphine)palladium(II) dichloride (1.5 g, 2.12 mmol) and tributyl(1-ethoxyvinyl) stannane (11.5 g, 31.7 mmol) were added, and the mixture was heated to 90°C under N2 protection and stirred for 14 hours. After cooling to room temperature, 2N hydrochloric acid (100 mL) was added and the mixture was stirred for 4 hours. Extraction was performed with ethyl acetate (200 mL x 3), the liquid was separated, the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1), obtaining 1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethane-1-one (B2-5, colorless liquid, 5.0 g, yield: 87.7%).

[0254] LC-MS, M / Z (ESI): 271.0 [M+H] + . Step 5: Synthesis of (S,E)-N-(1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide (B2-6)

[0255] [ka]

[0256] At room temperature, compound 1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethane-1-one (2.7 g, 10.0 mmol) was added to THF (150 mL), (S)-tert-butylsulfinamide (1.82 g, 15.0 mmol) and tetraethyl titanate (4.56 g, 20.0 mmol) were added, and the mixture was heated to 70°C and stirred for 16 hours. The mixture was cooled to room temperature, diluted with water (300 mL), extracted with ethyl acetate (200 mL x 3), the liquid was separated, the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 4:1), obtaining (S,E)-N-(1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethylene)ethylene)-2-methylpropane-2-sulfinamide (B2-6, white solid, 4.0 g, yield: 100%).

[0257] LC-MS, M / Z (ESI): 374.1 [M+H] + . Step 6: Synthesis of (S)-N-((R)-1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (B2-7)

[0258] [ka]

[0259] At room temperature, the starting material (S,E)-N-(1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide (1.5 g, 4.0 mmol) was added to methanol (30 mL), cooled to 0°C, and NaBH4 (744 mg, 20.1 mmol) was added to the methanol in batches. The mixture was heated to room temperature and stirred for 3 hours. The reaction mixture was concentrated and purified by TLC plate 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%).

[0260] LC-MS, M / Z (ESI): 376.1 [M+H] + . Step 7: Synthesis of (R)-1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethane-1-amine hydrochloride (B2-8)

[0261] [ka]

[0262] At room temperature, the starting material (S)-N-((R)-1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (250 mg, 0.67 mmol) was added to a 4 mol / L hydrogen chloride-dioxane solution (1 mL) and stirred for 4 hours. The reaction mixture was concentrated, methyl tert-butyl ether (20 mL) was added, and the mixture was stirred for 1 hour. The mixture was then filtered to obtain (R)-1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethane-1-amine hydrochloride (B2-8, white solid, 163 mg, yield: 79.6%).

[0263] LC-MS, M / Z (ESI): 272.2 [M+H] + . Step 8: Synthesis of (R)-4-((1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyridine[4,3-d]pyrimidine-7(6H)-one(I-2)

[0264] [ka]

[0265] At room temperature, the starting material 6-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyridine[4,3-d]pyrimidine-7(6H)-one (A1) (200 mg, 0.80 mmol) was added to acetonitrile (20 mL), potassium phosphate (678 mg, 3.20 mmol) and phosphonitrile chloride trimer (416 mg, 1.20 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The starting material (R)-1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethane-1-amine hydrochloride (163 mg, 0.53 mmol) was added to DCM (10 mL), DIPEA (2 mL) was added, and the mixture was stirred for 0.5 hours. This solution was then added to the above reaction system, and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated and (R)-4-((1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyridine[4,3-d]pyrimidine-7(6H)-one (I-2, white solid, 25 mg, yield: 6.2%) was obtained under acidic manufacturing conditions B.

[0266] 1 H NMR (400MHz, DMSO-d6) δ9.18 (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).

[0267] LC-MS, M / Z (ESI): 503.4 [M+H] + . Example 3: Synthesis of Compound I-3 The synthesis route is as follows:

[0268] [ka] Step 1: Synthesis of 1-(3-(pentafluorosulfanyl)phenyl)ethane-1-one (B3-2)

[0269] [ka]

[0270] At room temperature, compound 3-bromo-(pentafluorosulfanyl)benzene (3.00 g, 10.6 mmol) was added to dioxane (100 mL), bis(triphenylphosphine)palladium(II) dichloride (744 mg, 1.06 mmol) and tributyl(1-ethoxyvinyl) stannane (4.20 g, 11.7 mmol) were added, and the mixture was heated to 90°C under N2 protection and stirred for 14 hours. After cooling to room temperature, 2N hydrochloric acid (100 mL) was added and the mixture was stirred for 4 hours. Extraction was performed with ethyl acetate (200 mL x 3), the liquid was separated, the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 8:1), yielding 1-(3-(pentafluorosulfanyl)phenyl)ethane-1-one (B3-2, yellow liquid, 2.4 g, yield: 89%).

[0271] LC-MS, M / Z (ESI): 247.0 [M+H] + . Step 2: Synthesis of (S,E)-2-methyl-N-(1-(3-(pentafluorosulfanyl)phenyl)ethylene)propane-2-sulfinamide (B3-3)

[0272] [ka]

[0273] At room temperature, compound 1-(3-(pentafluorosulfanyl)phenyl)ethane-1-one (1.0 g, 4.06 mmol) was added to THF (150 mL), (S)-tert-butylsulfinamide (492 mg, 4.06 mmol) and tetraethyl titanate (1.14 g, 5.0 mmol) were added, and the mixture was heated to 70°C and stirred for 16 hours. The mixture was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (100 mL x 3), the liquid was separated, the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 4:1), obtaining (S,E)-2-methyl-N-(1-(3-(pentafluorosulfanyl)phenyl)ethylene)propan-2-sulfinamide (B3-3, white solid, 1.42 g, yield: 100%).

[0274] LC-MS, M / Z (ESI): 350.2 [M+H] + . Step 3: Synthesis of (S)-2-methyl-N-((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)propan-2-sulfinamide (B3-4)

[0275] [ka]

[0276] At room temperature, the starting material (S,E)-2-methyl-N-(1-(3-(pentafluorosulfanyl)phenyl)ethylene)propane-2-sulfinamide (1.5 g, 4.3 mmol) was added to methanol (30 mL), cooled to 0°C, and NaBH4 (744 mg, 20.1 mmol) was added to the methanol in batches. The mixture was heated to room temperature and stirred for 3 hours. The reaction mixture was concentrated and purified by TLC plate to obtain (S)-2-methyl-N-((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)propane-2-sulfinamide (B3-4, white solid, 600 mg, yield: 40.0%).

[0277] LC-MS, M / Z (ESI): 352.1 [M+H] + . Step 4: Synthesis of (R)-1-(3-(pentafluorosulfanyl)phenyl)ethane-1-amine hydrochloride (B3-5)

[0278] [ka]

[0279] At room temperature, the starting material (R)-2-methyl-N-((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)propan-2-sulfinamide (600 mg, 1.70 mmol) was added to a 4 mol / L hydrogen chloride-dioxane solution (10 mL) and stirred for 4 hours. The reaction mixture was concentrated, methyl tert-butyl ether (20 mL) was added, and the mixture was stirred for 1 hour. The mixture was then filtered to obtain (R)-1-(3-(pentafluorosulfanyl)phenyl)ethane-1-amine hydrochloride (B3-5, white solid, 350 mg, yield: 72.7%).

[0280] LC-MS, M / Z (ESI): 248.2 [M+H] + . Step 5: Synthesis of (R)-6-(1-(fluoromethyl)cyclopropyl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-7(6H)-one(I-3)

[0281] [ka]

[0282] At room temperature, the starting material 6-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyridine[4,3-d]pyrimidine-7(6H)-one (A1) (200 mg, 0.80 mmol) was added to acetonitrile (20 mL), potassium phosphate (678 mg, 3.20 mmol) and phosphonitrile chloride trimer (416 mg, 1.20 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The starting material (R)-1-(3-(pentafluorosulfanyl)phenyl)ethane-1-amine hydrochloride (160 mg, 0.56 mmol) was added to DCM (10 mL), DIPEA (2 mL) was added, and the mixture was stirred for 0.5 hours. This solution was then added to the above reaction system, and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated and (R)-6-(1-(fluoromethyl)cyclopropyl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-7(6H)-one (I-3, white solid, 44 mg, yield: 16.4%) was obtained under acidic manufacturing conditions B.

[0283] 1 H NMR (400MHz, DMSO-d6) δ9.18 (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).

[0284] LC-MS, M / Z (ESI): 479.4 [M+H] + . Example 4: Synthesis of Compound I-4 The synthesis of compound I-4 followed the method for synthesizing compound I-1, replacing sodium bromodifluoroacetate with trifluoroiodomethane in step 3 to obtain (R)-6-(1-(fluoromethyl)cyclopropyl)-2-methyl-4-((1-(2-methyl-3-((trifluoromethyl)sulfonyl)phenyl)ethyl)amino)pyridyl[4,3-d]pyrimidine 7(6H)-one (I-4). LC-MS, M / Z (ESI): 499.1 [M+H] + .

[0285] [ka]

[0286] Example 5: Synthesis of Compound I-5 The synthesis of compound I-5 followed the method for synthesizing compound I-1, but 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-methylpyridine[4,3-d]pyrimidine-7(6H)-one (I-5). 1 H NMR (400MHz, DMSO-d6) δ9.17 (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). LC-MS,M / Z (ESI): 485.0[M+H] + .

[0287] [ka]

[0288] Example 6: Synthesis of Compound I-6 The synthesis route is as follows:

[0289] [ka]

[0290] 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]pyrimidine-7(6H)-one(I-6) was obtained. LC-MS, M / Z (ESI): 495.2[M+H] + .

[0291] Example 7: Synthesis of Compound I-7 The synthesis route is as follows:

[0292] [ka]

[0293] Compound (R)-4-((1-(3-(cyclopropylsulfonyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methylpyrido[4,3-d]pyrimidine-7(6H)-one(I-7) was obtained. LC-MS, M / Z (ESI): 493.2 [M+H] + .

[0294] Example 8: Synthesis of Compound I-8 The synthesis route is as follows:

[0295] [ka]

[0296] Step 1: ((3-bromo-2-fluorophenyl)imino)dimethylsulfanone (B8-2)

[0297] [ka]

[0298] At room temperature, compound 1-bromo-2-fluoro-3-iodobenzene (1.00 g, 3.32 mmol) was added to dioxane (50 ml), and 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-bisdiphenylphosphine-9,9-dimethylxanthene (384 mg, 0.664 mmol) were added. The mixture was heated to 105°C under N2 protection and stirred for 3 hours. The mixture was cooled to room temperature, water (100 ml) was added, and the mixture was extracted with ethyl acetate (200 mL x 3). The liquid was separated, the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain the title compound ((3-bromo-2-fluorophenyl)imino)dimethylsulfanone as a yellow solid (B8-2) (500 mg, yield: 56.6%).

[0299] Step 2: ((3-acetyl-2-fluorophenyl)imino)dimethylsulfanone (B8-3)

[0300] [ka]

[0301] At room temperature, the compound ((3-bromo-2-fluorophenyl)imino)dimethylsulfanone (460 mg, 1.73 mmol) was added to dioxane (30 ml), bis(triphenylphosphine)palladium(II) dichloride (122 mg, 0.173 mmol) and tributyl(1-ethoxyvinyl) stannane (628 g, 1.73 mmol) were added, and the mixture was heated to 90°C under N2 protection and stirred for 14 hours. After cooling to room temperature, 2N hydrochloric acid (10 mL) was added and the mixture was stirred for 4 hours. Extraction was performed with ethyl acetate (50 mL x 3), the liquid was separated, the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain the title compound ((3-acetyl-2-fluorophenyl)imino)dimethylsulfanone as a yellow liquid (B8-3) (340 mg, yield: 85%).

[0302] Step 3: (S,E)-N-(1-(3-((dimethyl(oxo)sulfonyl)amino)-2-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide(B8-4)

[0303] [ka]

[0304] At room temperature, the compound ((3-acetyl-2-fluorophenyl)imino)dimethylsulfanone (340 mg, 1.50 mmol) was added to THF (15 mL), (S)-tert-butylsulfinamide (856 mg, 2.25 mmol) and tetraethyl titanate (273 mg, 3.75 mmol) were added, and the mixture was heated to 70°C and stirred for 16 hours. The solution was cooled to room temperature, diluted with water (100 ml), extracted with ethyl acetate (50 mL x 3), the liquid was separated, the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain the title compound (S,E)-N-(1-(3-((dimethyl(oxo)sulfonyl)amino)-2-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide) as a yellow solid (B8-4) (600 mg, yield >100%).

[0305] LC-MS, M / Z (ESI): 333.4[M+H] + . Step 4: (S)-N-((R)-1-(3-((dimethyl(oxo)sulfonyl)amino)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(B8-5)

[0306] [ka]

[0307] At room temperature, the starting material (S,E)-N-(1-(3-((dimethyl(oxo)sulfonyl)amino)-2-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide (600 mg, 1.8 mmol) was added to methanol (30 mL), cooled to 0°C, and sodium borohydride (96 mg, 2.5 mmol) was added to the methanol in batches. The mixture was heated to room temperature and stirred for 3 hours. The reaction mixture was concentrated and purified on a TLC plate (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain the title compound, the white solid (S)-N-((R)-1-(3-((dimethyl(oxo)sulfonyl)amino)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (B8-5) (200 mg, yield: 33.0%).

[0308] Step 5: (R)-((3-(1-aminoethyl)-2-fluorophenyl)imino)dimethylsulfanone hydrochloride (B8-6)

[0309] [ka]

[0310] At room temperature, the starting material (S)-N-((R)-1-(3-((dimethyl(oxo)sulfonyl)amino)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (200 mg, 0.60 mmol) was added to a 4 mol / L hydrogen chloride-dioxane solution (10 mL) and stirred for 4 hours. The reaction mixture was concentrated, methyl tert-butyl ether (20 mL) was added, and the mixture was stirred for 1 hour. The mixture was then filtered to obtain the title compound, the white solid (R)-((3-(1-aminoethyl)-2-fluorophenyl)imino)dimethylsulfanone hydrochloride (B8-6) (100 mg, yield: 62.9%).

[0311] LC-MS, M / Z (ESI): 231.2[M+H] + Step 6: (R)-6-(1-(difluoromethyl)cyclopropyl)-4-((1-(3-((dimethyl(oxo)sulfonyl)amino)-2-fluorophenyl)ethyl)amino)-2-methylpyridine[4,3-d]pyrimidine-7(6H)-one

[0312] [ka]

[0313] At room temperature, the starting material 6-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyridine[4,3-d]pyrimidine-7(6H)-one (200 mg, 0.80 mmol) was added to acetonitrile (20 mL), potassium phosphate (678 mg, 3.20 mmol) and phosphonitrile chloride trimer (416 mg, 1.20 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The starting material (R)-((3-(1-aminoethyl)-2-fluorophenyl)imino)dimethylsulfanone hydrochloride (149 mg, 0.56 mmol) was added to DCM (10 mL), DIPEA (2 mL) was added, and the mixture was stirred for 0.5 hours. This solution was then added to the above reaction system, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated and purified by silica gel column (dichloromethane:methanol (V / V) = 10:1) to obtain the title compound as a white solid (R)-6-(1-(difluoromethyl)cyclopropyl)-4-((1-(3-((dimethyl(oxo)sulfonyl)amino)-2-fluorophenyl)ethyl)amino)-2-methylpyridine[4,3-d]pyrimidine-7(6H)-one (9 mg, yield: 3.35%).

[0314] 1 H NMR (400MHz, DMSO-d6) δ9.17 (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). LC-MS, M / Z (ESI): 480.4[M+H] + .

[0315] Example 9: Synthesis of Compound I-9 The synthesis route is as follows:

[0316] [ka]

[0317] Compound (R)-4-((1-(3-((1,1-difluoroethyl)sulfonyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methylpyridine[4,3-d]pyrimidine 7(6H)-one(I-9) was obtained. LC-MS, M / Z (ESI): 517.2 [M+H] + .

[0318] Example 10: Synthesis of Compound I-10

[0319] [ka]

[0320] The synthesis method for compound I-10 followed the procedure for compound I-9, yielding compound (R)-6-(1-(difluoromethyl)cyclopropyl)-4-((1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethyl)amino)-2-methylpyridine[4,3-d]pyrimidine-7(6H)-one (I-10). LC-MS, M / Z (ESI): 521.2 [M+H] + .

[0321] Example 11: Synthesis of Compound I-11 The synthesis route is as follows:

[0322] [ka]

[0323] The synthesis of intermediate B11-1 followed the synthesis of intermediate A1, but with 1-(fluoromethyl)cyclopropane-1-amine hydrochloride replaced by the starting material 1-methylcyclopropylamine hydrochloride. The starting material 4-hydroxy-2-methyl-6-(1-methylcyclopropyl)pyrido[4,3-d]pyrimidine-7(6H)-one (B11-1) (100 mg, 0.43 mmol) was added to acetonitrile (10 ml), and then 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) were added. The mixture was stirred at room temperature for 24 hours, and then phosphonitrile chloride trimer (150 mg, 0.43 mmol) and triethylamine (137 mg, 1.29 mmol) were added. The mixture was continued stirring at room temperature for another 24 hours. The solution was concentrated under reduced pressure, and a white solid (R)-4-((1-(2-fluoro-3-((trifluoromethyl)sulfonyl)phenyl)ethyl)amino)-2-methyl-6-(1-methylcyclopropyl)pyridine[4,3-d]pyrimidine-7(6H)-one(I-11) (48 mg, yield: 22.9%) was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1).

[0324] 1 H NMR (400 MHz, DMSO) δ 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). LC-MS, M / Z (ESI): 485.5 [M+H] + .

[0325] Example 12: Synthesis of Compound I-12 The synthesis route is as follows:

[0326] [ka]

[0327] Step 1: 1-Bromo-3-(difluoromethoxy)-2-fluorobenzene(B12-2)

[0328] [ka]

[0329] At room temperature, compound 3-bromo-2-fluorophenol (7.20 g, 37.6 mmol) was added to DMF (100 ml), cesium carbonate (26.7 g, 75.2 mmol) and sodium bromodifluoroacetate (8.89 g, 45.1 mmol) were added, and the mixture was heated to 100°C and stirred for 2 hours. After cooling to room temperature, water (300 ml) was added, and the mixture was extracted with ethyl acetate (200 mL x 3). The liquid was separated, the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 8:1) to obtain the title compound 1-bromo-3-(difluoromethoxy)-2-fluorobenzene as a yellow liquid (035B) (5.0 g, yield: 55.2%).

[0330] Step 2: 1-(3-(difluoromethoxy)-2-fluorophenyl)ethane-1-one (B12-3)

[0331] [ka]

[0332] At room temperature, compound 1-bromo-3-(difluoromethoxy)-2-fluorobenzene (4.60 g, 19.0 mmol) was added to dioxane (100 mL), bis(triphenylphosphine)palladium(II) dichloride (2.13 g, 1.52 mmol) and tributyl(1-ethoxyvinyl) stannane (6.85 g, 19.0 mmol) were added, and the mixture was heated to 90°C under N2 protection and stirred for 14 hours. After cooling to room temperature, 2N hydrochloric acid (100 mL) was added and the mixture was stirred for 4 hours. Extraction was performed with ethyl acetate (200 mL x 3), the liquid was separated, the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain the yellow liquid 1-(3-(difluoromethoxy)-2-fluorophenyl)ethane-1-one (2.40 g, yield: 72%) of the title compound.

[0333] Step 3: (S,E)-N-(1-(3-(difluoromethoxy)-2-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide

[0334] [ka]

[0335] At room temperature, compound 1-(3-(difluoromethoxy)-2-fluorophenyl)ethane-1-one (5.0 g, 25.0 mmol) was added to THF (150 mL), (S)-tert-butylsulfinamide (4.55 g, 37.5 mmol) and tetraethyl titanate (14.3 g, 62.5 mmol) were added, and the mixture was heated to 70°C and stirred for 16 hours. The solution was cooled to room temperature, diluted with water (300 ml), extracted with ethyl acetate (200 mL x 3), the liquid was separated, the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain the yellow liquid (S,E)-N-(1-(3-(difluoromethoxy)-2-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide (8.50 g, yield: 100%) of the title compound.

[0336] LC-MS, M / Z (ESI): 308.2[M+H] + . Step 4: (S)-N-((R)-1-(3-(difluoromethoxy)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(B12-5)

[0337] [ka]

[0338] At room temperature, the starting material (S,E)-N-(1-(3-(difluoromethoxy)-2-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide (8.5 g, 27.6 mmol) was added to methanol (100 mL), cooled to 0°C, and sodium borohydride (1.50 g, 39.3 mmol) was added to the methanol in batches. The mixture was heated to room temperature and stirred for 3 hours. The reaction mixture was concentrated and purified on a TLC plate (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain the colorless liquid (S)-N-((R)-1-(3-(difluoromethoxy)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (2.0 g, yield: 23.5%) of the title compound.

[0339] 1 H-NMR (400MHz, DMSO-d6) δ7.38-7.20 (m, 3H), 7.25(t, 1H), 5.53(d, 1H), 4.71-4.68(m, 1H), 1.49(d, 3H), 1.09(s, 9H). LC-MS, M / Z (ESI): 310.1[M+H] + Step 5: (R)-1-(3-(difluoromethoxy)-2-fluorophenyl)ethane-1-amine hydrochloride

[0340] [ka]

[0341] At room temperature, the starting material (S)-N-((R)-1-(3-(difluoromethoxy)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (2.0 g, 6.45 mmol) was added to a 4 mol / L hydrogen chloride-dioxane solution (50 mL) and stirred for 4 hours. The reaction mixture was concentrated, methyl tert-butyl ether (50 mL) was added, and the mixture was stirred for 1 hour. The mixture was then filtered to obtain the title compound, a white solid (R)-1-(3-(difluoromethoxy)-2-fluorophenyl)ethane-1-amine hydrochloride (1.0 g, yield: 64.1%).

[0342] LC-MS, M / Z (ESI): 206.2[M+H] + Step 6: (R)-4-((1-(3-(difluoromethoxy)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methylpyridine[4,3-d]pyrimidine-7(6H)-one

[0343] [ka]

[0344] At room temperature, the starting material 6-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyridine[4,3-d]pyrimidine-7(6H)-one (200 mg, 0.80 mmol) was added to acetonitrile (20 mL), potassium phosphate (678 mg, 3.20 mmol) and phosphonitrile chloride trimer (416 mg, 1.20 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The starting material (R)-1-(3-(difluoromethoxy)-2-fluorophenyl)ethane-1-amine hydrochloride (181 mg, 0.75 mmol) was added to DCM (10 mL), DIPEA (2 mL) was added, and the mixture was stirred for 0.5 hours. This solution was then added to the above reaction system, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated, and the title compound was obtained as a white solid (R)-4-((1-(3-(difluoromethoxy)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methylpyridine[4,3-d]pyrimidine-7(6H)-one (15 mg, yield: 4.4%) by silica gel column chromatography (dichloromethane:methanol = 50:1 to 10:1).

[0345] 1 H NMR (400MHz, DMSO-d6) δ9.16 (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). LC-MS, M / Z (ESI): 455.3[M+H] + .

[0346] Example 13: Synthesis of Compound I-13 The synthesis route is as follows:

[0347] [ka]

[0348] Step 1: Synthesis of (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)-N-(1-(methoxymethyl)cyclopropyl)acetamide (B13-1)

[0349] [ka]

[0350] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)acetic acid (243 mg, 0.52 mmol) was dissolved in a mixture of dimethyl sulfoxide (2 ml) and acetonitrile (1 ml), and 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) were added, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was diluted with ethyl acetate (10 ml), washed with water (10 ml x 3), washed with saturated saline solution (10 ml x 3), concentrated the organic phase, and the residue was separated and purified by silica gel column (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)pyrimidine-4-yl)-N-(1-(methoxymethyl)cyclopropyl)acetamide (B13-1) (70 mg, yield: 24.5%).

[0351] LC-MS, M / Z (ESI): 553.2[M+H] + . Step 2: Synthesis of (R)-6-(1-(methoxymethyl)cyclopropyl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-7(6H)-one(I-13)

[0352] [ka]

[0353] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)-N-(1-(methoxymethyl)cyclopropyl)acetamide (70 mg, 0.13 mmol) was dissolved in isopropanol (2 ml), 2 M hydrochloric acid (1 ml) was added, and the mixture was stirred at 50°C for 4 hours. After the reaction was complete, the mixture was concentrated, and the residue was separated and purified by silica gel column (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]pyrimidine-7(6H)-one (I-13, 40 mg, yield: 56.3%).

[0354] 1 HNMR (400MHz, CDCl3) δ8.28 (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).

[0355] LC-MS, M / Z (ESI): 491.2[M+H] + . Example 14: Synthesis of Compound I-14 The synthesis route is as follows:

[0356] [ka]

[0357] Step 1: Synthesis of (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)-N-(3-methyloxetan-3-yl)acetamide (B14-1)

[0358] [ka]

[0359] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)acetic acid (583 mg, 1.24 mmol) was dissolved in a mixed solution of dimethyl sulfoxide (2 ml) and acetonitrile (1 ml), and 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) were added, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was diluted with ethyl acetate (10 ml), washed with water (10 ml x 3), washed with saturated saline solution (10 ml x 3), concentrated the organic phase, and the residue was separated and purified by silica gel column (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)pyrimidine-4-yl)-N-(3-methyloxetan-3-yl)acetamide (B14-1) (300 mg, yield: 44.9%).

[0360] LC-MS, M / Z (ESI): 539.1[M+H] + . Step 2: (R)-2-methyl-6-(3-methyloxetan-3-yl)-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyridine[4,3-d]pyrimidine-7(6H)-one(I-14)

[0361] [ka]

[0362] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)-N-(3-methyloxetan-3-yl)acetamide (300 mg, 0.56 mmol) was dissolved in isopropanol (2 ml), 2 M hydrochloric acid (1 ml) was added, and the mixture was stirred at 50°C for 4 hours. After the reaction was complete, the mixture was concentrated, and the residue was separated and purified using a silica gel column (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)pyridine[4,3-d]pyrimidine-7(6H)-one (I-14, 150 mg, yield: 56.6%).

[0363] 1 HNMR (400MHz, CDCl3) δ11.01 (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).

[0364] LC-MS, M / Z (ESI): 477.1[M+H] + . Example 15: Synthesis of Compound I-15 The synthesis route is as follows:

[0365] [ka]

[0366] Step 1: Synthesis of 2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)-N-((1r,3R)-3-hydroxy-3-methylcyclobutyl)acetamide (B15-1)

[0367] [ka]

[0368] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)acetic acid (400 mg, 0.83 mmol) was dissolved in a mixed solution of dimethyl sulfoxide (2 ml) and acetonitrile (1 ml). 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) were added, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was diluted with ethyl acetate (10 ml), washed with water (10 ml x 3), washed with saturated saline solution (10 ml x 3), concentrated the organic phase, and the residue was separated and purified by silica gel column (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)pyrimidine-4-yl)-N-((1r,3R)-3-hydroxy-3-methylcyclobutyl)acetamide (B15-1) (300 mg, yield: 65.6%).

[0369] LC-MS, M / Z (ESI): 553.1[M+H] + . Step 2: Synthesis of 6-((1r,3R)-3-hydroxy-3-methylcyclobutyl)-2-methyl-4-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyridine[4,3-d]pyrimidine-7(6H)-one(I-15)

[0370] [ka]

[0371] 2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)-N-((1r,3R)-3-hydroxy-3-methylcyclobutyl)acetamide (300 mg, 0.54 mmol) was dissolved in isopropanol (2 ml), 2 M hydrochloric acid (1 ml) was added, and the mixture was stirred at 50°C for 4 hours. After the reaction was complete, the mixture was concentrated, and the residue was separated and purified by silica gel column (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)pyridine[4,3-d]pyrimidine-7(6H)-one (I-15, 140 mg, yield: 52.6%).

[0372] 1 HNMR (400MHz, DMSO-d6) δ8.94 (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).

[0373] LC-MS, M / Z (ESI): 491.1[M+H]+ . Example 16: Synthesis of Compound I-16 The synthesis route is as follows:

[0374] [ka]

[0375] Step 1: Synthesis of (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)-N-(3,3-difluorocyclobutyl)acetamide (B16-1)

[0376] [ka]

[0377] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)acetic acid (291 mg, 0.62 mmol) was dissolved in a mixture of dimethyl sulfoxide (2 ml) and acetonitrile (1 ml), and triethylamine (0.17 ml, 1.24 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (354 mg, 0.93 mmol) and 3,3-difluorocyclobutylamine (116 mg, 0.80 mmol) were added, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was diluted with ethyl acetate (10 ml), washed with water (10 ml x 3), washed with saturated saline solution (10 ml x 3), concentrated the organic phase, and the residue was separated and purified by silica gel column (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)pyrimidine-4-yl)-N-(3,3-difluorocyclobutyl)acetamide (B16-1) (300 mg, yield: 86.4%).

[0378] LC-MS, M / Z (ESI): 559.1[M+H] + . Step 2: Synthesis of (R)-6-(3,3-difluorocyclobutyl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyridine[4,3-d]pyrimidine-7(6H)-one(I-16)

[0379] [ka]

[0380] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)-N-(3,3-difluorocyclobutyl)acetamide (300 mg, 0.54 mmol) was dissolved in isopropanol (2 ml), 2 M hydrochloric acid (1 ml) was added, and the mixture was stirred at 50°C for 4 hours. After the reaction was complete, the mixture was concentrated, and the residue was separated and purified by silica gel column (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)pyridine[4,3-d]pyrimidine-7(6H)-one (I-16, 150 mg, yield: 56.2%).

[0381] 1 HNMR (400MHz, CDCl3) δ8.89 (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). LC-MS, M / Z (ESI): 497.1[M+H] + .

[0382] Example 17: Synthesis of Compound I-17 The synthesis route is as follows:

[0383] [ka]

[0384] Step 1: Synthesis of 4-(((benzyloxy)carbonyl)amino)-4-methylpiperidine-1-carboxylate tert-butyl (B17-2)

[0385] [ka]

[0386] 4-amino-4-methylpiperidine-1-carboxylate tert-butyl (4g, 18.67 mmol) was dissolved in a mixed solution of dioxane (20 ml) and water (20 ml). Sodium bicarbonate (4.7 g, 56.0 mmol) and benzyl carbonate (2,5-dioxopyrrolidine-1-yl) (9.3 g, 37.3 mmol) were added, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, ethyl acetate (100 ml) was added to dilute the mixture, washed with water (100 ml x 3), and then washed with saturated brine (100 ml x 3). The organic phase was concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain the title compound 4-(((benzyloxy)carbonyl)amino)-4-methylpiperidine-1-carboxylate tert-butyl (B17-2) (6.4 g, yield: 98%).

[0387] LC-MS, M / Z (ESI): 349.2[M+H] + . Step 2: Synthesis of benzyl (4-methylpiperidine-4-yl)carbamate (B17-3)

[0388] [ka]

[0389] 4-(((benzyloxy)carbonyl)amino)-4-methylpiperidine-1-carboxylate tert-butyl (6.4 g, 18.37 mmol) was dissolved in a 4 M solution of dioxane hydrogen chloride (9.18 ml), stirred at room temperature for 12 hours, and after the reaction was complete, the mixture was concentrated to obtain the title compound (4-methylpiperidine-4-yl)carbamate benzyl (B17-3) (5.23 g, yield: 100%).

[0390] LC-MS, M / Z (ESI): 249.1[M+H] + . Step 3: Synthesis of (1-acetyl-4-methylpiperidine-4-yl)benzyl carbamate (B17-4)

[0391] [ka]

[0392] (4-methylpiperidine-4-yl)benzyl carbamate (5.23 g, 21.06 mmol) was dissolved in dichloromethane (50 ml), triethylamine (8.81 ml, 63.2 mmol) and acetic anhydride (3.23 g, 31.6 mmol) were added, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was diluted with dichloromethane (50 ml), washed with water (100 ml x 3), washed with saturated brine (100 ml x 3), the organic phase was concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain the title compound (1-acetyl-4-methylpiperidine-4-yl)benzyl carbamate (B17-4) (4 g, yield: 65.3%).

[0393] LC-MS, M / Z (ESI): 291.2[M+H] + . Step 4: Synthesis of 1-(4-amino-4-methylpiperidine-1-yl)ethane-1-one (B17-5)

[0394] [ka]

[0395] (1-acetyl-4-methylpiperidine-4-yl)carbamate benzyl (4 g, 13.78 mmol) was dissolved in methanol (40 ml), moist palladium carbon (1 g, 10%) was added, and the mixture was stirred at room temperature under a hydrogen gas atmosphere for 12 hours. After the reaction was complete, the mixture was filtered to obtain the title compound 1-(4-amino-4-methylpiperidine-1-yl)ethane-1-one (B17-5) (1.46 g, yield: 100%).

[0396] LC-MS, M / Z (ESI): 157.1[M+H] + . Step 5: Synthesis of (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)-N-(1-acetyl-4-methylpiperidine-4-yl)acetamide (B17-6)

[0397] [ka]

[0398] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)acetic acid (583 mg, 1.24 mmol) was dissolved in a mixed solution of dimethyl sulfoxide (2 ml) and acetonitrile (1 ml). 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-methylpiperidine-1-yl)ethane-1-one (291 mg, 1.86 mmol) were added, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was diluted with ethyl acetate (10 ml), washed with water (10 ml x 3), washed with saturated saline solution (10 ml x 3), concentrated the organic phase, and the residue was separated and purified by silica gel column (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)pyrimidine-4-yl)-N-(1-acetyl-4-methylpiperidine-4-yl)acetamide (B17-6) (150 mg, yield: 20.0%).

[0399] LC-MS, M / Z (ESI): 608.2[M+H] + . Step 6: Synthesis of (R)-6-(1-acetyl-4-methylpiperidine-4-yl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-7(6H)-one(I-17)

[0400] [ka]

[0401] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)-N-(1-acetyl-4-methylpiperidine-4-yl)acetamide (150 mg, 0.25 mmol) was dissolved in isopropanol (2 ml), 2 M hydrochloric acid (1 ml) was added, and the mixture was stirred at 50°C for 4 hours. After the reaction was complete, the mixture was concentrated, and the residue was separated and purified using a silica gel column (dichloromethane:methanol (V / V) = 10:1) to obtain the title compound (R)-6-(1-acetyl-4-methylpiperidine-4-yl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-7(6H)-one (I-17, 100 mg, yield: 74.0%).

[0402] 1 HNMR (400MHz, DMSO-d6) δ8.79 (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).

[0403] LC-MS, M / Z (ESI): 546.1[M+H] + . Example 18: Synthesis of Compound I-18 The synthesis route is as follows:

[0404] [ka]

[0405] Step 1: Synthesis of 3-(((benzyloxy)carbonyl)amino)-3-methylpyrrolidine-1-carboxylate tert-butyl(B18-2)

[0406] [ka]

[0407] 3-amino-3-methylpyrrolidine-1-carboxylate tert-butyl (2g, 9.99 mmol) was dissolved in a mixed solution of dioxane (10 ml) and water (10 ml). Sodium bicarbonate (2.52 g, 30.0 mmol) and benzyl carbonate (2,5-dioxopyrrolidine-1-yl) (4.98 g, 19.97 mmol) were added, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, ethyl acetate (50 ml) was added to dilute the mixture, washed with water (50 ml x 3), and then washed with saturated brine (50 ml x 3). The organic phase was concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain the title compound 3-(((benzyloxy)carbonyl)amino)-3-methylpyrrolidine-1-carboxylate tert-butyl (B18-2) (3.3 g, yield: 98.8%).

[0408] LC-MS, M / Z (ESI): 335.2[M+H] + . Step 2: Synthesis of benzyl (3-methylpyrrolidine-3-yl)carbamate (B18-3)

[0409] [ka]

[0410] 3-(((benzyloxy)carbonyl)amino)-3-methylpyrrolidine-1-carboxylate tert-butyl (3.3 g, 9.87 mmol) was dissolved in a 4 M dioxane hydrogen chloride solution (8 ml), stirred at room temperature for 12 hours, and after the reaction was complete, the mixture was concentrated to obtain the title compound (3-methylpyrrolidine-3-yl)carbamate benzyl (B18-3) (2.6 g, yield: 97%).

[0411] LC-MS, M / Z (ESI): 235.1[M+H] + . Step 3: Synthesis of benzyl (1-acetyl-3-methylpyrrolidine-3-yl)carbamate (B18-4)

[0412] [ka]

[0413] Benzyl (3-methylpyrrolidine-3-yl)carbamate (2.6 g, 11.10 mmol) was dissolved in dichloromethane (50 ml), triethylamine (4.64 ml, 33.3 mmol) and acetic anhydride (2.27 g, 22.19 mmol) were added, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was diluted with dichloromethane (50 ml), washed with water (100 ml x 3), washed with saturated brine (100 ml x 3), the organic phase was concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain the title compound (1-acetyl-3-methylpyrrolidine-3-yl)carbamate benzyl (B18-4) (2.4 g, yield: 78.2%).

[0414] LC-MS, M / Z (ESI): 277.1[M+H] + . Step 4: Synthesis of 1-(3-amino-3-methylpyrrolidine-1-yl)ethane-1-one (B18-5)

[0415] [ka]

[0416] (1-acetyl-3-methylpyrrolidine-3-yl)benzyl carbamate (2.4 g, 8.69 mmol) was dissolved in methanol (24 ml), moist palladium carbon (240 mg, 10%) was added, and the mixture was stirred at room temperature under a hydrogen gas atmosphere for 12 hours. After the reaction was complete, the mixture was filtered and concentrated to obtain the title compound 1-(3-amino-3-methylpyrrolidine-1-yl)ethane-1-one (B18-5) (1.23 g, yield: 100%).

[0417] LC-MS, M / Z (ESI): 143.1[M+H] + . Step 5: Synthesis of 2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)-N-(1-acetyl-3-methylpyrrolidine-3-yl)acetamide (B18-6)

[0418] [ka]

[0419] (R)-2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)acetic acid (583 mg, 1.24 mmol) was dissolved in a mixture of dimethyl sulfoxide (2 ml) and acetonitrile (1 ml), and 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-methylpyrrolidine-1-yl)ethane-1-one (176 mg, 1.24 mmol) were added, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was diluted with ethyl acetate (10 ml), washed with water (10 ml x 3), washed with saturated saline solution (10 ml x 3), concentrated the organic phase, and the residue was separated and purified by silica gel column (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)pyrimidine-4-yl)-N-(1-acetyl-3-methylpyrrolidine-3-yl)acetamide (B18-6) (100 mg, yield: 13.6%).

[0420] LC-MS, M / Z (ESI): 594.2[M+H] + . Step 6: Synthesis of 6-(1-acetyl-3-methylpyrrolidine-3-yl)-2-methyl-4-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-7(6H)-one(I-18)

[0421] [ka]

[0422] 2-(5-(1,3-dioxolan-2-yl)-2-methyl-6-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrimidine-4-yl)-N-(1-acetyl-3-methylpyrrolidine-3-yl)acetamide (100 mg, 0.17 mmol) was dissolved in isopropanol (2 ml), 2 M hydrochloric acid (1 ml) was added, and the mixture was stirred at 50°C for 4 hours. After the reaction was complete, the mixture was concentrated, and the residue was separated and purified using a silica gel column (dichloromethane:methanol (V / V) = 10:1) to obtain the title compound 6-(1-acetyl-3-methylpyrrolidine-3-yl)-2-methyl-4-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-7(6H)-one (I-18, 80 mg, yield: 88.9.0%).

[0423] 1 HNMR (400MHz, DMSO-d6) δ8.83 (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).

[0424] LC-MS, M / Z (ESI): 532.1[M+H] + . Example 19: Synthesis of Compound I-19 The synthesis route is as follows:

[0425] [ka]

[0426] Step 1: Synthesis of 1-((1r,3r)-3-fluorocyclobutyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate methyl (B19-1)

[0427] [ka]

[0428] At room temperature, dimethyl (Z)-2-((dimethylamino)methylene)-3-oxoglutarate (1.95 g, 9.65 mmol) was added to 2-methyltetrahydrofuran (30 ml), 4N hydrochloric acid (10 ml) was added, and the mixture was stirred for 3 hours. The liquids were separated, the aqueous phase was extracted with ethyl acetate (100 ml x 3), and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, methanol (30 ml) was added, and (1r,3r)-3-fluorocyclobutylamine hydrochloride (1.21 g, 9.65 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Sodium methoxide (1.04 g, 19.29 mmol) was added to the reaction system and the mixture was stirred for 2 hours. The pH was adjusted to 2 with concentrated hydrochloric acid, and the mixture was filtered to obtain the title compound, a white solid crude product, 1-((1r,3r)-3-fluorocyclobutyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate methyl(B19-1) (1.35 g, yield: 58.2%).

[0429] LC-MS, M / Z (ESI): 242.1[M+H] + . Step 2: Synthesis of 1-((1r,3r)-3-fluorocyclobutyl)-6-oxo-4-(toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylate methyl (B19-2)

[0430] [ka]

[0431] At room temperature, 1.35 g, 5.60 mmol of methyl 1-((1r,3r)-3-fluorocyclobutyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (methyl 1.35 g, 5.60 mmol) was added to acetonitrile (20 ml), cooled to 0°C, and triethylamine (1.56 ml, 11.19 mmol) and p-toluenesulfonyl chloride (1.28 g, 6.72 mmol) were added. The mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was concentrated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1 to 1:1) to obtain the title compound, the white solid 1-((1r,3r)-3-fluorocyclobutyl)-6-oxo-4-(toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylate (methyl 1.65 g, 5.60 mmol), at room temperature.

[0432] LC-MS, M / Z (ESI): 396.1[M+H] + . Step 3: Synthesis of 4-acetamido-1-((1r,3r)-3-fluorocyclobutyl)-6-oxo-1,6-dihydropyridine-3-carboxylate methyl (B19-3)

[0433] [ka]

[0434] At room temperature, 1.2 g, 3.0 mmol of methyl 1-((1r,3r)-3-fluorocyclobutyl)-6-oxo-4-(toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylate was added to 50 ml of dioxane, and potassium phosphate (700 mg, 3.3 mmol), xanthophos (173 mg, 0.3 mmol), and palladium (π-cinnamyl) chloride dimer (212 mg, 0.3 mmol) were added. The mixture was heated under reflux and stirred under N2 protection for 2 hours. The reaction mixture was cooled to room temperature, concentrated, and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 3:1 to 1:1) to obtain the title compound, the white solid 4-acetamido-1-((1r,3r)-3-fluorocyclobutyl)-6-oxo-1,6-dihydropyridine-3-carboxylate methyl (B19-3) (1.4 g, yield: 87%).

[0435] LC-MS, M / Z (ESI): 283.1[M+H] + . Step 4: Synthesis of 6-((1r,3r)-3-fluorocyclobutyl)-4-hydroxy-2-methylpyridine[4,3-d]pyrimidine-7(6H)-one

[0436] [ka]

[0437] At room temperature, methyl 4-acetamido-1-((1r,3r)-3-fluorocyclobutyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (1.4 g, 4.96 mmol) was added to 10 ml of 7 M ammonia-methanol solution and stirred at room temperature for 5 days. The mixture was concentrated to 3 ml, filtered, and the white solid 6-((1r,3r)-3-fluorocyclobutyl)-4-hydroxy-2-methylpyridine[4,3-d]pyrimidine-7(6H)-one (1 g, yield: 81%) of the title compound was obtained.

[0438] LC-MS, M / Z (ESI): 250.1[M+H] + . Step 5: Synthesis of 6-((1r,3R)-3-fluorocyclobutyl)-2-methyl-4-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-7(6H)-one(I-19)

[0439] [ka]

[0440] 6-((1r,3r)-3-fluorocyclobutyl)-4-hydroxy-2-methylpyridine[4,3-d]pyrimidine-7(6H)-one (200 mg, 0.80 mmol) was added to acetonitrile (10 ml), followed by compound (R)-1-(3-(pentafluorosulfanyl)phenyl)ethane-1-amine hydrochloride (250 mg, 0.88 mmol) and anhydrous potassium phosphate (426 mg, 2.0 mmol). The mixture was stirred at room temperature for 24 hours, then phosphonitrile chloride trimer (418 mg, 1.20 mmol) and triethylamine (0.28 ml, 1.60 mmol) were added, and the mixture was stirred at room temperature for another 24 hours. The solution was concentrated under reduced pressure, and a white solid 6-((1r,3R)-3-fluorocyclobutyl)-2-methyl-4-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-7(6H)-one (I-19, 150 mg, yield: 39.1%) was obtained by silica gel column chromatography (dichloromethane:methanol = 50:1 to 10:1).

[0441] 1 HNMR (400MHz, CDCl3) δ8.89 (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).

[0442] LC-MS, M / Z (ESI): 479.1[M+H] + . Example 20: Synthesis of Compound I-20 The synthesis route for the compound is as follows:

[0443] [ka] Step 1: Synthesis of 4-hydroxy-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate methyl (B20-1)

[0444] [ka]

[0445] At room temperature, dimethyl (Z)-2-((dimethylamino)methylene)-3-oxoglutarate (1.3 g, 5.67 mmol) was added to 2-methyltetrahydrofuran (30 ml), 4N hydrochloric acid (10 ml) was added, and the mixture was stirred for 3 hours. The liquids were separated, the aqueous phase was extracted with ethyl acetate (100 ml x 3), and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, methanol (30 ml) was added, and 3-methyltetrahydrofuran-3-amine (0.57 g, 5.67 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Sodium methoxide (0.61 g, 11.34 mmol) was added to the reaction system and the mixture was stirred for 2 hours. The pH was adjusted to 2 with concentrated hydrochloric acid, and the mixture was filtered to obtain the title compound, a white solid crude product, 4-hydroxy-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate methyl (B20-1) (0.7 g, yield: 48.7%).

[0446] LC-MS, M / Z (ESI): 254.1[M+H] + . Step 2: Synthesis of 1-(3-methyltetrahydrofuran-3-yl)-6-oxy-4-(p-toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylate methyl (B20-2)

[0447] [ka]

[0448] At room temperature, 0.7 g, 2.76 mmol of methyl 4-hydroxy-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate was added to 20 ml of acetonitrile, cooled to 0°C, and triethylamine (0.77 ml, 5.53 mmol) and p-toluenesulfonyl chloride (553 mg, 2.90 mmol) were added. The mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was concentrated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1 to 1:1) to obtain the title compound, the white solid 1-(3-methyltetrahydrofuran-3-yl)-6-oxy-4-(p-toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylate methyl (B20-2) (1 g, yield: 89%).

[0449] LC-MS, M / Z (ESI): 408.1[M+H] + . Step 3: Synthesis of 4-acetamido-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate methyl (B20-3)

[0450] [ka]

[0451] At room temperature, 1-(3-methyltetrahydrofuran-3-yl)-6-oxy-4-(p-toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylate methyl (1 g, 2.45 mmol) was added to dioxane (50 ml), potassium phosphate (0.78 g, 3.68 mmol), xanthophos (142 mg, 0.25 mmol), and palladium (π-cinnamyl) chloride dimer (225 mg, 0.25 mmol) were added, and the mixture was heated under reflux for 2 hours under N2 protection. After cooling to room temperature, the reaction mixture was concentrated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 3:1 to 1:1) to obtain the title compound, the white solid 4-acetamido-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate methyl (B20-3) (0.56 g, yield: 78%).

[0452] LC-MS, M / Z (ESI): 295.1[M+H] + . Step 4: Synthesis of 4-hydroxy-2-methyl-6-(3-methyltetrahydrofuran-3-yl)pyridine[4,3-d]pyrimidine-7(6H)-one

[0453] [ka]

[0454] At room temperature, methyl 4-acetamido-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (560 mg, 1.90 mmol) was added to 10 ml of 7 M ammonia-methanol solution and stirred at room temperature for 12 hours. The mixture was concentrated to 3 ml, filtered, and the white solid 4-hydroxy-2-methyl-6-(3-methyltetrahydrofuran-3-yl)pyridine[4,3-d]pyrimidine-7(6H)-one (B20-4) (350 mg, yield: 70.4%) of the title compound was obtained.

[0455] LC-MS, M / Z (ESI): 262.1[M+H] + . Step 5: Synthesis of 2-methyl-6-(3-methyltetrahydrofuran-3-yl)-4-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-7(6H)-one(I-20)

[0456] [ka]

[0457] 4-hydroxy-2-methyl-6-(3-methyltetrahydrofuran-3-yl)pyridine[4,3-d]pyrimidine-7(6H)-one (350 mg, 1.34 mmol) was added to acetonitrile (10 ml), followed by compound (R)-1-(3-(pentafluorosulfanyl)phenyl)ethane-1-amine hydrochloride (418 mg, 1.47 mmol) and anhydrous potassium phosphate (711 mg, 3.35 mmol). The mixture was stirred at room temperature for 24 hours, then phosphonitrile chloride trimer (699 mg, 2.01 mmol) and triethylamine (0.47 ml, 2.68 mmol) were added, and the mixture was stirred at room temperature for another 24 hours. The solution was concentrated under reduced pressure, and a white solid 2-methyl-6-(3-methyltetrahydrofuran-3-yl)-4-(((R)-1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-7(6H)-one (I-20, 200 mg, yield: 30.4%) was obtained by silica gel column chromatography (dichloromethane:methanol = 50:1 to 10:1).

[0458] 1 HNMR (400MHz, CDCl3) δ8.60 (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).

[0459] LC-MS, M / Z (ESI): 491.1[M+H] + . Example 21: Synthesis of Compound I-21 The synthesis route is as follows:

[0460] [ka]

[0461] Step 1: Synthesis of 4-hydroxy-1-(4-methyltetrahydro-2H-pyran-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate methyl (B21-1)

[0462] [ka]

[0463] At room temperature, compound (Z)-2-((dimethylamino)methylene)-3-oxoglutarate dimethyl (12 g, 52.3 mmol) was added to methanol (60 mL), and 4-methyltetrahydro-2H-pyran-4-amine hydrochloride (7.9 g, 52.3 mmol) was added. The mixture was stirred at room temperature for 16 hours. Sodium methoxide (6.5 g, 120.0 mmol) was added to the reaction system and the mixture was stirred for 2 hours. The pH was adjusted to 2 with concentrated hydrochloric acid, and the mixture was filtered to obtain the brown solid crude product of the title compound, 4-hydroxy-1-(4-methyltetrahydro-2H-pyran-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate methyl (2.2 g, yield: 15.9%).

[0464] LC-MS, M / Z (ESI): 268.1 [M+H] + . Step 2: Synthesis of 1-(4-methyltetrahydro-2H-pyran-4-yl)-6-oxy-4-(methylphenoxy)-1,6-dihydropyridine-3-carboxylate methyl (B21-2)

[0465] [ka]

[0466] At room temperature, the starting material 4-hydroxy-1-(4-methyltetrahydro-2H-pyran-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate methyl (2.2 g, 8.3 mmol) was added to acetonitrile (20 mL), cooled to 0°C, and triethylamine (1.68 g, 16.6 mmol) and p-toluenesulfonyl chloride (1.58 g, 8.3 mmol) were added. The mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was concentrated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1 to 1:1) to obtain the title compound, a white solid 1-(4-methyltetrahydro-2H-pyran-4-yl)-6-oxy-4-(methylphenoxy)-1,6-dihydropyridine-3-carboxylate methyl (1.26 g, yield: 57.2%).

[0467] LC-MS, M / Z (ESI): 422.1 [M+H] + . Step 3: Synthesis of 4-acetamido-1-(4-methyltetrahydro-2H-pyran-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate methyl (B21-3)

[0468] [ka]

[0469] At room temperature, the starting material 1-(4-methyltetrahydro-2H-pyran-4-yl)-6-oxy-4-(methylphenoxy)-1,6-dihydropyridine-3-carboxylate methyl (1.26 g, 3.0 mmol) was added to dioxane (50 mL), potassium phosphate (700 mg, 3.3 mmol), xanthophos (173 mg, 0.3 mmol), and palladium (π-cinnamyl) chloride dimer (212 mg, 0.3 mmol) were added, and the mixture was heated under reflux and stirred under N2 protection for 2 hours. The reaction mixture was cooled to room temperature, concentrated, and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 3:1 to 1:1) to obtain the title compound as a white solid 4-acetamido-1-(4-methyltetrahydro-2H-pyran-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate methyl (742 mg, yield: 79.3%).

[0470] LC-MS, M / Z (ESI): 309.1 [M+H] + . Step 4: Synthesis of 4-hydroxy-2-methyl-6-(4-methyltetrahydro-2H-pyran-4-yl)pyridine[4,3-d]pyrimidine-7(6H)-one (B21-4)

[0471] [ka]

[0472] At room temperature, the starting material methyl 4-acetamido-1-(4-methyltetrahydro-2H-pyran-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (742 mg, 2.41 mmol) was added to 10 mL of 7 mol / L ammonia-methanol solution and stirred at room temperature for 5 days. The mixture was concentrated to 3 ml, filtered, and the title compound, 4-hydroxy-2-methyl-6-(4-methyltetrahydro-2H-pyran-4-yl)pyridine[4,3-d]pyrimidine-7(6H)-one (220 mg, yield: 33.5%), was obtained.

[0473] LC-MS, M / Z (ESI): 276.1 [M+H] + . 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]pyrimidine-7(6H)-one(I-21)

[0474] [ka]

[0475] At room temperature, the starting material 4-hydroxy-2-methyl-6-(4-methyltetrahydro-2H-pyran-4-yl)pyridine[4,3-d]pyrimidine-7(6H)-one (220 mg, 0.80 mmol) was added to acetonitrile (20 mL), potassium phosphate (678 mg, 3.20 mmol) and phosphonitrile chloride trimer (416 mg, 1.20 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The starting material (R)-1-(3-(pentafluorothio)phenyl)ethane-1-amine hydrochloride (246 mg, 0.87 mmol) was added to DCM (10 mL), DIPEA (2 mL) was added, and the mixture was stirred for 0.5 hours. This solution was then added to the above reaction system, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated and obtained by silica gel column chromatography (dichloromethane:methanol = 50:1 to 10:1) as a white solid (R)-2-methyl-6-(4-methyltetrahydro-2H-pyran-4-yl)-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-7(6H)-one (I-21, 40 mg, yield: 9.9%).

[0476] 1H NMR (400MHz, DMSO-d6) δ8.90 (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).

[0477] LC-MS, M / Z (ESI): 505.1 [M+H] + . Example 22: Synthesis of Compound I-22 The synthesis route is as follows:

[0478] [ka]

[0479] The starting material 6-(1-(fluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidine-7(6H)-one(7) (100 mg, 0.43 mmol) was added to acetonitrile (10 ml), and then compound (R)-1-(3-(pentafluorosulfanyl)phenyl)ethane-1-amine hydrochloride (135 mg, 0.48 mmol) and anhydrous potassium phosphate (229 mg, 1.08 mmol) were added. The mixture was stirred at room temperature for 24 hours, and then phosphonitrile chloride trimer (150 mg, 0.43 mmol) and triethylamine (137 mg, 1.29 mmol) were added. The mixture was continued stirring at room temperature for another 24 hours. The solution was concentrated under reduced pressure, and a white solid (R)-2-methyl-6-(1-methylcyclopropyl)-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-7(6H)-one (I-22, 42 mg, yield: 22.1%) was obtained by silica gel column chromatography (dichloromethane:methanol = 50:1 to 10:1).

[0480] [ka]

[0481] 1 H NMR (400 MHz, DMSO) δ 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). LC-MS, M / Z (ESI): 461.5 [M+H] + .

[0482] Example 23: Synthesis of target compound I-23 The synthesis route is as follows:

[0483] [ka]

[0484] Step 1: Synthesis of 1-(1-(difluoromethyl)cyclopropyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate methyl (B23-1)

[0485] [ka]

[0486] Compound (Z)-2-((dimethylamino)methylene)-3-oxoglutarate dimethyl (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 hours. Next, sodium methoxide (1.76 g, 32.58 mmol) was added to the reaction mixture, and the reaction system was stirred at 25°C for 0.5 hours. HCl (1.0 N, 15.0 mL) was added to the reaction system to adjust the pH to 1-2, causing a white solid to precipitate. The mixture was filtered, the cake was washed with 10.0 mL of methanol, and the cake was dried to obtain the white solid compound 1-(1-(difluoromethyl)cyclopropyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate methyl (B23-1) (2.4 g, yield: 42.5%).

[0487] LC-MS, M / Z (ESI): 260.3 [M+H] + Step 2: Synthesis of 1-(1-(difluoromethyl)cyclopropyl)-6-oxo-4-(toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylate methyl (B23-2)

[0488] [ka]

[0489] 1-(1-(difluoromethyl)cyclopropyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate methyl (2.4 g, 9.26 mmol) was dissolved in acetonitrile (24.0 mL), then triethylamine (1.41 g, 13.89 mmol) was added to the reaction system, and p-toluenesulfonyl chloride (1.77 g, 9.26 mmol) was slowly added in batches. The reaction system was stirred at 25°C for 2 hours. The reaction solution was diluted with dichloromethane (20.0 mL), the pH was adjusted to 2-3 with 1N HCl (10.0 mL), and the organic phase was extracted and spin-dried to obtain a pale yellow solid 1-(1-(difluoromethyl)cyclopropyl)-6-oxo-4-(toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylate methyl (B23-2) (3.4 g, yield: 89%).

[0490] LC-MS, M / Z (ESI): 414.5 [M+H] + Step 3: Synthesis of 4-acetamido-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate methyl (B23-3)

[0491] [ka]

[0492] Compound 5 (3.3g, 7.98 mmol), acetamide (707.0 mg, 11.97 mmol), xanthophos (924.0 mg, 1.60 mmol), potassium phosphate (3.39 g, 15.97 mmol), and palladium (π-cinnamyl) chloride dimer (1.46 g, 1.60 mmol) were sequentially added to a 100 mL necked flask, dissolved in dioxane (30.0 mL), and after purging the atmosphere with nitrogen gas three times, the reaction system was heated to 115°C and stirred for 16 hours. After cooling the reaction mixture, it was filtered, the resulting mother liquor was spin-dried and mixed with the sample, and then separated and purified using a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1 to 1:1) to obtain the white solid 4-acetamido-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate methyl (B23-3) (1.6 g, yield: 67%).

[0493] Step 4: 6-(1-(difluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidine-7(6H)-one(B23-4)

[0494] [ka]

[0495] 4-acetamido-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate methyl (1.6 g, 5.33 mmol) was added to a 50.0 mL stew pot and dissolved in ammonia-methanol solution (7 N, 15.0 mL). The reaction system was heated to 50°C and stirred for 12 hours. After cooling the reaction mixture, it was filtered, and the cake was washed with methanol (15.0 mL) to obtain a pale yellow solid 6-(1-(difluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidine-7(6H)-one (B23-4) (900 mg, yield: 63%).

[0496] LC-MS, M / Z (ESI): 268.2 [M+H] + . Step 5: (R)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-7(6H)-one(I-23)

[0497] [ka]

[0498] 6-(1-(difluoromethyl)cyclopropyl)-4-hydroxy-2-methylpyrido[4,3-d]pyrimidine-7(6H)-one (300.0 mg, 1.12 mmol) was dissolved in acetonitrile (15.0 mL), potassium phosphate (596.0 mg, 2.81 mmol) was added, followed by phosphonitrile chloride trimer (585.0 mg, 1.68 mmol), and the mixture was stirred at room temperature for 2 hours. Then, (R)-1-(3-(pentafluorosulfanyl)phenyl)ethane-1-amine hydrochloride (318.0 mg, 1.12 mmol) was added. The reaction was carried out and stirred overnight at room temperature. First, the reaction mixture was filtered, the cake was washed with acetonitrile (15.0 mL), and the filtrate was spin-dried to obtain the crude product. Silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) yielded a pale yellow solid (R)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-4-((1-(3-(pentafluorosulfanyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-7(6H)-one (I-23, 166.0 mg, yield: 30%).

[0499] 1H NMR (400 MHz, DMSO-d6) δ 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).

[0500] LC-MS, M / Z (ESI): 497.2 [M+H] + . In the test examples of the present invention, the preparation of control compound I was carried out with reference to patent WO2019122129A1, and the preparation of control compound II was carried out with reference to patent WO2019122129A1. Its structure is as follows:

[0501] [ka]

[0502] Test Example 1: Inhibition test of compounds against KRAS G12C::SOS1 binding The test compounds were prepared as 10 mM stock solutions using DMSO, and the compounds were gradient diluted using 1X test buffer. 0.1 μL of compound solutions of different concentrations were transferred to a 384-well plate, 5 μL of GST-KRAS G12C was added to the 384-well plate, and the mixture was centrifuged at 1000 rpm for 1 minute. 5 μL of His-SOS1 was added to the 384-well plate, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 15 minutes.

[0503] After the culture was complete, 10 μL of a mixed solution of anti-6his-Tb monoclonal antibody (Cisbio, catalog number: 61HI2TLA) and anti-GST-XL665 monoclonal antibody (Cisbio, catalog number: 61GSTXLA) was added to the test well, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 1 hour.

[0504] After the culture is complete, the ratio of fluorescence signals at wavelengths of 665 nm and 615 nm is read using a multi-function microplate reader (Perkin Elmer, Envision 2104), and IC is calculated using Graphpad5 software. 50 The value was calculated.

[0505] [Table 1]

[0506] The experimental results show that the compound of the present invention has a significant inhibitory effect on KRAS G12C::SOS1 binding. Test Example 2: Inhibition test of compounds on KRAS G12C-SOS1 activity The inhibitory effect of compounds on KRAS G12C-SOS1 was detected using Transcreener® GDP-FI (BellBrook, catalog number: 3014-1K).

[0507] The test compound was prepared as a 10 mM stock solution using DMSO and gradient diluted with 1X test buffer (modified Tris buffer). The resulting compound solution was transferred to a 384-well plate, and the final DMSO content was 0.25%. The DMSO wells that did not contain the compound were set as high-signal controls.

[0508] A 1X test buffer (modified Tris buffer) was prepared, and KRAS G12C (SignalChem, catalog number: R06-32DH-BULK), SOS1 (Cytoskeleton, Inc., catalog number: GE02-XL), and GTP solution (BellBrook, catalog number: 3014-1K) were prepared using the test buffer. 10 μL of KRAS G12C was transferred to a 384-well plate, and another 10 μL of buffer was transferred to an empty well as a low-signal control. 5 μL of SOS1 and 5 μL of GTP were each transferred to a 384-well plate.

[0509] GDP detection reagents were prepared in test buffer, and 10 μL of the detection reagent solution was transferred to a 384-well plate and incubated at room temperature for 2 hours. After incubation, the plate was read using a multi-function microplate reader (SpectraMax Paradigm), and the excitation wavelength was 580 nm and the emission wavelength was 620 nm. The fluorescence signal was read and the inhibition rate was calculated.

[0510] The inhibition rate is calculated as (high signal control - sample signal) / (high signal control - low signal control) * 100, and IC is calculated using Graphpad5 software. 50 The value was calculated.

[0511] [Table 2]

[0512] The experimental results demonstrate that the compound of the present invention has a significant inhibitory effect on KRAS G12C-SOS1. Test Example 3: Compound Inhibition Test on ERK Phosphorylation Levels in DLD-1 Cells Intracellular Western blot quantitative analysis was used to detect the inhibitory levels of compounds on ERK phosphorylation in DLD-1 cells.

[0513] DLD-1 cells (ATCC, CCL-221) were placed in a T75 culture flask in a 2.5 × 10⁶ container. 6Individual cells were inoculated in flasks and cultured for 2 days in RPMI 1640 medium containing 10% FBS. On day 3, cells were inoculated into 384-well plates and cultured overnight at 37°C and 5% CO2. After overnight, serially diluted compounds (final DMSO content was 0.5%) were added, and DMSO was added to the negative group. The cells were then cultured in an incubator at 37°C and 5% CO2.

[0514] Cells were fixed, washed once with PBS to disrupt the cell membrane, and blocked at room temperature for 1 hour. The blocking solution was removed, the primary antibody (CST, catalog number: #4370S) was added, and the cells were incubated overnight at 4°C. The cells were washed three times with PBST (PBS solution with 0.05% Tween 20 added), immersed for 2 minutes each time. The secondary antibody (LI-COR, catalog number: 926-32211) was added, and the cells were incubated at room temperature in the dark. The cells were washed three times with PBST, immersed for 2 minutes each time. The culture plates were centrifuged at 1000 rpm for 1 minute, scanned with a two-color infrared laser imaging system (Odyssey® CLX), and the signal was read.

[0515] Relative signal = 800 channel signal value / 700 channel signal value Relative expression level of ERK phosphorylation = (Test compound - Control compound I) / (DMSO group - Control compound I) Using Graphpad5 software for IC 50 The value was calculated.

[0516] [Table 3]

[0517] The experimental results demonstrate that the compound of the present invention has a significant inhibitory effect on ERK phosphorylation levels in DLD-1 cells. Test Example 4: Inhibition Test of Compounds on 3D Cell Proliferation H358 cells were inoculated into T75 flasks and cultured for 2 days in RPMI 1640 medium containing 10% FBS for subsequent culture or for experimentation in 384-well plates.

[0518] On day 1, cells were inoculated into a 384-well plate. 40 μL of culture medium was added to each well, followed by serially diluted compounds or DMSO. Wells without cell inoculation were designated as blank controls. The cells were incubated at 37°C and 5% CO2 for 7 days. On day 8, 3D CellTiter-Glo reagent (Promega, catalog number: G9683) was added, the mixture was shaken at 320 rpm for 20 minutes, and then left at room temperature for 2 hours. Luminescence signals were read using a multi-function microplate reader. Cell viability inhibition rates were calculated: Cell viability inhibition rate = (DMSO group - test compound) / (DMSO group - blank control group) × 100% Using Graphpad5 software for IC 50 The value was calculated.

[0519] [Table 4]

[0520] The experimental results show that the compound of the present invention has a strong inhibitory effect on 3D proliferation of H358 cells. Test Example 5: Human Liver Microsome Stability Test Human liver microsome stability was detected by co-culturing the compound with human liver microsomes in vitro. First, the test compound was prepared as a 10 mM stock solution in DMSO solvent, and then diluted to 0.5 mM with acetonitrile. Human liver microsomes (Corning) were diluted in microsome / buffer using PBS, and the 0.5 mM compound was diluted with this solution to prepare the working solution. The concentration of the compound in the working solution was 1.5 μM, and the concentration of human liver microsomes was 0.75 mg / mL. A deep-well plate was prepared, 30 μL of the working solution was added to each well, and then 15 μL of preheated 6 mM NADPH solution was added to start the reaction, and the cells were incubated at 37°C. At 0, 5, 15, 30, and 45 minutes after incubation, 135 μL of acetonitrile was added to the corresponding well to stop the reaction. After stopping the reaction with acetonitrile at the last 45 minutes, the deep-well plate was vortexed and shaken (600 rpm / min) for 10 minutes, and then centrifuged for 15 minutes. After centrifugation, the supernatant was taken, purified water was added in a 1:1 ratio, and LC-MS / MS detection was performed. The ratio of the peak area of ​​the compound to the peak area of ​​the internal standard at each time point was determined, and the peak area ratio of the compound at 5, 15, 30, and 45 minutes was compared with the peak area ratio at 0 minutes to calculate the remaining percentage of the compound at each time point. The results were then analyzed using Graphpad5 software. 1 / 2 I calculated it.

[0521] [Table 5]

[0522] The experimental results show that the compound of the present invention exhibits superior hepatic metabolic stability compared to control compound I, resulting in slower metabolism in the human body and higher exposure levels. Test Example 6: Inhibition Test of Compounds Against Cytochrome P450 The inhibitory potential of compounds against cytochrome P450 (CYP450) subtype CYP3A4 (two substrates: midazolam and testosterone) was detected. First, the test compound was prepared as 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 400-fold with acetonitrile to their final concentrations (compound: 10 μM, ketoconazole: 2.5 μM).

[0523] NADPH cofactors and substrates were prepared at four times the final concentration in potassium phosphate buffer (0.1 M, pH 7.4) (by adding 66.7 mg of NADPH to 10 mL of potassium phosphate buffer). The final concentration of the CYP3A4 substrate midazolam was 320 μM, and the final concentration of the CYP3A4 substrate testosterone was 20 μM.

[0524] Human liver microsome solution was prepared to a concentration of 0.2 mg / mL using potassium phosphate buffer on ice. Test compound and control inhibitor (control compound) solutions were prepared at twice the final concentration using the human liver microsome solution on ice. 30 mL of the test compound and control inhibitor solutions were added to each test well, followed by 15 mL of substrate, and a double-well procedure was performed. A 96-well assay plate and NADPH solution were incubated at 37°C for 5 minutes, and 15 μL of preheated 8 mM NADPH solution was added to the assay plate to initiate the reaction. The CYP3A4 assay plate was incubated at 37°C for 5 minutes. The reaction was stopped by adding 120 μL of acetonitrile, quenched, and the plate was shaken on a shaker (IKA, MTS2 / 4) for 10 minutes (600 rpm / min), followed by centrifugation for 15 minutes. After centrifugation, the supernatant was collected, purified water was added in a 1:1 ratio, and LC-MS / MS detection was performed. The ratio of the peak area of ​​the compound to the peak area of ​​the internal standard was determined, and the inhibition rate was calculated by comparing the peak area ratio of the compound with that of the control inhibitor.

[0525] [Table 6]

[0526] The experimental results show that, compared to control compound I, the compounds of the present invention exhibit weak or no inhibitory effect on the CYP3A4 enzyme at 10 μM, indicating a lower potential risk of drug-drug interaction. Of these, compound I-3 shows a more significant advantage in its inhibitory effect on the CYP3A4 enzyme.

[0527] Test Example 7: Plasma protein binding rate of compounds The plasma protein binding rate of the compound was detected by equilibrium dialysis (HTDdialysis, HTD 96b). The compound was prepared as a 0.5 nM stock solution using DMSO, and then diluted 25-fold with 0.05 M sodium phosphate buffer as a working solution. A blank 96-well plate was taken, 380 μL of plasma was pre-filled into each well, and then 20 μL / well of the working solution was added to the plasma and mixed thoroughly. The final concentration of the compound was 1 μM, and each well contained 0.2% DMSO.

[0528] 100 μL of 0.05 M sodium phosphate buffer was added to the receiving side of each dialysis chamber (HTD 96b), and then 100 μL of plasma containing the compound was added to the supply side. After covering with a plastic cover, the chambers were incubated at 37°C for 5 hours with shaking.

[0529] After the culture was complete, 25 μL of sample was taken from both the supply and receiving sides of the dialysis chamber and placed in a blank 96-well plate. The same volume of plasma was added to each supply sample, and the same volume of 0.05 M sodium phosphate buffer was added to each receiving sample and mixed thoroughly. After adding 200 μL of acetonitrile solution containing an internal standard to each well, the 96-well plate was vortexed at 600 rpm for 10 minutes, shaken, and centrifuged at 5594 g for 15 minutes (Thermo Multifuge × 3R). 50 μL of the supernatant was taken and transferred to a new 96-well plate, and the sample was mixed with 50 μL of ultrapure water for LC-MS / MS analysis.

[0530] The plasma protein binding rate and free fraction were calculated using the following formula: % binding rate = 100 × ([supply concentration])5h -[receptor concentration] 5h ) / [supply side concentration] 5h % Free fraction = 100 - % binding rate

[0531] [Table 7]

[0532] The experimental results indicate that the compound of the present invention has a higher proportion of free drug in human and mouse plasma than the control drug, demonstrating good drug discovery potential. Test Example 8: Mouse Pharmacokinetic Study Male ICR mice weighing 20-25 g were used and fasted overnight. Three mice were collected and orally administered 10 mg / kg. Blood samples were collected before administration and at 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after administration. 6800 g of blood samples were centrifuged at 2-8°C for 6 minutes to collect plasma, which was stored at -80°C. Plasma was collected at each time point, mixed with 3-5 times the volume of acetonitrile solution containing an internal standard, vortexed for 1 minute, centrifuged at 13000 rpm at 4°C for 10 minutes, the supernatant was taken, 3 times the volume of water was added and mixed, and an appropriate amount of the mixed solution was collected and performed LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed using a non-compartment model of WinNonlin 7.0 software.

[0533] [Table 8]

[0534] The results of mouse pharmacokinetic experiments indicate that the compound of the present invention has high oral exposure levels, good pharmacokinetic properties, and good drug discovery potential. Test Example 9: In vivo drug efficacy experiment of Mia Paca-2 in pancreatic cancer After feeding mice an adaptive diet for one week, logarithmic phase Mia Paca-2 cells were resuspended in serum-free DMEM, mixed with Matrigel in a 1:1 ratio, and 1 × 10⁶ cells were added at 100 mL / mouse. 7Mia Paca-2 cells were subcutaneously inoculated into the right flank of mice, and tumor growth was observed periodically. When the tumor reached an average volume of 150-200 mm², 3 At the point when the tumors proliferated, the mice were randomly divided into a model group and a treatment group (monotherapy, or combination therapy with trametinib) according to tumor size and body weight. Tumor size and animal body weight were measured and recorded before and during administration. After the completion of treatment, the difference in tumor size between the model group and the treatment group was compared to determine the effectiveness of the drug.

[0535] [Table 9]

[0536] The experimental results (see Figure 1 for details) show that when the compound of the present invention is used alone or in combination with trametinib, it has a significant inhibitory effect on the proliferation of Mia Paca-2 cancer, and the combined effect is superior to that when used alone.

[0537] Test Example 10: In vivo drug efficacy experiment for LOVO colorectal cancer After feeding mice adaptive diets for one week, logarithmic phase LOVO cells were resuspended in serum-free F12K and 5 × 10⁶ cells were collected at 100 μL / mouse. 6 LOVO cells were subcutaneously inoculated into the right flank of mice, and tumor growth was observed periodically. When the tumor reached an average volume of 150-200 mm², 3 At the point when the tumors had grown, the mice were randomly divided into a model group and a treatment group according to tumor size and body weight. Tumor size and animal body weight were measured and recorded before and during administration, and after the completion of treatment, the difference in tumor size between the model group and the treatment group was compared to determine the effectiveness of the drug.

[0538] [Table 10]

[0539] The experimental results (see Figure 2 for details) show that the compound of the present invention has a significant inhibitory effect on the proliferation of LOVO tumor tissue, and is superior to the effect of control compound II. Although embodiments of the present invention have been shown and described above, these embodiments are illustrative and should not be construed as limiting the present invention. It should be understood that changes, modifications, substitutions, and variations of the above embodiments can be made by those skilled in the art within the scope of the present invention.

Claims

1. Pyridopyrimidinone derivatives represented by formula I, their tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts. 【Chemistry 1】 (Here, ring A is phenyl, R １ is a 3- to 10-membered cycloalkyl or a 4- to 10-membered heterocycloalkyl, and said R １ is optionally substituted by one or more R １１ , and said R １１ is halogen, hydroxyl, C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ alkoxy, and 【Chemistry 2】 A substituent selected from, Substituent R １１ If there are multiple substituents R １１ They are the same or different. The aforementioned R １１ C １ ~C ６ Alkyl, C １ ~C ６ Optionally substituted with alkoxy or halogen, R １４ is hydrogen, C １ ~C ６ Alkyl, or C １ ~C ６ It is a haloalkyl, R ２ It is hydrogen, R ３ C １ ~C ６ It is alkyl, R ４ C １ ~C ６ It is alkyl, R ５ is either hydrogen, or a halogen, C １ ~C ６ Alkyl, C １ ~C ６ A substituent selected from haloalkyl groups, R ６ is, -SF ５ or 【Transformation 3】 The R61 is a C substituted with a halogen. １ ~C ６ It is alkyl, m is either 1 or 2.

2. A pyridopyrimidinone derivative represented by formula I, its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts, 【Chemistry 4】 Here, ring A is phenyl, R １ is a 3- to 10-membered cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein the cycloalkyl has one or more R １１ It is optionally replaced by the R １１ is halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, or C １ ~C ６ A substituent selected from alkoxy, wherein substituent R １１ If there are multiple substituents R １１ They are the same or different. R ２ It is hydrogen, R ３ C １ ~C ６ It is alkyl, R ４ C １ ~C ６ It is alkyl, R ５ is either hydrogen, or a halogen, C １ ~C ６ Alkyl, C １ ~C ６ A substituent selected from haloalkyl groups, R ６ is, -SF ５ or 【Transformation 5】 The R61 is a C substituted with a halogen. １ ~C ６ It is alkyl, A pyridopyrimidinone derivative represented by formula I according to claim 1, characterized in that m is 1 or 2, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.

3. The pyridopyrimidinone derivative represented by formula I has structure I-2, 【Transformation 6】 Here, R １ , R ２ , R ３ , R ５ , R ６ The definition of m is as described in claim 1, and R ４ A pyridopyrimidinone derivative represented by formula I as described in claim 1, characterized in that the compound is methyl, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.

4. R ５ m is hydrogen, fluorine, or methyl, and m is 1 or 2. R ６ is, -SF ５ or 【Transformation 7】 Thus, R61 is replaced by one or more Fs. １ ~C ６ A pyridopyrimidinone derivative represented by formula I according to claim 1 or 2, characterized by being alkyl, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.

5. R 6 is -SF 5 or 【Transformation 8】 And, A pyridopyrimidinone derivative represented by formula I according to claim 1 or 2, characterized in that R 61 is -CH2F, -CHF2, -CF3, or -CF2CH3, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof. 【Request Item 6】 【Chemistry 9】 teeth, 【Chemistry 10】 A pyridopyrimidinone derivative represented by formula I according to claim 1 or 2, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that it is a pyridopyrimidinone derivative represented by formula I according to claim 1 or 2.

7. R ５ is hydrogen, R ６ Ha - SF ５ , 【Chemistry 11】 A pyridopyrimidinone derivative represented by formula I according to claim 1 or 2, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that it is a pyridopyrimidinone derivative represented by formula I according to claim 1 or 2.

8. A pyridopyrimidinone derivative represented by formula I according to claim 1 or 2, characterized in that R 6 is -SF 5, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.

9. R ４ A pyridopyrimidinone derivative represented by formula I according to claim 1 or 2, characterized in that the compound is methyl, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.

10. A pyridopyrimidinone derivative represented by formula I according to claim 1 or 2, characterized in that the halogen is fluorine, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.

11. The aforementioned R １ In this case, the 3- to 10-membered cycloalkyl group is 【Chemistry 12】 And, Alternatively, the 4-10 member heterocycloalkyl is 【Chemistry 13】 A pyridopyrimidinone derivative represented by formula I according to claim 1 or 2, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that it is a pyridopyrimidinone derivative represented by formula I according to claim 1 or 2.

12. R １ teeth 【Chemistry 14】 And R １１ is C １ ~C ６ C substituted with alkyl or fluorine １ ~C ６ A pyridopyrimidinone derivative represented by formula I according to claim 1 or 2, characterized by being alkyl, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.

13. R １ is a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocycloalkyl, and the R １ is optionally substituted by one or more R １１ , and the R １１ is halogen, hydroxyl, C １ to C ６ alkyl, C １ to C ６ alkoxy, 【Chemistry 15】 A substituent selected from, R １４ is hydrogen, C １ ~C ３ alkyl, or C １ ~C ３ haloalkyl, and The aforementioned R １１ C １ ~C ３ A pyridopyrimidinone derivative represented by formula I according to claim 1, characterized by being optionally substituted with an alkoxy or halogen, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.

14. R １ is selected from cyclopropyl, cyclobutyl, tetrahydrofuranil, tetrahydropyranil, propylene oxide, pyrrolidinil, or piperidinil, and the R １ is one or more R １１ It is optionally replaced by the R １１ fluorine, hydroxyl, C １ ~C ６ Alkyl, C １ ~C ３ C substituted with alkoxy １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, 【Chemistry 16】 A substituent selected from R １４ is C １ ~C ６ A pyridopyrimidinone derivative represented by formula I as described in claim 1, characterized by being alkyl, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.

15. R1 is, 【Chemistry 17】 A pyridopyrimidinone derivative represented by formula I according to claim 1, characterized by being selected from the following, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.

16. R ５ is hydrogen, R ６ Ha - SF ５ And R ４ is methyl, R ３ is methyl, R ２ A pyridopyrimidinone derivative represented by formula I according to claim 1 or 2, characterized in that the derivative is hydrogen, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.

17. R ３ A pyridopyrimidinone derivative represented by formula I according to claim 1 or 2, characterized in that the compound is methyl, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.

18. The pyridopyrimidinone derivative represented by formula I according to claim 1, characterized in that the pyridopyrimidinone derivative is one of the compounds of the following formula, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof. [Chemistry 18] 【change】

19. A method for producing a pyridopyrimidinone derivative represented by formula I as described in claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein the method is: 1) The process includes the step of reacting intermediate B-1 and intermediate B-2 to obtain a pyridopyrimidinone derivative represented by formula I, 【Chemistry 19】 Here, rings A and R １ , R ２ , R ３ , R ４ , R ５ , R ６ The definitions of m, p, and n are as described in claim 1, R ７ is a hydroxyl, chlorine, bromine, iodine, or sulfonic acid group, The aforementioned sulfonic acid group is -SO ３ R ７１ And here, R ７１ is methyl, -CF ３ A method characterized by using phenyl or 2,4,6-trimethylbenzene.

20. The method according to claim 19, characterized in that R7 is hydroxyl.

21. The method according to claim 19, further comprising the step of 2) converting the intermediate B-1 to an ammonium salt of B-1, and then reacting it with intermediate B-2 to obtain a pyridopyrimidinone derivative represented by formula I.

22. A pharmaceutical composition comprising a pyridopyrimidinone derivative represented by formula I as described in any one of claims 1 to 18, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

23. A pharmaceutical composition comprising a pyridopyrimidinone derivative represented by formula I as described in any one of claims 1 to 18, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, and at least one other pharmacologically active inhibitor.

24. The other pharmacologically active inhibitors mentioned above are inhibitors of MEK and / or its variants, or The pharmaceutical composition according to claim 23, characterized in that the other pharmacologically active inhibitor is trametinib.

25. A pyridopyrimidinone derivative represented by formula I according to any one of claims 1 to 18, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 22 to 24, for use in the prevention and / or treatment of diseases related to SOS1 and RAS family proteins.

26. A pyridopyrimidinone derivative represented by formula I, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt or pharmaceutical composition for use according to claim 25, wherein the diseases associated with SOS1 and RAS family proteins include cancer and RAS disease.

27. ​​A pyridopyrimidinone derivative represented by formula I for use according to claim 25, wherein the RAS family protein is KRAS G12C, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

28. The RAS disease includes Noonan syndrome, cardiac-facial-skin syndrome, hereditary gingival fibromatosis type 1, neurofibromatosis type 1, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, and Regius syndrome, Alternatively, the cancer is selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, stomach cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial carcinoma, ureteral tumors, prostate cancer, seminoma, testicular tumors, leukemia, head and neck tumors, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma, and glioma, and the pyridopyrimidinone derivative represented by formula I for use according to claim 26, its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts, or pharmaceutical compositions.

29. The liver cancer is hepatocellular carcinoma, Alternatively, the head and neck tumor is a squamous cell carcinoma of the head and neck. Alternatively, the sarcoma is osteosarcoma, and the colorectal cancer is colon cancer or rectal cancer, a pyridopyrimidinone derivative represented by formula I, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 28.

30. A pyridopyrimidinone derivative represented by formula I, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 25, wherein trametinib is used in combination with the pyridopyrimidinone derivative represented by formula I, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.

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