Compounds, tautomers of said compounds, stereoisomers of said compounds, hydrates of said compounds, solvates of said compounds or pharma- ceutically acceptable salts of said compounds, and pharmaceutical compositions

Abstract

The present disclosure proposes new compounds that effectively inhibit CD73 activity, which are compounds of formula I, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, methods for their preparation, and their use in the manufacture of medicaments. [C215] TIFF2023548204000227.tif25170

Description

[Technical field]

[0001] The present disclosure belongs to the field of medicinal chemistry; specifically, the present disclosure relates to CD73 inhibitors and their applications; more specifically, the present disclosure relates to pyrimidinedione compounds and their preparation methods and uses in drug manufacturing. [Background technology]

[0002] CD73, also known as extracellular 5'-nucleotidyl hydrolase, is an exonuclease that belongs to the metallophosphoesterase superfamily. It is a peripheral glycoprotein that is anchored to the plasma membrane mainly by glycosylphosphatidylinositol (GPI), has a molecular weight of 70 KD, and is encoded by the NT5E gene. CD73 is widely expressed on the cell surface of different tissues, including brain, lung, heart, spleen, lymph nodes, kidney, colon, vascular endothelium, and bone marrow, and is also expressed on various immune cells, including macrophages, neutrophils, myeloid suppressor cells (MDSCs), dendritic cells (DCs), natural killer cells (NKs), and regulatory T cells (Tregs) (Soleimani A et al., Biochimie, 2020, 176: 21-30.), and there is also high expression of CD73 on multiple types of tumor cells, including melanoma, breast cancer, pancreatic cancer, ovarian cancer, colon cancer, and prostate cancer (Gao Z et al., Biomed Res Int, 2014, 2014: 460654.). CD73 is also present in biological fluids, including serum, in a soluble form (sCD73), and retains full enzymatic activity.

[0003] CD73 plays a physiological and pathological role mainly by hydrolyzing AMP (adenosine monophosphate) to generate extracellular adenosine (ADO), which functions by interacting with four G protein-coupled receptors (GPCRs): A1 adenosine receptor (A1AR), A2A adenosine receptor (A2AR), A2B adenosine receptor (A2BR) and A3 adenosine receptor (A3AR), with the A2AR playing the main role (Linden J et al., Annu. Rev. Immunol., 2019, 37: 325-347.). Adenosine receptors (ARs) are expressed not only on tumor cells but also on the cell surface of immune cells and vascular endothelial cells infiltrating in the tumor microenvironment, and ADO binds to the receptor to exert various immunosuppressive and tumor-promoting effects.

[0004] CD73 is closely related to tumor growth, angiogenesis and metastasis. Under normal physiological conditions, extracellular ADO levels are 20-300 nM, but in the tumor microenvironment, they are elevated and maintained at micromolar levels (30-100 μM), and high extracellular ADO concentrations are mainly influenced by CD73 hydrolyzing AMP. Studies have revealed that the levels of soluble CD73 (sCD73) in the plasma of cancer patients are increased compared to healthy subjects (Klemens MR et al., Biochem. Biophys. Res. Commun., 1990, 172: 1371-7..). In gastrointestinal stromal tumors, tumor-infiltrating NK cells express higher levels of CD73, and the deletion of A2AR signaling in NK cells reduces CD73 expression. +It can improve tumor metastasis and enhance antitumor immune responses (Young A et al., Cancer Cell. 2016;30(3):391-403.). CD73 is upregulated in pancreatic ductal adenocarcinoma (PDAC) compared to normal pancreatic tissue, and is associated with tumor size, metastasis, and poor prognosis (Harvey Jerry B et al., Front Immunol, 2020, 11: 508.). In preclinical studies by ORIC, the CD73-selective inhibitor ORIC-533 significantly reduced ADO concentrations in the tumor microenvironment and, at the same time, reduced tumor volume. These research results revealed that CD73 is upregulated in various tumors, and that inhibition of CD73 may reduce ADO concentrations and suppress tumor growth and metastasis.

[0005] CD73 inhibitors can be used alone, but also in combination with other targeted therapies and / or immunotherapies, and radiation therapy to block tumor growth by releasing immune suppression, and can increase antitumor effects. In some mouse tumor models, anti-CD73, anti-PD-1 / L1 (progression death receptor-1 / ligand 1) and / or anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) antibody combination therapy was more effective than antibody therapy using anti-PD-L1 and / or anti-CTLA-4 alone (Allard B et al., Clin. Cancer Res., 2013, 19: 5626-35.), and elevated CD73 levels were observed in melanoma patients who received anti-PD-1 antibody immunotherapy, but after anti-PD-1 treatment, glioblastoma patients maintained a unique population of CD73-highly expressing macrophages, and CD73 deficiency reduced the efficacy of anti-PD-1 and anti-CTLA-4 in mouse glioblastoma models (Goswami S et al., Nat. Med., 2020, 26: 39-46.), and radiation therapy causes the destruction of some tumor cells, releasing a large amount of intracellular ATP into the extracellular space, which is converted to adenosine under the action of CD73 on the surface of tumor cells or free CD73, exerting an immunosuppressive effect, which is thought to be one of the reasons for the poor prognosis of some patients after radiation therapy. Therefore, the combination of CD73 inhibitors with radiation therapy may play a synergistic effect (Wennerberg E et al., Cancer Immunol Res, 2020, 8: 465-478.).

[0006] At present, several anti-CD73 monolides (MEDI9447, BMS986179, SRF373 / NZV930, CPI-006 / CPX-006, TJ004309) and selective small molecule inhibitors (LY3475070, AB680) have entered the clinical phase, and some trials have obtained desirable early results (NCT02754141), suggesting that CD73 inhibition may be a promising method for treating tumors. Summary of the Invention [Problem to be solved by the invention]

[0007] The present disclosure aims to propose new CD73 inhibitors that can be used for the manufacture of drugs for treating tumor-related diseases. [Means for solving the problem]

[0008] In a first aspect of the present disclosure, the present disclosure proposes a compound, the compound being represented by formula I, a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof, [ka] however, R 1 teeth [ka] Selected from the following: a are independently selected from hydrogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a 5-8 membered aryl group, a 5-8 membered heteroaryl group, a 4-8 membered heterocyclic alkyl group, or a C1-C6 alkyl group substituted with 1-5 identical or different halogens, wherein the 5-8 membered heteroaryl group has one or more heteroatoms selected from N, S, O and P, and the number of heteroatoms is 1-3; the 4-8 membered heterocyclic alkyl group has one or more heteroatoms selected from N, S, O and P, and the number of heteroatoms is 1-3; the 4-8 membered heterocyclic alkenyl group has one or more heteroatoms selected from N, S, O and P, and the number of heteroatoms is 1-3; R 2 is hydrogen, halogen, hydroxyl group, cyano group, amino group, unsubstituted or R b C1-C6 alkyl group, unsubstituted or substituted with R b C1-C6 alkyl-O-, unsubstituted or substituted with R b C1-C6 alkyl-S-, unsubstituted or substituted with R b 5-8 membered aryl, unsubstituted or substituted with R b 5-8 membered heteroaryl, unsubstituted or substituted with R b 4-8 membered heterocyclic alkyl group substituted with Rb or unsubstituted or R b C2-C6 alkenyl groups substituted with R b Of the C1-C6 alkyl substituted with R b Of the C1-C6 alkyl-O- substituted with R b Of the C1-C6 alkyl-S- substituted with R b Of the 5-8 membered aryl substituted with R b Of the 5-8 membered heteroaryl substituted with R b Among the 4-8 membered heterocyclic alkyl groups substituted with R b or R b Among the C2-C6 alkenyl groups substituted with R b The substitutions in R are one or more substitutions. b are each independently selected from a halogen, a hydroxyl group, a cyano group, an amino group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, and a C1-C6 alkyl-O-; when there are multiple substituents, the substituents may be the same or different; The unsubstituted or R b The heteroatom is one or more selected from N, S, O and P, and the number of heteroatoms is 1 to 3. b The heteroatom is one or more selected from N, S, O and P, and the number of heteroatoms is 1 to 3. b In the 4-8 membered heterocyclic alkenyl group substituted with, the heteroatom is one or more selected from N, S, O and P, and the number of heteroatoms is 1 to 3.

[0009] In one preferred embodiment of the present disclosure, the compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof is [ka] and however, R 1 teeth [ka] where R a are independently selected from hydrogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a 5-8 membered aryl group, a 5-8 membered heteroaryl group, a 4-8 membered heterocyclic alkyl group, or a C1-C6 alkyl group substituted with 1-5 identical or different halogens, wherein the 5-8 membered heteroaryl group has one or more heteroatoms selected from N, S, O and P, and the number of heteroatoms is 1-3; the 4-8 membered heterocyclic alkyl group has one or more heteroatoms selected from N, S, O and P, and the number of heteroatoms is 1-3; the 4-8 membered heterocyclic alkenyl group has one or more heteroatoms selected from N, S, O and P, and the number of heteroatoms is 1-3; R 2 is hydrogen, halogen, hydroxyl group, cyano group, amino group, unsubstituted or R b C1-C6 alkyl group, unsubstituted or substituted with R b C1-C6 alkyl-O-, unsubstituted or substituted with R b C1-C6 alkyl-S-, unsubstituted or substituted with R b 5-8 membered aryl, unsubstituted or substituted with R b 5-8 membered heteroaryl, unsubstituted or substituted with R b 4-8 membered heterocyclic alkyl group substituted with R b or unsubstituted or R b C2-C6 alkenyl groups substituted with R b Of the C1-C6 alkyl substituted with R b Of the C1-C6 alkyl-O- substituted with R b Of the C1-C6 alkyl-S- substituted with R b Of the 5-8 membered aryl substituted with R b Of the 5-8 membered heteroaryl substituted with R bAmong the 4-8 membered heterocyclic alkyl groups substituted with R b or R b Among the C2-C6 alkenyl groups substituted with R b The substitutions in R are one or more substitutions. b are each independently selected from a halogen, a hydroxyl group, a cyano group, an amino group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, and a C1-C6 alkyl-O-; when there are multiple substituents, the substituents may be the same or different; The unsubstituted or R b The heteroatom is one or more selected from N, S, O and P, and the number of heteroatoms is 1 to 3. b The heteroatom is one or more selected from N, S, O and P, and the number of heteroatoms is 1 to 3. b In the 4-8 membered heterocyclic alkenyl group substituted with, the heteroatom is one or more selected from N, S, O and P, and the number of heteroatoms is 1 to 3.

[0010] In one preferred embodiment of the present disclosure, R a is a C1-C6 alkyl group, said C1-C6 alkyl group is a C1-C4 alkyl group, preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or an isobutyl group.

[0011] In one preferred embodiment of the present disclosure, R a is a C1-C6 alkyl group substituted with 1 to 5 identical or different halogens, said C1-C6 alkyl group is a C1-C4 alkyl group, preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or an isobutyl group.

[0012] In one preferred embodiment of the present disclosure, R ais a C1-C6 alkyl group substituted with 1-5 identical or different halogens, said halogens are F, Cl, Br or I, preferably F or Cl.

[0013] In one preferred embodiment of the present disclosure, R a When is a C1-C6 alkyl group substituted with 1 to 5 identical or different halogens, the number of the halogens substituted is 1, 2 or 3, and preferably 3.

[0014] In one preferred embodiment of the present disclosure, R a is a C3-C6 cycloalkyl group, said C3-C6 cycloalkyl is independently a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, preferably a cyclopropyl group.

[0015] In one preferred embodiment of the present disclosure, R a When is a 5-8 membered aryl, said 5-8 membered aryl is independently a phenyl group or a naphthyl group, preferably a phenyl group.

[0016] In one preferred embodiment of the present disclosure, R a is a 5-8 membered heteroaryl, said 5-8 membered heteroaryl is independently pyrrole, pyrazole, triazole, furan, oxazole, thiophene, thiazole, pyridine, pyrazine or pyrimidine, preferably pyrazole, furan, thiophene or pyridine.

[0017] In one preferred embodiment of the present disclosure, R a When is a 4-8 membered heterocycloalkyl group, said 4-8 membered heterocycloalkyl group is independently azetidine, oxetane, tetrahydropyrrolidine, tetrahydrofuran, hexahydropyran or tetrahydro-2H-thiopyran 1,1-dioxide, preferably azetidine or oxetane.

[0018] In one preferred embodiment of the present disclosure, R ais a 4- to 8-membered heterocyclic alkenyl group, the 4- to 8-membered heterocyclic alkenyl group is independently a dihydropyridyl group, a tetrahydropyridyl group, a tetrahydropyrimidinyl group, a pyrrolinyl group, an imidazolinyl group, a pyrazolyl group, a dihydroimidazole group, a dihydropyrazole group, a dihydrooxazolyl group, a dihydrooxadiazole group, a dihydrothiazolyl group, a dihydroisothiazolyl group, a dihydrothiophene group, a dihydropyrrole group, a 3,4-dihydro-2H-pyran group, a dihydrofuryl group, a dihydropyrazinyl group, a dihydropyrimidinyl group or a fluorodihydrofuryl group, preferably a 1,2,3,4-tetrahydropyridyl group, a 1,2-dihydropyridyl group, a 1,4-dihydropyridyl group, a 1,2,3,6-tetrahydropyridyl group, a 3,4-dihydro-2H-pyran group or a dihydrofuryl group.

[0019] In one preferred embodiment of the present disclosure, R 2 is a cyano group.

[0020] In one preferred embodiment of the present disclosure, R 2 When is a halogen, said halogen is F, Cl, Br or I, preferably Cl.

[0021] In one preferred embodiment of the present disclosure, R 2 is unsubstituted or R b When it is a C1-C6 alkyl group substituted with, said C1-C6 alkyl group is a C1-C4 alkyl group, preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group or an isobutyl group.

[0022] In one preferred embodiment of the present disclosure, R 2 is unsubstituted or R b When it is C1-C6 alkyl-O- substituted with, said C1-C6 alkyl-O- is C1-C4 alkyl-O-, preferably methyl-O-.

[0023] In one preferred embodiment of the present disclosure, R 2 is unsubstituted or R bWhen it is C1-C6 alkyl-S- substituted with, said C1-C6 alkyl-S- is C1-C4 alkyl-S-, preferably methyl-S-.

[0024] In one preferred embodiment of the present disclosure, R 2 is unsubstituted or R b When it is a 5-8 membered aryl substituted with, said 5-8 membered aryl is independently a phenyl group or a naphthyl group, preferably a phenyl group.

[0025] In one preferred embodiment of the present disclosure, R 2 is unsubstituted or R b When it is a 5-8 membered heteroaryl substituted with, said 5-8 membered heteroaryl is independently pyrrole, pyrazole, triazole, furan, oxazole, thiophene, thiazole, pyridine, pyrazine or pyrimidine, preferably pyrazole, furan, thiophene or pyridine.

[0026] In one preferred embodiment of the present disclosure, R 2 is unsubstituted or R b When the 4-8 membered heterocycloalkyl group is independently azetidine, oxetane, tetrahydropyrrolidine, tetrahydrofuran, hexahydropyran or tetrahydro-2H-thiopyran 1,1-dioxide, preferably azetidine or oxetane.

[0027] In one preferred embodiment of the present disclosure, R 2 is unsubstituted or R bIn the case of a 4- to 8-membered heterocyclic alkenyl group substituted with one of the following, the 4- to 8-membered heterocyclic alkenyl groups are independently a dihydropyridyl group, a tetrahydropyridyl group, a tetrahydropyrimidinyl group, a pyrrolinyl group, an imidazolinyl group, a pyrazolyl group, a dihydroimidazole group, a dihydropyrazole group, a dihydrooxazolyl group, a dihydrooxadiazole group, a dihydrothiazolyl group, a dihydroisothiazolyl group, a dihydrothiophene group, a dihydropyrrole group, a 3,4-dihydro-2H-pyran group, a dihydrofuryl group, a dihydropyrazinyl group, a dihydropyrimidinyl group, or a fluorodihydrofuryl group, and preferably a 1,2,3,4-tetrahydropyridyl group, a 1,2-dihydropyridyl group, a 1,4-dihydropyridyl group, a 1,2,3,6-tetrahydropyridyl group, a 3,4-dihydro-2H-pyran group, or a dihydrofuryl group.

[0028] In one preferred embodiment of the present disclosure, R 2 is unsubstituted or R b When it is a C2-C6 alkenyl group substituted with , the C2-C6 alkenyl group is a vinyl group, a 1-propenyl group, a 2-propenyl group, or an allyl group, preferably a vinyl group or an allyl group.

[0029] In one preferred embodiment of the present disclosure, [ka] teeth [ka] or [ka] It is.

[0030] In a preferred embodiment of the present disclosure, [ka] teeth [ka] and However, the above R 1 teeth [ka] Selected from the following: a is a C1-C6 alkyl group unsubstituted or substituted with one or more of the same or different halogens.

[0031] In one preferred embodiment of the present disclosure, R a is selected from C1-C4 alkyl groups unsubstituted or substituted with 1 to 5 identical or different halogens.

[0032] In one preferred embodiment of the present disclosure, R a is selected from a methyl group, trifluoromethyl or difluoromethyl.

[0033] In one preferred embodiment of the present disclosure, R 2 is hydrogen, halogen, cyano, unsubstituted or R b C1-C4 alkyl groups substituted with R b are each independently a halogen.

[0034] In one preferred embodiment of the present disclosure, R 2 is selected from Cl or a methyl group.

[0035] In a preferred embodiment of the present disclosure, the R b are each independently a halogen, said halogen being F, Cl or Br.

[0036] In a preferred embodiment of the present disclosure, [ka] teeth [ka] and However, the above R 1 teeth [ka] Selected from.

[0037] In one preferred embodiment of the present disclosure, R 2 is hydrogen, halogen, cyano, unsubstituted or R b C1-C4 alkyl groups substituted with R b are each independently a halogen.

[0038] In one preferred embodiment of the present disclosure, R 2 is Cl.

[0039] In a preferred embodiment of the present disclosure, [ka] teeth [ka] and [ka] It is a racemic mixture of

[0040] In one preferred embodiment of the present disclosure, R 2 is hydrogen, halogen, cyano, unsubstituted or R b is selected from C1-C4 alkyl groups substituted with

[0041] In one preferred implementation of the present disclosure, the C1-C4 alkyl group is selected from a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, or an isobutyl group.

[0042] In one preferred embodiment of the present disclosure, R 2 is Cl.

[0043] In a more preferred embodiment of the present disclosure, [ka] teeth [ka] and [ka] is a racemic mixture of However, the above R 1 teeth [ka] and R 2 is hydrogen, halogen, cyano, unsubstituted or R b C1-C4 alkyl groups substituted with R 2 is selected from halogen, said halogen being F, Cl, Br or I, preferably Cl.

[0044] In one preferred embodiment of the present disclosure, the compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof is [ka] or [ka] and however, R 1 teeth [ka] or [ka] where R aare independently selected from hydrogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a 5-8 membered aryl group, a 5-8 membered heteroaryl group, a 4-8 membered heterocyclic alkyl group, or a C1-C6 alkyl group substituted with 1-5 identical or different halogens, wherein the 5-8 membered heteroaryl group has one or more heteroatoms selected from N, S, O and P, and the number of heteroatoms is 1-3; the 4-8 membered heterocyclic alkyl group has one or more heteroatoms selected from N, S, O and P, and the number of heteroatoms is 1-3; and the 4-8 membered heterocyclic alkenyl group has one or more heteroatoms selected from N, S, O and P, and the number of heteroatoms is 1-3.

[0045] In one preferred embodiment of the present disclosure, the compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof is [ka] or [ka] and however, R 1 teeth [ka] or [ka] where R aare independently selected from hydrogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a 5-8 membered aryl group, a 5-8 membered heteroaryl group, a 4-8 membered heterocyclic alkyl group, or a C1-C6 alkyl group substituted with 1-5 identical or different halogens, wherein the 5-8 membered heteroaryl group has one or more heteroatoms selected from N, S, O and P, and the number of heteroatoms is 1-3; the 4-8 membered heterocyclic alkyl group has one or more heteroatoms selected from N, S, O and P, and the number of heteroatoms is 1-3; and the 4-8 membered heterocyclic alkenyl group has one or more heteroatoms selected from N, S, O and P, and the number of heteroatoms is 1-3.

[0046] In one preferred embodiment of the present disclosure, the compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof is [ka] and however, R 2 is hydrogen, halogen, hydroxyl group, cyano group, amino group, unsubstituted or R b C1-C6 alkyl group, unsubstituted or substituted with R b C1-C6 alkyl-O-, unsubstituted or substituted with R b C1-C6 alkyl-S-, unsubstituted or substituted with R b 5-8 membered aryl, unsubstituted or substituted with R b 5-8 membered heteroaryl, unsubstituted or substituted with R b 4-8 membered heterocyclic alkyl group substituted with R b or unsubstituted or R b C2-C6 alkenyl groups substituted with R b Of the C1-C6 alkyl substituted with R b Of the C1-C6 alkyl-O- substituted with R b Of the C1-C6 alkyl-S- substituted with R bOf the 5-8 membered aryl substituted with R b Of the 5-8 membered heteroaryl substituted with R b Among the 4-8 membered heterocyclic alkyl groups substituted with R b or R b Among the C2-C6 alkenyl groups substituted with R b The substitutions in R are one or more substitutions. b are each independently selected from a halogen, a hydroxyl group, a cyano group, an amino group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, and a C1-C6 alkyl-O-; when there are multiple substituents, the substituents may be the same or different; The unsubstituted or R b The heteroatom is one or more selected from N, S, O and P, and the number of heteroatoms is 1 to 3. b The heteroatom is one or more selected from N, S, O and P, and the number of heteroatoms is 1 to 3. b In the 4-8 membered heterocyclic alkenyl group substituted with, the heteroatom is one or more selected from N, S, O and P, and the number of heteroatoms is 1 to 3.

[0047] In one preferred embodiment of the present disclosure, the compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof is [ka] and however, R 2 is hydrogen, halogen, hydroxyl group, cyano group, amino group, unsubstituted or R b C1-C6 alkyl group, unsubstituted or substituted with R b C1-C6 alkyl-O-, unsubstituted or substituted with R b C1-C6 alkyl-S-, unsubstituted or substituted with R b5-8 membered aryl, unsubstituted or substituted with R b 5-8 membered heteroaryl, unsubstituted or substituted with R b 4-8 membered heterocyclic alkyl group substituted with R b or unsubstituted or R b C2-C6 alkenyl groups substituted with R b Of the C1-C6 alkyl substituted with R b Of the C1-C6 alkyl-O- substituted with R b Of the C1-C6 alkyl-S- substituted with R b Of the 5-8 membered aryl substituted with R b Of the 5-8 membered heteroaryl substituted with R b Among the 4-8 membered heterocyclic alkyl groups substituted with R b or R b Among the C2-C6 alkenyl groups substituted with R b The substitutions in R are one or more substitutions. b are each independently selected from a halogen, a hydroxyl group, a cyano group, an amino group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, and a C1-C6 alkyl-O-; when there are multiple substituents, the substituents may be the same or different; The unsubstituted or R b The heteroatom is one or more selected from N, S, O and P, and the number of heteroatoms is 1 to 3. b The heteroatom is one or more selected from N, S, O and P, and the number of heteroatoms is 1 to 3. b In the 4-8 membered heterocyclic alkenyl group substituted with, the heteroatom is one or more selected from N, S, O and P, and the number of heteroatoms is 1 to 3.

[0048] In one preferred embodiment of the present disclosure, the compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof is [ka] and however, R 2 is hydrogen, halogen, hydroxyl group, cyano group, amino group, unsubstituted or R b C1-C6 alkyl group, unsubstituted or substituted with R b C1-C6 alkyl-O-, unsubstituted or substituted with R b C1-C6 alkyl-S-, unsubstituted or substituted with R b 5-8 membered aryl, unsubstituted or substituted with R b 5-8 membered heteroaryl, unsubstituted or substituted with R b 4-8 membered heterocyclic alkyl group substituted with R b or unsubstituted or R b C2-C6 alkenyl groups substituted with R b Of the C1-C6 alkyl substituted with R b Of the C1-C6 alkyl-O- substituted with R b Of the C1-C6 alkyl-S- substituted with R b Of the 5-8 membered aryl substituted with R b Of the 5-8 membered heteroaryl substituted with R b Among the 4-8 membered heterocyclic alkyl groups substituted with R b or R b Among the C2-C6 alkenyl groups substituted with R b The substitutions in R are one or more substitutions. b are each independently selected from a halogen, a hydroxyl group, a cyano group, an amino group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, and a C1-C6 alkyl-O-; when there are multiple substituents, the substituents may be the same or different; The unsubstituted or Rb The heteroatom is one or more selected from N, S, O and P, and the number of heteroatoms is 1 to 3. b The heteroatom is one or more selected from N, S, O and P, and the number of heteroatoms is 1 to 3. b In the 4-8 membered heterocyclic alkenyl group substituted with, the heteroatom is one or more selected from N, S, O and P, and the number of heteroatoms is 1 to 3.

[0049] In one preferred embodiment of the present disclosure, the compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof is [ka] and however, R 2 is hydrogen, halogen, hydroxyl group, cyano group, amino group, unsubstituted or R b C1-C6 alkyl group, unsubstituted or substituted with R b C1-C6 alkyl-O-, unsubstituted or substituted with R b C1-C6 alkyl-S-, unsubstituted or substituted with R b 5-8 membered aryl, unsubstituted or substituted with R b 5-8 membered heteroaryl, unsubstituted or substituted with R b 4-8 membered heterocyclic alkyl group substituted with R b or unsubstituted or R b C2-C6 alkenyl groups substituted with R b Of the C1-C6 alkyl substituted with R b Of the C1-C6 alkyl-O- substituted with R b Of the C1-C6 alkyl-S- substituted with R b Of the 5-8 membered aryl substituted with R bOf the 5-8 membered heteroaryl substituted with R b Among the 4-8 membered heterocyclic alkyl groups substituted with R b or R b Among the C2-C6 alkenyl groups substituted with R b The substitutions in R are one or more substitutions. b are each independently selected from a halogen, a hydroxyl group, a cyano group, an amino group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, and a C1-C6 alkyl-O-; when there are multiple substituents, the substituents may be the same or different; The unsubstituted or R b The heteroatom is one or more selected from N, S, O and P, and the number of heteroatoms is 1 to 3. b The heteroatom is one or more selected from N, S, O and P, and the number of heteroatoms is 1 to 3. b In the 4-8 membered heterocyclic alkenyl group substituted with, the heteroatom is one or more selected from N, S, O and P, and the number of heteroatoms is 1 to 3.

[0050] In one preferred embodiment of the present disclosure, the compound of formula I, a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof is [ka] It is any compound selected from the following:

[0051] In a second aspect of the present disclosure, the present disclosure proposes a pharmaceutical composition, said pharmaceutical composition comprising a therapeutically effective amount of the above compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug and a pharmaceutically acceptable excipient.

[0052] According to a specific embodiment of the present disclosure, the therapeutically effective amount of the compound, its tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug, and pharma- ceutically acceptable pharmaceutical carrier, diluent or excipient contained in the pharmaceutical composition of the present disclosure may be mixed to prepare a pharmaceutical formulation suitable for oral or parenteral administration. The administration method includes, but is not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and oral routes. The formulation may be administered by any route, such as infusion or push injection, or a route absorbed through epithelium or skin mucosa (e.g., oral mucosa, rectum, etc.). Administration may be systemic or local. Examples of oral administration formulations include solid or liquid dosage forms, specifically including tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, etc. The formulation may be prepared by a method known in the art and may include carriers, diluents or excipients commonly used in the pharmaceutical formulation field.

[0053] In a third aspect of the present disclosure, the present disclosure proposes the use of the above-mentioned compound, or a tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug thereof in combination with a PD-1 / PD-L1 / CTLA-4 antibody or a PD-1 / PD-L1 / CTLA-4 inhibitor in the manufacture of a medicament for treating a CD73-related disease, which can be used to treat cancer, such as bladder cancer, breast cancer, bile duct cancer, rectal cancer, colon cancer, gastric cancer, gallbladder cancer, neuroblastoma, head and neck cancer, liver cancer, lung cancer, lymphoma, neurotuberous blastoma, melanoma, ovarian cancer, pancreatic cancer, prostate cancer or renal cancer.

[0054] In a fourth aspect, the present disclosure proposes the use of the above-mentioned compound, its tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition in the manufacture of a medicament for treating a CD73-related disease.

[0055] According to a specific embodiment of the present disclosure, there is provided a use of the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug, or the above-mentioned pharmaceutical composition, in the manufacture of a medicament for treating a CD73-related disease, which can be used to treat cancer, such as bladder cancer, breast cancer, bile duct cancer, colorectal cancer, colon cancer, gastric cancer, gallbladder cancer, glioblastoma, head and neck cancer, liver cancer, lung cancer, lymphoma, neuroangioblastoma, melanoma, ovarian cancer, pancreatic cancer, prostate cancer or renal cancer.

[0056] In a fifth aspect of the present disclosure, the present disclosure proposes a method for treating a CD73-related disease, the method comprising administering to a subject in need thereof the above-mentioned compound, its tautomer, stereoisomer, hydrate, solvate, pharma- ceutically acceptable salt or prodrug and / or the above-mentioned pharmaceutical composition. The CD73-related disease is cancer. These cancers include, for example, bladder cancer, breast cancer, bile duct cancer, rectal cancer, colon cancer, gastric cancer, gallbladder cancer, neuroblastoma, head and neck cancer, liver cancer, lung cancer, lymphoma, neurotuberous blastoma, melanoma, ovarian cancer, pancreatic cancer, prostate cancer or renal cancer. Terms and Definitions

[0057] Unless otherwise stated, the terms and definitions used in the specification and claims of this application are as follows.

[0058] Those skilled in the art will understand that, according to the convention used in the art, in the structural formulas of this application: TIFF0007651694000034.tif22170 is used to describe a chemical bond, which is the point at which a moiety or substituent is attached to a core structure or backbone structure.

[0059] The term "pharmacologically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0060] The term "pharmaceutically acceptable salts" refers to pharma- ceutically acceptable non-toxic acid or base salts including inorganic acids and bases and organic acids and bases.

[0061] In addition to pharma- ceutically acceptable salts, other salts are contemplated in the disclosure, which may be used in the purification of the compounds or as intermediates in the preparation of other pharma- ceutically acceptable salts, or to identify, characterize, or purify the compounds of the disclosure.

[0062] The term "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein or their physiologically / pharmaceutical acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutical acceptable carriers and excipients. The pharmaceutical composition is intended to facilitate administration of the compound to an organism.

[0063] The term "auxiliary material" refers to pharma- ceutically acceptable inactive ingredients. Examples of classes of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, etc. Excipients can enhance the handling properties, i.e., flowability and / or cohesiveness, of a drug formulation, making the formulation suitable for direct compression.

[0064] The term "prodrug" refers to a compound of the present disclosure that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrug of the present disclosure is produced by modifying a functional group in the compound, and the modification can be removed by conventional manipulation or in vivo to obtain the parent compound. Prodrugs include compounds formed by connecting one hydroxyl group or amino group in the compound of the present disclosure to any group, and when the prodrug of the compound of the present disclosure is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group, a free amino group.

[0065] The term "stereoisomer" refers to isomers resulting from different arrangements of atoms in molecules in space, and includes cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0066] Depending on the choice of raw materials and methods, the compounds of the present disclosure may exist as one of the possible isomers or as a mixture thereof, e.g., pure chiral isomers, or as isomeric mixtures, e.g., racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing a compound having optical activity, the prefixes D and L or R and S indicate the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes D and L or (+) and (-) are symbols to designate the rotation of plane polarized light by the compound, with (-) or L indicating that the compound is levorotatory. Compounds with a prefix of (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are similar except that they are mirror images of each other. Specific stereoisomers can also be referred to as enantiomers, and mixtures of said isomers are usually referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and said racemic mixture or racemate can occur when a chemical reaction or process is in the absence of stereoselectivity or stereospecificity. Many geometric isomers of olefins, C=N double bonds, and the like can also exist in the compounds described herein, and all such stable isomers are contemplated in this disclosure. When a compound described herein contains an olefinic double bond, unless otherwise specified, such double bond includes both E and Z geometric isomers. When the compound contains a disubstituted cycloalkyl, the cycloalkyl substituents can be in either cis or trans (cis- or trans-) configuration.

[0067] When bonds to chiral carbons in the formulae of this disclosure are drawn as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the enantiomerically pure compounds and mixtures generated therefrom are included within the scope of this general formula. In this specification, the method of depicting racemic or enantiomerically pure compounds is taken from Maehr, J.Chem.Ed.1985, 62:114-120. Unless otherwise indicated, wedged bonds and dashed bonds indicate the absolute configuration of a single stereocenter.

[0068] Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be separated in optically active or racemic form. Resolution of racemic mixtures of compounds can be accomplished by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids that are optically active salt-forming organic acids. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or the D and L forms of various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization include stereoisomerically pure α-methyl-benzylamine (e.g., S and R forms or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of racemic mixtures can also be performed by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). It can be performed by high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC). The selection of specific methods and elution conditions, as well as the selection of chromatographic columns, can be selected by those skilled in the art according to the structure and test results of the compounds. In addition, any enantiomer or diastereomer of the compounds described in this disclosure can be formed by stereoorganic synthesis using optically pure starting materials or reagents of known configuration.

[0069] The term "tautomer" refers to an isomer of a functional group resulting from the rapid migration of an atom in a molecule at two positions. Compounds of the present disclosure may exhibit the phenomenon of tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Proton-shift tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium forms, and attempts to isolate a single tautomer usually produce a mixture whose physical and chemical properties match the mixture of compounds. The position of the equilibrium is determined by the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the ketone type predominates, while in phenols, the enol type predominates. The present disclosure includes all tautomeric forms of the compounds.

[0070] The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). All variations in the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are within the scope of the present disclosure.

[0071] For a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. For oral dosage forms in this disclosure, the "effective amount" of one active agent in a composition refers to the amount required to achieve the desired effect when used in combination with another active agent in the composition. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active agent, and the appropriate effective amount in each case can be determined by those skilled in the art based on routine experimentation.

[0072] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity capable of effectively treating a targeted disorder, disease, or condition.

[0073] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Ketone substitution does not occur on aromatic groups. "Optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents can be any on a chemically achievable basis.

[0074] The term "C1-C6 alkyl" should be understood to refer to a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl is, for example, methyl, ethyl, propyl, butyl, amyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylamyl, 3-methylamyl, 2-methylamyl, 1-methylamyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or isomers thereof. In particular, the group has 1, 2 or 3 carbon atoms ("C1-C3 alkyl"), for example, methyl, ethyl, n-propyl or isopropyl.

[0075] The term "C1-C6 alkyl-O-" is to be understood as meaning that the alkyl group is connected to the remainder of the molecule via an oxygen atom, where "C1-C6 alkyl" has the above definition. For example, methyl-O-, ethyl-O-.

[0076] The term "C1-C6 alkyl-S-" should be understood to mean that the alkyl group is connected to the remainder of the molecule via a sulfur atom, where "C1-C6 alkyl" has the above definition. Methyl-S-, ethyl-S-.

[0077] The term "C2-C6 alkenyl group" should be understood as a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one double bond, having 2 to 6 carbon atoms and connected to the rest of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, butyl-1-alkenyl, butyl-2-alkenyl, pentyl-1-alkenyl, pentyl-1,4-dienyl, etc.

[0078] The term "C3-C6 cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring, including fused or bridged polycyclic ring systems, having 3 to 6 carbon atoms, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups.

[0079] The term "4-8 membered heterocyclic group" or "4-8 membered heterocyclic alkyl group" should be understood to denote a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring containing 4 to 8 atoms, where 1, 2, 3, 4 or 5 ring atoms are selected from N, O and S and may be connected through carbon or nitrogen, unless otherwise stated, except -CH 2-イルis optionally replaced by -C(O)-, and, unless otherwise specified, a ring nitrogen atom or ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide, or a ring nitrogen atom is optionally quaternized, with the proviso that -NH in the ring is optionally replaced by an acetyl group, a formyl group, a methyl group, or a methanesulfonyl group, and the ring is optionally substituted with one or more halogens. It is to be understood that when the total number of S and O atoms in a heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. When the heterocyclic group is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic ring or an aromatic ring, with the proviso that at least one ring is non-heteroaromatic. When the heterocyclic group is monocyclic, it must not be aromatic. Examples of heterocyclic groups include, but are not limited to, piperidyl, N-acetylpiperidyl, N-methylpiperidyl, N-formylpiperazine, N-ethylsulfonylpiperazine, higher piperazine, piperazine, azetidine, oxetanyl, morpholino, tetrahydroisoquinoline, tetrahydroquinoline, dihydroindole, tetrahydropyran, dihydro-2H-pyran, tetrahydrofuran, tetrahydropyran, tetrahydropyran-1-oxide, tetrahydropyran-1,1-dioxide, 1H-pyridin-2-one, and 2,5-dioxoxyimidazole alkyl.

[0080] The term "4-8 membered heterocyclic alkenyl group" should be understood as a non-aromatic monocyclic or polycyclic group containing 4 to 8 ring atoms, preferably 5 to 6 ring atoms, provided that said 4-8 membered heterocyclic alkenyl group contains 1 to 3 heteroatoms selected from N, O, S and P and contains at least one carbon-carbon double bond or carbon-nitrogen double bond. The nitrogen hetero, oxygen hetero or sulfur hetero in the group name means that at least one nitrogen, oxygen or sulfur atom is a ring atom, respectively. The nitrogen or sulfur atom of the 4-8 membered heterocyclic alkenyl group can be optionally oxidized to the corresponding N-oxide, S-oxide or S-dioxide. Preferred 4-8 membered heterocyclic alkenyl groups include, but are not limited to, 1,2,3,4-tetrahydropyridyl group, 1,2-dihydropyridyl group, 1,4-dihydropyridyl group, 1,2,3,6-tetrahydropyridyl group, 1,4,5,6-tetrahydropyrimidinyl group, 2-pyrrolinyl group, 3-pyrrolinyl group, 2-imidazolinyl group, 2-pyrazolyl group, dihydroimidazole group, dihydrooxazolyl group, dihydrooxadiazole group, dihydrothiazolyl group, 3,4-dihydro-2H-pyran group, dihydrofuryl group, fluorodihydrofuryl group and oxides thereof. The "4-8 membered heterocyclic alkenyl group" may further include those in which two available hydrogen atoms on the same carbon atom on the ring are simultaneously replaced with a single group =O (i.e., forming a carbonyl group).

[0081] The term "5-8 membered aryl" should be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 5-8 carbon atoms, in particular a ring having 6 carbon atoms ("C6 aryl"), such as phenyl, which may be mono- or polysubstituted if said 5-8 membered aryl is substituted, and there is no restriction on the substitution site, for example ortho, para or meta substitution is possible.

[0082] The term "5-8 membered heteroaryl" is to be understood as a monovalent monocyclic, bicyclic or tricyclic aromatic ring radical having 5-8 ring atoms, in particular 5 or 6 carbon atoms, and containing 1-5 heteroatoms independently selected from N, O and S. Preferably, it is a monovalent monocyclic, bicyclic or tricyclic aromatic ring radical containing 1-3 heteroatoms independently selected from N, O and S, and which in each case may be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridyl, carbazolyl, acridine, phenazinyl, phenothiazinyl, phenoxazinyl, etc.

[0083] The term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0084] It is also necessary to explain that, unless otherwise specified, the description method "independently" used in the present disclosure should be understood in a broad sense, and means that each described individual is independent of each other and may be the same or different specific groups. More specifically, the description method "independently" may mean that specific options shown between the same symbols in different groups do not affect each other, or may also indicate that specific options shown between the same symbols in the same group do not affect each other. Effect of the Invention

[0085] According to embodiments of the present disclosure, the present disclosure provides small molecule CD73 inhibitors that have novel structures, excellent pharmacokinetic properties, and excellent pharmacological efficacy or drug formability, and can be used to effectively treat diseases and pathological conditions associated with CD73.

[0086] The compounds of the present disclosure not only have good inhibitory effects on recombinant human CD73 enzyme, and have strong inhibitory activity on CD73 enzyme bound to the surface of A375 cells, but also suppress AMP-induced CD4 + The compound of the present disclosure has a high plasma free fraction and shows better drug formation than the control compound. In addition, the results of the pharmacokinetic test in mice and dogs show that the compound of the present disclosure shows good pharmacokinetic properties, and in particular, compound 3, compound 4, compound 9 and compound 11 show significantly improved pharmacokinetic properties and good drug formation compared to the positive control.

[0087] In addition, the compounds of the present disclosure have a significant effect of suppressing the growth of CT-26 colorectal cancer and E.G7-OVA T cell lymphoma whether used alone or in combination with a PD-1 / L1 antibody, and the combined use of compound 1 of the present disclosure with a PD-1 antibody can significantly improve the inhibitory effect of the PD-1 antibody on the growth of A375 melanoma, and has a more pronounced synergistic pharmacological effect compared to positive compounds.

[0088] The results of the in vivo efficacy test show that the combination of the disclosed compound with PD-1 antibody can significantly improve the inhibitory effect of PD-1 antibody on the growth of A375 melanoma, and the synergistic efficacy of compound 1 at the same dose is better than that of the positive compound.

[0089] Additional aspects and advantages of the disclosure will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the disclosure. [Brief description of the drawings]

[0090] [Figure 1] FIG. 1 shows changes in tumor volume measured at different times after administration according to an embodiment of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0091] The following examples are used in combination to illustrate the present disclosure. Those skilled in the art can understand that the following examples are only used to illustrate the present disclosure and should not be considered as limiting the scope of the present disclosure. If no specific techniques or conditions are shown in the examples, they should be carried out according to the techniques or conditions described in the literature of the field or according to the product specifications. If no manufacturer is shown for the reagents or equipment used, they are conventional products that can be purchased commercially.

[0092] Unless otherwise indicated, the structures of compounds of this disclosure are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are in units of 10 -6 The solvents used for NMR measurements are deuterated dimethylsulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).

[0093] Definitions of abbreviations in this publication are as follows: M: Molar concentration, 1M hydrochloric acid indicates a 1 mol / L hydrochloric acid solution. DCM: dichloromethane PCC: Pyridine chlorochromate DAST: Diethylaminosulfur trifluoride THF: tetrahydrofuran TEMPO: 2,2,6,6-tetramethylpiperidine oxide DMSO: Dimethyl sulfoxide LC-MS: Liquid chromatography mass spectrometry SFC: Supercritical Fluid Chromatography Flash: Rapid Production Chromatography I C 50 : Median inhibitory concentration, the concentration at which half of the maximum inhibitory effect is achieved.

[0094] Test Example 1: Preparation of positive control compound 1 5-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (reference compound 1) [ka] It is produced by referring to the method of patent WO2019168744Al. 1 H NMR (400 MHz, DMSO-d6) δ 11.51 (s,2H), 8.27 (s, 1H), 7.77 (s, 1H), 6.17-5.85 (m, 1H), 2.69 (s, 3H), 2.32-2.29 (m, 1H), 1.77-1.70(m, 1H), 1.32-1.18 (m, 2H). LC-MS, M / Z (ESI): 295.0 [M+H] + .

[0095] In the following, "Control Compound 1" refers to the compound of Test Example 1.

[0096] Test Example 2: Preparation of positive control compound 2 5-(6-chloro-5-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (Reference compound 2) [ka] It is produced by referring to the method of patent WO2019168744Al. 1 H NMR (400 MHz, CD3OD) δ 8.42 (s, 1H), 8.13 (s, 1H), 5.78-6.08 (m, 1H), 2.48-2.52 (m, 1H), 1.89-1.94 (m, 1H), 1.46-1.51 (m, 1H), 1.33-1.35 (m, 1H). LC-MS, M / Z (ESI): 315.0 [M+H] + .

[0097] In the following, "Control Compound 2" refers to the compound of Test Example 2.

[0098] Test Example 3: Preparation of positive control compound 3 5-(5-((1S,2R)-2-isopropylcyclopropyl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (reference compound 3) [ka] It is produced by referring to the method of patent WO2019168744Al. 1 H NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 8.22 (s, 1H), 2.89 (s, 3H), 2.07-2.10 (m, 1H), 1.33-1.45 (m, 4H), 1.10 (d, 6H). LC-MS, M / Z (ESI): 287.0 [M+H] + .

[0099] In the following, "Control Compound 3" refers to the compound of Test Example 3.

[0100] Example 1: Preparation of target compound 1 5-(6-chloro-5-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 1) [ka] The synthetic route to target compound 1 is shown below. [ka] Step 1: Synthesis of (1S,2S)-2-(((benzyloxy)methyl)cyclopropane-1-carboxylate tert-butyl ester (1C) [ka] Under nitrogen protection, suspend sodium hydride (14.6 g, 365.4 mmol, content 60%) in toluene (500 mL), then add diethylphosphonyl t-butyl acetate (92.2 g, 365.4 mmol) dropwise, and after the dropwise addition is completed, stir at 25°C for 30 minutes, add (S)-2-((((benzyloxy)methyl)ethylene oxide (50.0 g, 304.5 mmol) to the reaction solution, heat to 130°C, and react for 8 hours. Dilute the reaction mixture with water (100 mL). The crude product is obtained by diluting the crude product in a 100 mL x 100 ml column and extracting it with ethyl acetate (100 mL x 2). The organic layers are combined, washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The crude product is purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-10:1, gradient elution) to obtain yellow oily (1S,2S)-2-((((benzyloxy)methyl)cyclopropane-1-carboxylate tert-butyl (1C) (55 g, 68.8% yield). 1 H NMR (400 MHz, CDCl3) δ 7.29-7.37 (m, 5H), 4.53 (s, 2H), 3.35-3.46 (m, 2H), 1.66-1.71 (m, 1H), 1.46-1.50 (m, 1H), 1.45 (s, 9H), 1.13-1.17 (m, 1H), 0.79-0.82 (m, 1H).

[0101] Step 2: Synthesis of (1S,2S)-t-butyl 2-(methylol)cyclopropane-1-carboxylate (1D) [ka] (1S,2S)-2-(((benzyloxy)methyl)cyclopropane-1-carboxylate t-butyl (1C) (55 g, 209.6 mmol) is dissolved in ethanol (500 mL), and under nitrogen protection, palladium on carbon (20.0 g, 10% content) is added, and the mixture is purged with hydrogen gas three times, and then reacted at 50° C. for 24 hours under 50 Psi pressure. The mixture is cooled to room temperature, and filtered through diatomaceous earth to remove palladium on carbon. The filter cake is washed three times with ethanol, and the filtrate is concentrated to obtain yellow oily (1S,2S)-2-(methylol)cyclopropane-1-carboxylate (1D) (36.0 g, 99.7% yield). 1 H NMR (400 MHz, CDCl3) δ 3.50-3.63 (m, 2H), 1.67-1.72 (m, 1H), 1.47 (s, 9H), 1.38 (t, 1H), 1.14-1.89 (m, 1H), 0.78-0.84 (m, 1H).

[0102] Step 3: Synthesis of (1S,2S)-2-(fluoromethyl)cyclopropane-1-carboxylate t-butyl ester (1E) [ka] (1S,2S)-t-Butyl 2-(methylol)cyclopropane-1-carboxylate (1D) (2.5 g, 14.5 mmol) is dissolved in dichloromethane (25 mL), diethylaminosulfur trifluoride (4.68 g, 3.84 mL, 29.0 mmol) is added dropwise at 0° C., and then the mixture is stirred and reacted for 1 hour at 0° C. The reaction mixture is quenched with saturated aqueous sodium bicarbonate solution (100 mL), extracted with dichloromethane (100 mL×2), the organic layers are combined, the organic phase is washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The residue is purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-10:1, gradient elution) to obtain a yellow oily substance, (1S,2S)-2-(fluoromethyl)cyclopropane-1-carboxylate tert-butyl (1E) (2.0 g, 79% yield). 1H NMR (400 MHz, CDCl3) δ 4.19-4.42 (m, 2H), 1.75-1.82 (m, 1H), 1.55-1.59 (m, 1H), 1.46 (s, 9H), 1.18-1.23 (m, 1H), 0.83-0.88 (m, 1H).

[0103] Step 4. Synthesis of (1S,2S)-2-(fluoromethyl)cyclopropane-1-carboxylic acid (1F) [ka] (1S,2S)-t-Butyl 2-(fluoromethyl)cyclopropane-1-carboxylate (1E) (2.0 g, 11.5 mmol) is dissolved in a solution of hydrogen chloride in 1,4-dioxane (4 M, 10 mL) and stirred for 1 hour at 20° C. The reaction is concentrated to give (1S,2S)-2-(fluoromethyl)cyclopropane-1-carboxylate (1F) (1.3 g, 95% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 4.16-4.52 (m, 2H), 1.88-1.94 (m, 1H), 1.67-1.71 (m, 1H), 1.34-1.37 (m, 1H), 1.01-1.05 (m, 1H).

[0104] Step 5. Synthesis of 3,6-dichloro-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazine (1H) [ka] Dissolve 3,6-dichloropyridazine (630 mg, 4.23 mmol) and (1S,2S)-2-(fluoromethyl)cyclopropane-1-carboxylic acid (1F) (500 mg, 4.23 mmol) in water, then add concentrated sulfuric acid (0.5 mL) and heat to 70 ° C under nitrogen protection. Add an aqueous solution of silver nitrate (359.6 mg, 2.12 mmol, 5 mL) quickly, add an aqueous solution of ammonium persulfate (2.90 g, 12.7 mmol, 10 mL) slowly, and continue reacting at 70 ° C for 1 hour. Adjust the reaction solution to about pH 9 with aqueous ammonia, extract with ethyl acetate (100 mL × 2), combine the organic layers, wash the organic phase with saturated brine (50 mL), dry with sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-3:1, gradient elution) to obtain 3,6-dichloro-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazine (1H) (500 mg, 26% yield) as a yellow oil.

[0105] Step 6. Synthesis of 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazine (1J) [ka] Dissolve 3,6-dichloro-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazine (300 mg, 1.36 mmol) and 2,4-dimethoxypyrimidine-5-boronic acid in 1,4-dioxane (10 mL) and water (2 mL), add sodium carbonate (359.6 mg, 3.39 mmol) and [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium (99.3 mg, 135.7 μmol) under nitrogen protection, heat to 70 °C, and react for 2 hours. Dilute the reaction mixture with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic layers, wash the organic phase with saturated saline (50 mL), dry over sodium sulfate, and concentrate to obtain the crude product. The crude product was separated by reversed-phase high performance liquid chromatography (chromatography column: Phenomenex Luna C18 150×25 mm×10 μm, mobile phase, A=water+0.01% by volume trifluoroacetic acid (99%), B=acetonitrile, gradient: 35%-65% B, 10 min) to obtain a yellow solid, 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazine (1J) (150 mg, 34% yield). 1 H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 7.55 (s, 1H), 4.45-4.58 (m, 2H), 4.10 (s, 3H), 4.08 (s, 3H), 2.24-2.29 (m, 1H), 1.65-1.69 (m, 1H), 1.31-1.35 (m, 1H), 1.19-1.23 (m, 1H). LC-MS, M / Z (ESI): 324.9 [M+H] + .

[0106] Step 7, Synthesis of 5-(6-chloro-5-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (1) [ka] 3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazine (150 mg, 461.9 μmol) is dissolved in aqueous hydrochloric acid (1M, 10 mL), heated to 75° C., and reacted for 2 hours. The reaction solution is cooled to room temperature, and a solid precipitates. The solid is filtered, collected, and dried to obtain a yellow solid, 5-(6-chloro-5-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (1) (60 mg, 42% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (d, 1H), 7.96 (s, 1H), 4.39-4.61 (m, 2H), 2.20-2.24 (m, 1H), 1.68-1.72 (m, 1H), 1.19-1.28 (m, 2H). LC-MS, M / Z (ESI): 297.1 [M+H] + .

[0107] Example 2: Preparation of target compound 2 5-(6-chloro-5-(trans-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 2) [ka] The synthetic route to target compound 2 is shown below. [ka] Step 1. Synthesis of trans-2-(trifluoromethyl)cyclopropane-1-carboxylate (2B) [ka] Under nitrogen protection, sodium hydride (2.62 g, 65.4 mmol, content 60%) is slowly added in batches to a solution of trimethyl iodide sulfoxide (14.4 g, 65.4 mmol) in dimethyl sulfoxide (60 mL), and stirred at 25 ° C for 30 minutes. Then, a solution of (E)-ethyl 4,4,4-trifluorobutan-2-enoate (10 g, 59.5 mmol) in dimethyl sulfoxide (30 mL) is added dropwise to the reaction system, and stirred at 25 ° C for 30 minutes. The reaction system is poured into an aqueous solution of ammonium chloride (500 mL), stirred for 20 minutes, and then extracted with petroleum ether (200 mL × 2), the organic phases are combined, the organic phase is washed with saturated saline (200 mL), dried over sodium sulfate, and concentrated to obtain trans-2-(trifluoromethyl)cyclopropane-1-carboxylate (2B) (5.00 g, crude product) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 4.17-4.19 (m, 2H), 2.00-2.10 (m, 1H), 1.98-1.99 (m, 1H), 1.10-1.20 (m, 2H), 0.88-0.91 (m, 3H).

[0108] Step 2. Synthesis of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid (2C) [ka] Dissolve trans-2-(trifluoromethyl)cyclopropane-1-carboxylate (5 g, 27.5 mmol) in tetrahydrofuran (50 mL) and water (25 mL), add lithium hydroxide monohydrate (2.88 g, 68.6 mmol) in a batch, and heat to 80 ° C. and react for 6 hours. Spin-dry the reaction system, add water (50 mL), and extract with ethyl acetate (50 mL x 2). Adjust the separated aqueous phase to pH = 3 with 2 M aqueous hydrochloric acid, then extract the aqueous phase with ethyl acetate (50 mL x 2), combine the organic phase, wash the organic phase with saturated saline (100 mL), dry over sodium sulfate, and concentrate to obtain trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid (2C) (1.5 g, yield 35.5%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 11.09 (br.s, 1H), 2.16-2.23 (m, 1H), 2.02-2.05 (m, 1H), 1.33-1.43 (m, 2H).

[0109] Step 3. Synthesis of 3,6-dichloro-4-(trans-2-(trifluoromethyl)cyclopropyl)pyridazine (2E) [ka] Dissolve 3,6-dichloropyridazine (1.2 g, 8.05 mmol) and trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid (1.24 g, 8.05 mmol) in water (40 mL), add concentrated sulfuric acid (1.2 mL), and heat to 70 ° C under nitrogen protection. Add an aqueous solution of silver nitrate (3.68 g, 21.7 mmol, 5 mL), slowly add an aqueous solution of ammonium persulfate (5.51 g, 24.2 mmol, 20 mL), and continue reacting at 70 ° C for 1 hour. Adjust the reaction solution to about pH 9 with aqueous ammonia, extract with ethyl acetate (200 mL × 2), combine the organic layers, wash the organic phase with saturated saline (300 mL), dry with sodium sulfate, and concentrate to obtain the crude product. The product is purified by separation on a column (petroleum ether:ethyl acetate (V / V) = 10:1, gradient elution) to obtain 3,6-dichloro-4-(trans-2-(trifluoromethyl)cyclopropyl)pyridazine (2E) (650 mg, yield 19.2%) as a yellow oil. LC-MS, M / Z (ESI): 257.0 [M+H] + .

[0110] Step 4. Synthesis of 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-(trans-2-(trifluoromethyl)cyclopropyl)pyridazine (2G) [ka] Dissolve 3,6-dichloro-4-(trans-2-(trifluoromethyl)cyclopropyl)pyridazine (500 mg, 1.39 mmol) and 2,4-dimethoxypyrimidine-5-boric acid (255.2 mg, 1.39 mmol) in 1,4-dioxane (15 mL) and water (5 mL), add sodium carbonate (367.5 mg, 3.47 mmol) and [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium (101.5 mg, 138.7 μmol) under nitrogen protection, heat to 50 °C and react for 12 hours. Dilute the reaction mixture with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic layers, wash the organic phase with saturated saline (50 mL), dry over sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by separation using a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-5:1, gradient elution) to obtain a yellow oily substance, 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-(trans-2-(trifluoromethyl)cyclopropyl)pyridazine (2G) (300 mg, yield 33.6%). LC-MS, M / Z (ESI): 361.1 [M+H] +

[0111] Step 5. Synthesis of 5-(6-chloro-5-(trans-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (2) [ka] 3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-(trans-2-(trifluoromethyl)cyclopropyl)pyridazine (300 mg, 560 μmol) is dissolved in aqueous hydrochloric acid (1 M, 8.32 mL), heated to 50 °C, and reacted for 12 hours. The reaction solution is cooled to 20 °C, a solid precipitates, and the solid is filtered and collected. Methanol (10 mL) is added to the solid, stirred at 50 °C for 1 hour, filtered, and dried to obtain a white solid, 5-(6-chloro-5-(trans-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (2) (63.7 mg, 33.2% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.13 (s, 1H), 2.53-2.58 (m, 1H), 2.37-2.47 (m, 1H), 1.51-1.56 (m, 1H), 1.43-1.48 (m, 1H). LC-MS, M / Z (ESI): 333.0[M+H] + .

[0112] Example 3: Preparation of target compounds 3 and 4 5-(6-chloro-5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 3) [ka] 5-(6-chloro-5-((1R,2R)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 4) [ka] The preparation of target compounds 3 and 4 is shown below. [ka] Step 1, Preparation of 5-(6-chloro-5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (3) and 5-(6-chloro-5-((1R,2R)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (4) [ka] 5-(6-chloro-5-(trans-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (900 mg, 2.49 mmol) was dissolved in dimethyl sulfoxide (20 mL) and then separated by supercritical fluid chromatography. The separation method was (chromatography column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm), mobile phase: A: CO2, B: 0.05% diethylaminoethanol solution, gradient: 50% B, time: 60 min, flow rate: 3 mL / min, column temperature: 35 °C, column pressure: 100 Bar). ) to give white solids 5-(6-chloro-5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (3) (360.4 mg, 43.4% yield) and 5-(6-chloro-5-((1R,2R)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (4) (332.5 mg, 39.9% yield).

[0113] Compound 3: SFC retention time Rt=0.743min, ee%=100%, detection method: Chromatography column: Chiralpak IG-3 50×4.6mm ID, 3μm, mobile phase: A: CO2, B: 0.05% diethylaminoethanol solution, gradient: 40% B, flow rate: 3mL / min, column temperature: 35°C, column pressure: 100 Bar. 1H NMR (400 MHz, CD3OD) δ 8.42 (s, 1H), 8.17 (s, 1H), 2.60-2.65 (m, 1H), 2.22-2.29 (m, 1H), 1.47-1.62 (m, 2H). LC-MS, M / Z (ESI): 333.0 [M+H] + .

[0114] Compound 4: SFC retention time Rt=1.031min, ee%=99.3%, detection method: Chromatography column: Chiralpak IG-3 50×4.6mm ID, 3μm, mobile phase: A: CO2, B: 0.05% diethylaminoethanol solution, gradient: 40% B, flow rate: 3mL / min, column temperature: 35°C, column pressure: 100 Bar. 1 H NMR (400 MHz, CD3OD) δ 8.42 (s, 1H), 8.17 (s, 1H), 2.60-2.64 (m, 1H), 2.24-2.28 (m, 1H), 1.48-1.62 (m, 2H). LC-MS, M / Z (ESI): 333.0 [M+H] + .

[0115] Example 4: Preparation of target compound 3 5-(6-chloro-5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 3) [ka] The synthetic route to target compound 3 is shown below. [ka] Step 1: Synthesis of (1S,2S)-2-(ethoxycarbonyl)cyclopropaneformic acid (3B) [ka] (1S,2S)-2-(methylol)cyclopropane ethyl formate (5.0 g, 34.7 mmol) is dissolved in acetonitrile (50 mL), and 2,2,6,6-tetramethylpiperidine oxide (436.3 mg, 2.8 mmol), sodium dihydrogen phosphate (6.66 g, 55.5 mmol), and disodium hydrogen phosphate (7.88 g, 55.5 mmol) are added in sequence at 25 ° C. Then, sodium hypochlorite solution (0.5 mL) and sodium chlorite (6.27 g, 69.4 mmol) are dissolved in 25 mL water and slowly added dropwise to the reaction system at zero degrees, followed by stirring at 25 ° C for 12 hours. The reaction system is diluted with water (100 mL), then extracted with ethyl acetate (100 mL × 2), the organic layer phase is combined, saturated aqueous sodium carbonate solution (100 mL) is added, and the mixture is stirred for 10 minutes. The organic phase is separated, and the aqueous phase is adjusted to pH=2-3 with 6M hydrochloric acid solution, then extracted with ethyl acetate (100 mL×2), the organic layers are combined, the organic phase is washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated to obtain a colorless oil, (1S,2S)-2-(ethoxycarbonyl)cyclopropaneformic acid (3B) (4.8 g, 87.5% yield). 1 H NMR (400 MHz, CDCl3) δ 10.34 (br.s, 1H), 4.14 (q, 2H), 2.11-2.22 (m, 2H), 1.43-1.50 (m, 2H), 1.25 (t, 3H).

[0116] Step 2. Synthesis of (1S,2S)-ethyl 2-(trifluoromethyl)cyclopropaneformate (3C) [ka] (1S,2S)-2-(ethoxycarbonyl)cyclopropaneformic acid (3.0 g, 19.0 mmol) is added to an autoclave, and sulfur tetrafluoride (9.0 g, 83.3 mmol) is added at -78°C, and then the reaction system is heated to 70°C in the autoclave and reacted for 16 hours. Dichloromethane (20 mL) is added to the reaction system, and the organic phase is washed with saturated aqueous sodium bicarbonate (500 mL), dried over sodium sulfate, and concentrated to obtain a yellow oily product, ethyl (1S,2S)-2-(trifluoromethyl)cyclopropaneformate (3C) (1.17 g, 33.9% yield). 1 H NMR (400 MHz, CDCl3) δ 4.17-4.19 (m, 2H), 2.10-2.20 (m, 1H), 2.00-2.05 (m, 1H), 1.20-1.40 (m, 5H).

[0117] Step 3. Synthesis of (1S,2S)-2-(trifluoromethyl)cyclopropaneformic acid (3D) [ka] Dissolve (1S,2S)-2-(trifluoromethyl)cyclopropaneformic acid ethyl ester (1.1 g, 6.0 mmol) in tetrahydrofuran (10 mL) and water (5 mL), then add lithium hydroxide monohydrate (634 mg, 15.1 mmol) and react at 80° C. for 6 hours. After the reaction is completed, add water (20 mL), extract with dichloromethane (30 mL×2), collect the aqueous phase, adjust the aqueous phase to pH=3 with 6M hydrochloric acid, then extract with dichloromethane (30 mL×3), combine the organic phase, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain brown oily (1S,2S)-2-(trifluoromethyl)cyclopropaneformic acid (3D) (500 mg, 53.7% yield). 1 H NMR (400 MHz, CDCl3) δ 9.80 (br.s, 1H), 2.20-2.23 (m, 1H), 2.04-2.06 (m, 1H), 1.27-1.44 (m, 2H).

[0118] Step 4. Synthesis of 3,6-dichloro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine (3F) [ka] 3,6-Dichloropyridazine (450 mg, 3.02 mmol) and (1S,2S)-2-(trifluoromethyl)cyclopropaneformic acid (465 mg, 3.02 mmol) are dissolved in water (15 mL), then concentrated sulfuric acid (0.5 mL) is added and the mixture is heated to 70 ° C under nitrogen protection. Then, an aqueous solution of silver nitrate (257 mg, 1.51 mmol, 1.5 mL) is quickly added, and an aqueous solution of ammonium persulfate (2.07 g, 9.06 mmol, 5 mL) is slowly added dropwise, and the reaction is continued at 70 ° C for 1 hour. The reaction solution is adjusted to about pH 9 with aqueous ammonia, extracted with ethyl acetate (40 mL × 2), the organic layers are combined, the organic phase is washed with saturated saline (50 mL), dried over sodium sulfate, and concentrated to obtain the crude product. Separation was performed by reversed-phase high performance liquid chromatography (chromatography column: Phenomenex luna C18 150 x 40 mm x 15 μm, mobile phase: A = water + 0.1 vol% TFA, B = acetonitrile, gradient: 35%-65% B, 10 min), and a yellow oily substance, 3,6-dichloro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine (3F) (350 mg, yield 43.8%), was obtained. LC-MS, M / Z (ESI): 256.9[M+H] + .

[0119] Step 5. Synthesis of 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine (3H) [ka] 3,6-Dichloro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine (350 mg, 1.32 mmol) and 2,4-dimethoxypyrimidine-5-boronic acid (343 mg, 1.32 mmol) are dissolved in dioxane (5 mL) and water (1 mL), and sodium carbonate (420 mg, 3.96 mmol) and [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium (97 mg, 132 μmol) are added under nitrogen protection, and the temperature is raised to 50 ° C. and the reaction is carried out for 12 hours. The reaction mixture is diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 2), and the organic phases are combined, washed with saturated saline (50 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The mixture is purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-3:1, gradient elution) to obtain a yellow oily substance, 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine (3H) (300 mg, yield 44%). LC-MS, M / Z (ESI): 361.0 [M+H] + .

[0120] Step 6. Synthesis of 5-(6-chloro-5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (3) [ka] 3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine (30 mg, 58 μmol) is dissolved in aqueous hydrochloric acid (1 M, 1 mL), and the mixture is heated to 50° C. and reacted for 12 hours. A solid precipitates in the reaction system, which is filtered to obtain a white solid, 5-(6-chloro-5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4-diketone (3) (10.04 mg, 50% yield).

[0121] SFC retention time Rt=0.743min, ee%=100%, detection method: Chromatography column: Chiralpak IG-3 50×4.6mm ID, 3μm, mobile phase: A: CO2, B: 0.05% diethylaminoethanol solution, gradient: 40% B, flow rate: 3mL / min, column temperature: 35°C, column pressure: 100 Bar. 1 H NMR (400 MHz, CD3OD) δ 8.42 (s, 1H), 8.17 (s, 1H), 2.60-2.64 (m, 1H), 2.24-2.28 (m, 1H), 1.48-1.62 (m, 2H). LC-MS, M / Z (ESI): 333.0 [M+H] + .

[0122] The SFC retention time of the target compound 3 in this embodiment can be identified by matching the absolute configuration of 5-(6-chloro-5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (compound 3) and 5-(6-chloro-5-((1R,2R)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (compound 4) in Example 3.

[0123] Example 5: Preparation of target compound 5 5-(6-chloro-5-((1S,2S)-2-(2-hydroxypropan-2-yl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 5) [ka] The synthetic route to target compound 5 is shown below. [ka] Step 1. Synthesis of (1S,2S)-2-((S)-1-hydroxyethyl)cyclopropane-1-carboxylate (5B) [ka] (1S,2S)-2-formyl cyclopropane-1-carboxylate t-butyl (5.00 g, 29.4 mmol) is dissolved in tetrahydrofuran (50 mL), methylmagnesium bromide (3 M, 19.6 mL) is added dropwise at 20 ° C., and the mixture is reacted at 20 ° C. for 2 hours. After the reaction is completed, the mixture is quenched with methanol (3 mL), and water (100 mL) is added, followed by extraction with ethyl acetate (100 mL x 2), and the organic phases are combined, washed with saturated saline (50 mL), dried over sodium sulfate, and concentrated to obtain yellow oily (1S,2S)-2-((S)-1-hydroxyethyl)cyclopropane-1-carboxylate t-butyl (5B) (3.84 g, 70.2% yield), which is used directly in the next step.

[0124] Step 2: Synthesis of (1S,2S)-t-butyl 2-acetylcyclopropane-1-carboxylate (5C) [ka] (1S,2S)-2-((S)-1-hydroxyethyl)cyclopropane-1-carboxylate t-butyl (5B) (3.84 g, 20.6 mmol) is dissolved in dichloromethane (50 mL), chlorochromate pyridine (13.3 g, 61.8 mmol) is added, and the mixture is reacted at 20 °C for 2 hours. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, the filter cake is washed twice with dichloromethane (50 mL), and the organic phases are combined and concentrated to obtain the crude product. The crude product is separated and purified on a silica gel column (petroleum ether: ethyl acetate (V / V) = 10:1-5:1, gradient elution) to obtain yellow oily (1S,2S)-2-acetylcyclopropane-1-carboxylate t-butyl (5C) (2.60 g, 68.5% yield). 1 H NMR (400 MHz, CDCl3) δ 2.37-2.42 (m, 1H), 2.30 (s, 3H), 2.08-2.12 (m, 1H), 1.46 (s, 9H), 1.34-1.38 (m, 2H).

[0125] Step 3. Synthesis of (1S,2S)-2-acetylcyclopropane-1-carboxylic acid (5D) [ka] (1S,2S)-2-acetylcyclopropane-1-carboxylate t-butyl (5C) (2.60 g, 14.1 mmol) is dissolved in hydrogen chloride (4 M) in 1,4-dioxane (25 mL) and reacted for 1 h at 20° C. After completion of the reaction, the reaction solution is concentrated to obtain (1S,2S)-2-acetylcyclopropane-1-carboxylate (5D) (1.80 g, 99% yield) as a yellow oil, which is used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ 2.50-2.55 (m, 1H), 2.33 (s, 3H), 2.17-2.21 (m, 1H), 1.47-1.51 (m, 2H).

[0126] Step 4. Synthesis of 1-((1S,2S)-2-(3,6-dichloropyridazin-4-yl)cyclopropyl)ethyl-1-one (5F) [ka] 3,6-Dichloropyridazine (581.4 mg, 3.90 mmol) and (1S,2S)-2-acetylcyclopropane-1-carboxylic acid (5D) (500 mg, 3.90 mmol) are dissolved in water (20 mL), concentrated sulfuric acid (0.5 mL) is added, and the mixture is heated to 70 ° C under nitrogen protection. Then, an aqueous solution of silver nitrate (331.5 mg, 1.95 mmol, 5 mL) is quickly added, and an aqueous solution of ammonium persulfate (2.67 g, 11.7 mmol, 10 mL) is slowly added dropwise, and the reaction is continued at 70 ° C for 1 hour. After the reaction is completed, the reaction solution is adjusted to about pH 9 with ammonia water, extracted with ethyl acetate (50 mL × 2), the organic layers are combined, the organic phase is washed with saturated saline (25 mL), dried over sodium sulfate, and concentrated to obtain the crude product. Separation was carried out by reversed-phase high performance liquid chromatography (chromatography column: 3_Phenomenex Luna C18 75×30 mm×3 μm, mobile phase: A=water+0.05% HCl (36.5%), B=acetonitrile, gradient: 22%-42% B, 8 min), to obtain a yellow oily substance, 1-((1S,2S)-2-(3,6-dichloropyridazin-4-yl)cyclopropyl)ethyl-1-one (5F) (200 mg, yield 22.2%). LC-MS, M / Z (ESI): 231.1 [M+H] + .

[0127] Step 5. Synthesis of 1-((1S,2S)-2-(3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-4-yl)cyclopropyl)ethyl-1-one (5H) [ka] 1-((1S,2S)-2-(3,6-dichloropyridazin-4-yl)cyclopropyl)ethyl-1-one (185 mg, 0.80 mmol) and 2,4-dimethoxypyrimidine-5-boric acid (154.6 mg, 0.84 mmol) are dissolved in 1,4-dioxane (5 mL) and water (1 mL), and sodium carbonate (212.1 mg, 2.00 mmol) and [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium (58.6 mg, 80.1 μmol) are added under nitrogen protection, and the mixture is heated to 70 °C and reacted for 2 hours. The reaction mixture is diluted with water (50 mL), extracted with ethyl acetate (50 mL × 2), the organic layers are combined, the organic phase is washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The mixture is purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-1:1, gradient elution) to obtain a yellow solid, 1-((1S,2S)-2-(3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-4-yl)cyclopropyl)ethyl-1-one (5H) (150 mg, 56% yield). LC-MS, M / Z (ESI): 335.2 [M+H] +

[0128] Step 6. Synthesis of 2-((1S,2S)-2-(3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-4-yl)cyclopropyl)propyl-2-ol (5I) [ka] Dissolve 1-((1S,2S)-2-(3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-4-yl)cyclopropyl)ethyl-1-one (5H) (100 mg, 0.29 mmol) in tetrahydrofuran (5 mL), add methylmagnesium bromide (3 M, 0.2 mL) dropwise at 0 ° C, and react at 20 ° C for 1 hour. After the reaction is completed, quench with methanol (1 mL), add water (25 mL), extract with ethyl acetate (25 mL × 2), combine the organic phase, wash the organic phase with saturated saline (25 mL), dry with sodium sulfate, and concentrate to obtain the crude product. Separation was carried out by reversed-phase high performance liquid chromatography (chromatography column: 3_Phenomenex Luna C18 75×30 mm×3 μm, mobile phase: A=water+0.05% HCl (36.5%), B=acetonitrile, gradient: 27%-47% B, 8.5 min), to obtain the yellow oily compound 2-((1S,2S)-2-(3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-4-yl)cyclopropyl)propyl-2-ol (5I) (20 mg, yield 12.7%). LC-MS, M / Z (ESI): 351.3 [M+H] + .

[0129] Step 7, synthesis of 5-(6-chloro-5-((1S,2S)-2-(2-hydroxypropan-2-yl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 5) [ka] 2-((1S,2S)-2-(3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-4-yl)cyclopropyl)propyl-2-ol (5I) (20 mg, 57.0 μmol) is dissolved in aqueous hydrochloric acid (1 M, 2 mL), and the temperature is raised to 50° C. and the reaction is allowed to proceed for 12 hours. The reaction solution is concentrated and separated by reversed-phase high performance liquid chromatography (chromatography column: 3_Phenomenex Luna C18 75×30 mm×3 μm, mobile phase: A=water+0.05% by volume HCl (36.5%), B=acetonitrile, gradient: 11%-31% B, 7.5 min), to obtain a white solid compound 5-(6-chloro-5-((1S,2S)-2-(2-hydroxypropan-2-yl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (5) (10 mg, yield 49%). 1 H NMR (400 MHz, CD3OD) δ 8.53 (s, 1H), 8.06 (s, 1H), 2.38-2.42 (m, 1H), 1.57-1.62 (m, 1H), 1.48-1.51 (m, 1H), 1.35 (s, 3H), 1.34 (s, 3H), 1.22-1.28 (m, 1H). LC-MS, M / Z (ESI): 323.3 [M+H] + .

[0130] Example 6: Preparation of target compound 6 5-(6-chloro-5-((1S,2S)-2-(1-hydroxyethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 6) [ka] The synthetic route to target compound 6 is shown below. [ka] Step 1. Synthesis of 1-((1S,2S)-2-(3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-4-yl)cyclopropyl)ethyl-1-ol (6B) [ka] 1-((1S,2S)-2-(3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-4-yl)cyclopropyl)ethyl-1-one (100 mg, 0.29 mmol) (see Example 5 for synthesis method) is dissolved in methanol (5 mL), sodium borohydride (11.3 mg, 0.29 mmol) is added at 0 ° C., and the mixture is reacted at 20 ° C. for 1 hour. After the reaction is completed, the mixture is quenched with water (25 mL), extracted with ethyl acetate (25 mL × 2), the organic phase is combined, the organic phase is washed with saturated saline (25 mL), dried over sodium sulfate, and concentrated to obtain a yellow oily substance, 1-((1S,2S)-2-(3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-4-yl)cyclopropyl)ethyl-1-ol (6B) (100 mg, 99% yield), which is used directly in the next step. LC-MS, M / Z (ESI): 337.2 [M+H] + .

[0131] Step 2. Synthesis of 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(1-fluoroethyl)cyclopropyl)pyridazine (6C) [ka] (S)-1-((1S,2S)-2-(3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-4-yl)cyclopropyl)ethyl-1-ol (6B) (100 mg, 0.29 mmol) is dissolved in dichloromethane (5 mL), and diethylaminosulfur trifluoride (95.7 mg, 0.078 mL, 0.59 mmol) is added dropwise at 0° C., and then the mixture is stirred at 0° C. for 0.5 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (20 mL) and then extracted with dichloromethane (25 mL × 3), the organic layers were combined, the organic phase was washed with saturated brine (25 mL), dried over sodium sulfate, and concentrated to give a yellow oil, 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-((S)-1-fluoroethyl)cyclopropyl)pyridazine (6C) (100 mg, 99% yield), which was used directly in the next step. LC-MS, M / Z (ESI): 339.3 [M+H] + .

[0132] Step 3. Synthesis of 5-(6-chloro-5-((1S,2S)-2-(1-hydroxyethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (6) [ka] 3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(1-fluoroethyl)cyclopropyl)pyridazine (6C) (100 mg, 0.29 mmol) is dissolved in aqueous hydrochloric acid (1 M, 3 mL), and the temperature is raised to 60° C. and the reaction is allowed to proceed for 1 hour. The reaction solution is concentrated and separated by reversed-phase high performance liquid chromatography (chromatography column: 3_Phenomenex Luna C18 75×30 mm×3 μm, mobile phase: A=water+0.05% by volume HCl (36.5%), B=acetonitrile, gradient: 8%-28% B, 7 min), to obtain a pale yellow solid, 5-(6-chloro-5-((1S,2S)-2-(1-hydroxyethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (6) (5 mg, yield 4.8%). 1 H NMR (400 MHz, CD3OD) δ 8.59 (s, 1H), 8.08 (s, 1H), 3.63-3.68 (m, 1H), 2.28-2.33 (m, 1H), 1.54-1.57 (m, 1H), 1.44-1.48 (m, 1H), 1.32-1.34 (m, 4H). LC-MS, M / Z (ESI): 309.1 [M+H] + .

[0133] Example 7: Preparation of target compound 7 5-(6-Methyl-5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 7) [ka] The synthetic route to target compound 7 is shown below. [ka] Step 1, Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine (7B) [ka] 3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine (240 mg, 467 μmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxytriborane (176 mg, 700 μmol) are dissolved in dioxane (5 mL) and water (1 mL), and potassium carbonate (161 mg, 1.17 mmol) and [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium (68.3 mg, 93.4 μmol) are added under nitrogen protection, and the mixture is heated to 90°C and reacted for 12 hours. The reaction system is spin-dried to obtain the crude product. The residue is purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-1:1, gradient elution) to obtain 6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine (7B) (150 mg, yield 63.9%) as a yellow oil. LC-MS, M / Z (ESI): 341.1 [M+H] + .

[0134] Step 2. Synthesis of 5-(6-methyl-5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (7) [ka] 6-(2,4-Dimethoxypyrimidin-5-yl)-3-methyl-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine (150 mg, 441 μmol) is dissolved in aqueous hydrochloric acid (1 M, 3 mL), and the temperature is raised to 50° C. and the reaction is allowed to proceed for 12 hours. The reaction system is spun dry to obtain a crude product, which is then separated by reverse-phase high performance liquid chromatography (chromatography column: 3_Phenomenex Luna C18 75×30 mm×3 μm, mobile phase: A=water+hydrochloric acid (0.05%), B=acetonitrile, gradient: 12%-32% B, 6.5 min), to obtain a white solid, 5-(6-methyl-5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (7) (108.5 mg, yield 77.6%). 1 H NMR (400 MHz, CD3OD) δ 8.67 (s, 1H), 8.51 (s, 1H), 2.89 (s, 3H), 2.69-2.72 (m, 1H), 2.45-2.49 (m, 1H), 1.64-1.74 (m, 2H). LC-MS, M / Z (ESI): 313.0 [M+H] + .

[0135] Example 8: Preparation of target compound 8 5-(6-chloro-5-((1R,2R)-2-(fluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 8) [ka] The synthetic route to target compound 8 is shown below. [ka] Step 1: Synthesis of (1R,2R)-2-(((benzyloxy)methyl)cyclopropane-1-carboxylate tert-butyl ester (8C) [ka] Under nitrogen protection, sodium hydride (2.92 g, 73.1 mmol, 60% purity) is suspended in toluene (100 mL), diethylphosphonyl t-butyl acetate (16.9 g, 66.9 mmol) is added dropwise, and after the addition is completed, the mixture is stirred at 25 ° C for 30 minutes, then (R)-(+)-glycidyl benzyl ether (10.0 g, 60.9 mmol) is added to the reaction solution, and the temperature is raised to 130 ° C and the reaction is carried out for 1 hour. The reaction mixture is diluted with water (200 mL), then extracted with ethyl acetate (200 mL × 2), the organic layers are combined, the organic phase is washed with saturated saline solution (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product is purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-10:1, gradient elution) to obtain a yellow oily substance, (1R,2R)-2-(((benzyloxy)methyl)cyclopropane-1-carboxylate (8C) (12 g, 75.1% yield). 1 H NMR (400 MHz, CDCl3) δ 7.29-7.36 (m, 5H), 4.53 (s, 2H), 3.38-3.43 (m, 2H), 1.66-1.71 (m, 1H), 1.46-1.50 (m, 1H), 1.45 (s, 9H), 1.13-1.17 (m, 1H), 0.79-0.82 (m, 1H).

[0136] Step 2: Synthesis of (1R,2R)-t-butyl 2-(methylol)cyclopropane-1-carboxylate (8D) [ka] (1R,2R)-2-(((benzyloxy)methyl)cyclopropane-1-carboxylate t-butyl (12.0 g, 45.7 mmol) is dissolved in ethanol (100 mL), and under nitrogen protection, palladium on carbon (3.00 g, 10% content) is added, and the mixture is purged with hydrogen gas three times, and then reacted at 50 Psi pressure and 60° C. for 12 hours. The mixture is cooled to room temperature, and filtered through diatomaceous earth to remove palladium on carbon. The filter cake is washed three times with ethanol, and the filtrate is concentrated to obtain yellow oily (1R,2R)-2-(methylol)cyclopropane-1-carboxylate (8D) (7.50 g, 95.2% yield). 1 H NMR (400 MHz, CDCl3) δ 3.56-3.61 (m, 1H), 3.70-3.75 (m, 1H), 1.63-1.71 (m, 2H), 1.45 (s, 9H), 1.14-1.17 (m, 1H), 0.77-0.81 (m, 1H).

[0137] Step 3: Synthesis of (1R,2R)-2-(fluoromethyl)cyclopropane-1-carboxylate t-butyl ester (8E) [ka] (1R,2R)-t-butyl 2-(methylol)cyclopropane-1-carboxylate (7.50 g, 43.6 mmol) is dissolved in dichloromethane (100 mL), diethylaminosulfur trifluoride (10.5 g, 8.63 mL, 65.3 mmol) is added dropwise at 0° C., and the reaction is stirred for 1 h at 0° C. The reaction mixture is quenched with saturated aqueous sodium bicarbonate solution (100 mL), then extracted with dichloromethane (100 mL×2), the organic layers are combined, the organic phase is washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The residue is purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-10:1, gradient elution) to obtain a yellow oily substance, (1R,2R)-2-(fluoromethyl)cyclopropane-1-carboxylate tert-butyl (8E) (4.00 g, yield 52.7%). 1H NMR (400 MHz, CDCl3) δ 4.14-4.44 (m, 2H), 1.75-1.82 (m, 1H), 1.57-1.59 (m, 1H), 1.46 (s, 9H), 1.18-1.23 (m, 1H), 0.83-0.89 (m, 1H).

[0138] Step 4. Synthesis of (1R,2R)-2-(fluoromethyl)cyclopropane-1-carboxylic acid (8F) [ka] (1R,2R)-2-(fluoromethyl)cyclopropane-1-carboxylate t-butyl (4.00 g, 22.9 mmol) is dissolved in hydrogen chloride (4 M) in 1,4-dioxane (20 mL) and stirred for 1 hour at 25° C. The reaction mixture is concentrated to obtain a yellow oily compound (1R,2R)-2-(fluoromethyl)cyclopropane-1-carboxylate (8F) (2.50 g, 92.2% yield). 1 H NMR (400 MHz, CDCl3) δ 4.16-4.97 (m, 2H), 1.88-1.93 (m, 1H), 1.66-1.71 (m, 1H), 1.32-1.36 (m, 1H), 0.99-1.04 (m, 1H).

[0139] Step 5. Synthesis of 3,6-dichloro-4-((1R,2R)-2-(fluoromethyl)cyclopropyl)pyridazine (8H) [ka] Dissolve 3,6-dichloropyridazine (3.15 g, 21.2 mmol) and (1R,2R)-2-(fluoromethyl)cyclopropane-1-carboxylic acid (2.50 g, 21.2 mmol) in water (30 mL), then add concentrated sulfuric acid (2.71 mL) and heat to 70 ° C under nitrogen protection. Add aqueous silver nitrate (1.80 g, 10.6 mmol, 10 mL) quickly, add aqueous ammonium persulfate (14.5 g, 63.5 mmol, 30 mL) dropwise slowly, and continue reacting at 70 ° C for 1 hour. Adjust the reaction solution to pH about 9 with aqueous ammonia, then extract with ethyl acetate (200 mL × 2), combine the organic layers, wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-3:1, gradient elution) to obtain a yellow oily substance, 3,6-dichloro-4-((1R,2R)-2-(fluoromethyl)cyclopropyl)pyridazine (8H) (200 mg, yield 4.3%). LC-MS, M / Z (ESI): 221.0 [M+H] + .

[0140] Step 6. Synthesis of 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1R,2R)-2-(fluoromethyl)cyclopropyl)pyridazine (8J) [ka] 3,6-Dichloro-4-((1R,2R)-2-(fluoromethyl)cyclopropyl)pyridazine (200 mg, 1.36 mmol) and 2,4-dimethoxypyrimidine-5-boronic acid (149.8 mg, 0.814 mmol) are dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), and sodium carbonate (287.7 mg, 2.71 mmol) and [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium (66.2 mg, 90.5 μmol) are added under nitrogen protection, and the temperature is raised to 50 ° C. and the reaction is carried out for 12 hours. The reaction mixture is diluted with water (20 mL), and then extracted with ethyl acetate (20 mL × 3), and the organic layers are combined, and the organic phase is washed with saturated saline solution (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product is purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-3:1, gradient elution) to obtain a yellow oily substance, 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1R,2R)-2-(fluoromethyl)cyclopropyl)pyridazine (8J) (100 mg, 34% yield). LC-MS, M / Z (ESI): 325.1 [M+H] + .

[0141] Step 7, synthesis of 5-(6-chloro-5-((1R,2R)-2-(fluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 8) [ka] 3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1R,2R)-2-(fluoromethyl)cyclopropyl)pyridazine (80 mg, 246.4 μmol) is dissolved in aqueous hydrochloric acid (1 M, 2 mL), and the temperature is raised to 50° C. and the reaction is allowed to proceed for 2 hours. The reaction system was spin-dried to obtain the crude product, which was then separated by reverse-phase high performance liquid chromatography (chromatography column: 3_Phenomenex Luna C18 75×30 mm×3 μm, solvent: A=water+hydrochloric acid (0.05%), B=acetonitrile, gradient: 17% - 37% B, 6.5 min), to obtain the white solid compound 5-(6-chloro-5-((1R,2R)-2-(fluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (8) (19 mg, yield 26%).

[0142] 1 H NMR (400 MHz, CD3OD) δ 8.75 (s, 1H), 8.20 (s, 1H), 4.37-4.65 (m, 2H), 2.43-2.47 (m, 1H), 1.98-2.01 (m, 1H), 1.45-1.56 (m, 2H). LC-MS, M / Z (ESI): 297.1 [M+H] + .

[0143] Example 9: Preparation of target compound 9 5-(6-chloro-5-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 9) [ka] The synthetic route to target compound 9 is shown below. [ka] Step 1, (S)-2-Bromosuccinic acid (9B) [ka] (S)-2-aminosuccinic acid (50.0 g, 375.6 mmol) is dissolved in concentrated sulfuric acid (134.8 mL) and water (900 mL), potassium bromide (205.6 g, 1.73 mol) is added at 0 ° C, and an aqueous solution of sodium nitrite (46.7 g, 676.2 mmol, 100 mL) is slowly added dropwise at 0 ° C, and the mixture is reacted at 25 ° C for 4 hours. After the reaction is completed, the reaction solution is extracted with ethyl acetate (500 mL × 2), the organic phase is combined, washed with saturated saline (500 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which is then slurried with petroleum ether (100 mL) to obtain (S)-2-bromosuccinic acid (9B) (70 g, crude product).

[0144] Step 2, (S)-2-Bromobutane-1,4-diol (9C) [ka] Dissolve (S)-2-bromosuccinic acid (210.0 g, 1.07 mol) in tetrahydrofuran (2100 mL), then slowly add borane dimethylsulfide solution (10 M, 319.8 mL) at 0°C, and react at room temperature for 2 hours. After the reaction is complete, add water (320 mL) dropwise at 0°C to quench the reaction, add solid potassium carbonate (480 g), continue stirring for 1 hour, filter, wash the filter cake with tetrahydrofuran (250 mL x 2), and concentrate the filtrate to obtain (S)-2-bromobutane-1,4-diol (9C) (255.0 g, crude product).

[0145] Step 3, (R)-2-(2-(benzyloxy)ethyl)oxapropion ring (9D) [ka] Under nitrogen protection, add sodium hydride (50.3g, 1.26mmol, 60%) to tetrahydrofuran (900mL), then dissolve (S)-2-bromobutane-1,4-diol (85.0g, 502.9mmol) in tetrahydrofuran (100mL) and slowly add dropwise to the above solution, controlling the temperature at about 0°C. Then, dissolve benzyl bromide (120.4g, 704.1mmol) in tetrahydrofuran (100mL) and add it to the reaction solution together with tetrabutylammonium iodide (18.6g, 50.3mmol), and react at 25°C for 5 hours. After the reaction is completed, the reaction mixture is quenched with water (500 mL), and then extracted with ethyl acetate (500 mL x 2). The organic phases are combined, washed with saturated saline (500 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-10:1) to obtain (R)-2-(2-(benzyloxy group)ethyl)oxapropion ring (9D) (65 g, yield 72.2%).

[0146] Step 4, (1S,2R)-2-(2-(benzyloxy)ethyl)cyclopropaneformate ethyl (9E) [ka] Under nitrogen protection, sodium hydride (5.25 g, 131.3 mmol, 60%) is suspended in toluene (300 mL), then triethyl phosphonoacetate (27.6 g, 123.2 mmol) is added dropwise at 0°C, and after the addition is completed, the mixture is stirred at 25°C for 1 hour, then (R)-2-(2-(benzyloxy group)ethyl)oxapropion ring (18.0 g, 100.9 mmol) is added to the reaction solution, and the temperature is raised to 130°C and the mixture is reacted for 3 hours. The reaction mixture is diluted with water (300 mL), then extracted with ethyl acetate (300 mL x 2), the organic layer phase is combined, the organic phase is washed with saturated saline solution (200 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The mixture is separated and purified using a silica gel column (petroleum ether:ethyl acetate (V / V) = 1:0-10:1) to obtain the yellow oily compound (1S,2R)-ethyl 2-(2-(benzyloxy)ethyl)cyclopropaneformate (9E) (17 g, yield 67.8%).

[0147] Step 5, (1S,2R)-ethyl 2-(2-hydroxyethyl)cyclopropaneformate (9F) [ka] (1S,2R)-ethyl 2-(2-(benzyloxy)ethyl)cyclopropaneformate (32.0 g, 128.9 mmol) is dissolved in ethanol (400 mL), and under nitrogen protection, palladium on carbon (9.0 g, 10%) is added, purged with hydrogen gas three times, and then reacted at 50 Psi pressure at 60° C. for 24 hours. Cool to room temperature, filter through diatomaceous earth to remove palladium on carbon, wash the filter cake three times with ethanol, and concentrate the filtrate to obtain the yellow oily compound (1S,2R)-ethyl 2-(2-hydroxyethyl)cyclopropaneformate (9F) (20.1 g, crude product).

[0148] Step 6. 2-((1R,2S)-2-(ethoxycarbonyl)cyclopropyl)acetic acid (9G) [ka] (1S,2R)-ethyl 2-(2-hydroxyethyl)cyclopropaneformate (15.0 g, 94.8 mmol) is dissolved in acetonitrile (380 mL), and 2,2,6,6-tetramethylpiperidine oxide (1.19 g, 7.59 mmol), sodium dihydrogen phosphate (18.2 g, 151.7 mmol), and disodium hydrogen phosphate (21.5 g, 151.7 mmol) are added in sequence at 25 ° C. Next, sodium hypochlorite solution (1.46 mL, 8%) and sodium chlorite (17.2 g, 189.6 mmol) are dissolved in water (190 mL), and slowly added dropwise to the reaction system at 0 ° C., and then stirred at 25 ° C. for 12 hours. The reaction mixture is diluted with water (500 mL), then extracted with ethyl acetate (200 mL x 2), the organic layers are combined, saturated aqueous sodium carbonate solution (500 mL) is added, and the mixture is stirred for 10 minutes. The organic layers are separated, the aqueous phase is adjusted to pH = 2-3 with 6 M hydrochloric acid solution, extracted with ethyl acetate (300 mL x 2), the organic layers are combined, the organic phase is washed with saturated brine (500 mL), dried over sodium sulfate, and concentrated to obtain the yellow oily compound 2-((1R,2S)-2-(ethoxycarbonyl)cyclopropyl)acetic acid (9G) (9.00 g, 55.1% yield).

[0149] Step 7, (1S,2R)-ethyl 2-(2,2,2-trifluoroethyl)cyclopropaneformate (9H) [ka] 2-((1R,2S)-2-(ethoxycarbonyl)cyclopropyl)acetic acid (9.00 g, 45.9 mmol) is added to the autoclave, and sulfur tetrafluoride (18.0 g, 166.6 mmol) is added at -78 °C. The reaction system is heated to 70 °C in the autoclave and reacted for 16 hours. Dichloromethane (100 mL) is added to the reaction system, and the organic phase is washed with saturated aqueous sodium bicarbonate solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the yellow oily compound (1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropaneformate ethyl (9H) (8.00 g, crude product), which is used directly in the next step.

[0150] Step 8, (1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropanecarboxylic acid (9I) [ka] Dissolve (1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropaneformate ethyl (8.00 g, 40.8 mmol) in tetrahydrofuran (80 mL) and water (40 mL), add lithium hydroxide monohydrate (5.13 g, 122.4 mmol), and react at 50 ° C for 12 hours. After the reaction is completed, add water (100 mL), extract with dichloromethane (100 mL × 2), collect the aqueous phase, adjust the aqueous phase to pH = 3-4 with 6 M hydrochloric acid, then extract with dichloromethane (100 mL × 2), combine the organic phase, wash with saturated saline (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the brown oily compound (1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropanecarboxylic acid (9I) (6.30 g, yield 91.9%).

[0151] Step 9. Synthesis of 3,6-dichloro-4-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazine (9K) [ka] 3,6-Dichloropyridazine (4.5g, 30.2mmol) and (1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropanecarboxylic acid (5.08g, 16.1mmol) are dissolved in water (90mL), then concentrated sulfuric acid (4.60mL) is added, and the temperature is raised to 70°C under nitrogen protection. Next, an aqueous solution of silver nitrate (2.05g, 12.1mmol, 25.0mL) is quickly added, and then an aqueous solution of ammonium persulfate (20.7g, 90.6mmol, 45.0mL) is slowly added dropwise, and the reaction is continued at 70°C for 1 hour. The reaction solution is adjusted to pH about 9 with aqueous ammonia, extracted with ethyl acetate (100mL x 2), the organic layers are combined, the organic phase is washed with saturated saline (100mL), dried over sodium sulfate, and concentrated to obtain the crude product. Then, the mixture is separated by reverse phase Flash to obtain the yellow oily compound 3,6-dichloro-4-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazine (9K) (300 mg, yield 2.98%). LC-MS, M / Z: 271.0[M+H] + .

[0152] Step 10. Synthesis of 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazine (9M) [ka] Dissolve 3,6-dichloro-4-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazine (300 mg, 1.11 mmol) and 2,4-dimethoxypyrimidine-5-boronic acid (204 mg, 1.11 mmol) in dioxane (3 mL) and water (0.8 mL), add sodium carbonate (352 mg, 3.32 mmol) and [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane (90.4 mg, 111 μmol) under nitrogen protection, heat to 70 ° C and react for 1 hour. Dilute the reaction mixture with water (50 mL), extract with ethyl acetate (50 mL × 3), combine the organic phase, wash the organic phase with saturated saline (50 mL), dry with sodium sulfate, and concentrate to obtain the crude product. The crude product is separated by reversed-phase high performance liquid chromatography (chromatography column: Phenomenex Gemini-NX C18 75×30 mm×3 μm, mobile phase: A=water+0.225% by volume formic acid (99.9%), B=acetonitrile, gradient: 38%-68%, 7.0 min), to obtain the compound 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazine (9M) (80.0 mg, yield 19.3%) as a pale yellow solid. LC-MS, M / Z: 375.1[M+H] + .

[0153] Step 11: Synthesis of 5-(6-chloro-5-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (9) [ka] 3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazine (75.0 mg, 200 μmol) is dissolved in tetrahydrofuran (0.5 mL), added to aqueous hydrochloric acid (1 M, 0.2 mL), heated to 50° C., and reacted for 12 hours. After the reaction system was concentrated to dryness, the crude product was first separated by reversed-phase high performance liquid chromatography (chromatography column: Phenomenex Gemini-NX C18 75×30 mm×3 μm, mobile phase: A=water+0.225% by volume formic acid (99%), B=acetonitrile, gradient: 22%-52%, 7.0 min), and then separated by supercritical fluid chromatography (chromatography column: DAICEL CHIRALPAK AD (250 mm×30 mm, 10 μm), mobile phase: 0.1% ammonia water-methanol solution, gradient: 50% - 50%, 40 min) to obtain the white solid compound 5-(6-chloro-5-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (9) (10 mg, 14.3% yield).

[0154] SFC: Rt=0.787min, de%=100%, Detection method: Chromatography column: Chiralpak AD-3 50×4.6mm ID, 3μm, Mobile phase: A: CO2, B: 0.05% diethylamine in methanol, Elution gradient: 40% methanol (containing 0.05% diethylamine) and 60% carbon dioxide, Flow rate: 3mL / min, Detector: PDA, Column temperature: 35℃, Column pressure: 100 Bar 1 H NMR (400 MHz, CD3OD):δ 8.40 (s, 1H), 8.03 (s, 1H), 2.45-2.48 (m, 1H), 2.36-2.38 (m, 1H), 2.24-2.26 (m, 1H), 1.46-1.48 (m, 1H), 1.27-1.30 (m, 2H). LC-MS, M / Z: 347.0[M+H] + .

[0155] Example 10: Preparation of target compound 10 5-(6-chloro-5-((1S,2S)-2-(perfluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 10) [ka] See Example 4 for the synthesis method. LC-MS, M / Z (ESI): 383.0 [M+H] + .

[0156] Example 11: Preparation of target compound 11 5-(6-chloro-5-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 11) [ka] The synthetic route to target compound 11 is shown below. [ka] Step 1: Synthesis of (1S,2S)-2-((trifluoromethoxy)methyl)cyclopropane-1-carboxylate t-butyl ester (11B) [ka] Under nitrogen protection, (1S,2S)-2-(methylol)cyclopropane-1-tert-butyl carboxylate (11A) (20 g, 116 mmol), potassium fluoride (27.0 g, 465 mmol), selective fluorine reagent (61.6 g, 174 mmol) and silver trifluoromethanesulfonate (90 g, 348 mmol) were added in sequence to a light-shielded reaction bottle, and a solution of 2-fluoropyridine (33.8 g, 348 mmol) and trifluoromethyltrimethylsilane (49.5 g, 348 mmol) in ethyl acetate (600 mL) was added dropwise. After the addition was completed, the reaction was continued at room temperature for 18 h. Add water (500 mL) to dilute, separate the liquid, extract the aqueous phase with ethyl acetate (500 mL × 2), combine the organic layers, dry over anhydrous sodium sulfate, and concentrate. Separate and purify the residue on a silica gel column (petroleum ether: ethyl acetate (V / V) = 500:1) to obtain a colorless liquid, (1S,2S)-2-((trifluoromethoxy)methyl)cyclopropane-1-carboxylate t-butyl (11B) (8.5 g, yield 30.5%).

[0157] Step 2. Synthesis of (1S,2S)-2-((trifluoromethoxy)methyl)cyclopropane-1-carboxylic acid (11C) [ka] Dissolve (1S,2S)-2-((trifluoromethoxy)methyl)cyclopropane-1-carboxylate t-butyl (11B) (8.5 g, 35.4 mmol) in hydrogen chloride dioxane (50 mL, 4 M) and react at room temperature for 20 h with stirring. Concentrate the reaction mixture to obtain (1S,2S)-2-((trifluoromethoxy)methyl)cyclopropane-1-carboxylate (11C) (5.5 g, 84.5% yield) as a yellow oil.

[0158] Step 3. Synthesis of 3,6-dichloro-4-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazine (11E) [ka] 3,6-Dichloropyridazine (4.05g, 27.2mmol) and (1S,2S)-2-((trifluoromethoxy)methyl)cyclopropane-1-carboxylic acid (11C) (5g, 27.2mmol) are dissolved in water (100mL), silver nitrate (2.307g, 13.58mmol) is added, and concentrated sulfuric acid (3.5mL) is added. The mixture is heated to 70℃ under nitrogen protection. An aqueous solution of ammonium persulfate (20.45g, 90mmol, 100mL) is slowly added dropwise, and the reaction is continued at 70℃ for 2 hours. The reaction solution is adjusted to pH about 9 with aqueous ammonia, extracted with ethyl acetate (300mL×3), the organic layers are combined, dried over sodium sulfate, and concentrated to obtain the crude product. The crude product is purified by separation using a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-3:1) to obtain a pale yellow solid, 3,6-dichloro-4-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazine (11E) (5.3 g, yield 68.0%). LC-MS, M / Z: 287.1[M+H] + .

[0159] Step 4. Synthesis of 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazine (11G) [ka] Under nitrogen protection, 3,6-dichloro-4-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazine (11E) (5.3 g, 18.46 mmol), 2,4-dimethoxypyrimidine-5-boronic acid (3.06 mg, 16.62 mmol), sodium carbonate (5.87 g, 55.4 mmol) and [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium (1.351 g, 1.846 mmol) are dissolved in dioxane (100 mL) and water (20 mL), and the mixture is heated to 70° C. and reacted for 2 hours. The reaction mixture is diluted with water (200 mL), and then extracted with ethyl acetate (150 mL×3), and the organic layers are combined, dried over sodium sulfate, and concentrated to obtain the crude product. The crude product is separated by reversed-phase high performance liquid chromatography, the separation method is chromatography column: Phenomenex Luna C18 150 x 25 mm x 10 μm, mobile phase: [water (0.01% TFA)-ACN], B%: 35%-65%, 10 min, and a pale yellow oily substance, 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazine (11G) (2 g, yield 27.7%) is obtained. LC-MS, M / Z: 391.1[M+H] + .

[0160] Step 5. Synthesis of 5-(6-chloro-5-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (11) [ka] 3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazine (11G) (2 g, 0.038 mmol) is dissolved in tetrahydrofuran (10 mL), added to aqueous hydrochloric acid (1 M, 25.6 mL), heated to 50° C., and reacted for 20 hours. The organic solvent in the reaction solution is concentrated, filtered, and the white solid is collected and dried to obtain 5-(6-chloro-5-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (11) (1.4 g, 75.0% yield). 1 H NMR (400 MHz, DMSO_d6) δ11.58~11.56(d, 1H), 11.52(s, 1H), 8.28~8.27 (d, 1H), 7.94 (s, 1H), 4.24~4.12 (m, 2H), 2.27~2.22 (m, 1H), 1.67~1.62 (m, 1H), 1.30-1.19 (m, 2H). LC-MS, M / Z: 363.0[M+H] + .

[0161] Example 12: Preparation of target compound 12 5-(6-chloro-5-((1S,2S)-2-(methoxymethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 12) [ka] The synthetic route to target compound 12 is shown below. [ka] Step 1: Synthesis of (1S,2S)-2-(methoxymethyl)cyclopropane-1-carboxylate t-butyl ester (12B) [ka] (1S,2S)-t-Butyl 2-(methylol)cyclopropane-1-carboxylate (12A) (1 g, 5.81 mmol) was dissolved in dry tetrahydrofuran (10 mL), cooled to about 0° C., and sodium hydride (0.255 g, 6.39 mmol, 60%) was added. After the addition, the mixture was allowed to return to room temperature and stirred, and reacted for 30 minutes. Next, iodomethane (4.12 g, 29.0 mmol) was added, and the mixture was allowed to react for 20 hours while continuing to stir at room temperature. The reaction mixture was quenched by adding saturated ammonium chloride solution (50 mL), and then extracted with ethyl acetate (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 100:1-50:1) to obtain yellow oily (1S,2S)-t-butyl 2-(methoxymethyl)cyclopropane-1-carboxylate (12B) (530 mg, yield 49.0%).

[0162] Step 2. Synthesis of (1S,2S)-2-(methoxymethyl)cyclopropane-1-carboxylic acid (12C) [ka] Dissolve (1S,2S)-2-(methoxymethyl)cyclopropane-1-carboxylate tert-butyl (12B) (530 mg, 2.85 mmol) in hydrogen chloride dioxane (10 mL, 4 M) and react at room temperature for 20 h with stirring. Concentrate the reaction mixture to obtain (1S,2S)-2-(methoxymethyl)cyclopropane-1-carboxylate (12C) (370 mg, 100% yield) as a yellow oil.

[0163] Step 3. Synthesis of 3,6-dichloro-4-((1S,2S)-2-(methoxymethyl)cyclopropyl)pyridazine (12E) [ka] 3,6-Dichloropyridazine (424 mg, 2.84 mmol) and (1S,2S)-2-(methoxymethyl)cyclopropane-1-carboxylic acid (12C) (370 mg, 2.84 mmol) are dissolved in water (10 mL), then concentrated sulfuric acid (0.43 mL) is added, and the temperature is raised to 70 ° C under nitrogen protection. Next, an aqueous solution of silver nitrate (270 mg, 1.592 mmol, 1 mL) is added quickly, and an aqueous solution of ammonium persulfate (1.946 g, 8.53 mmol, 5 mL) is slowly added dropwise, and the reaction is continued at 70 ° C for 1 hour. The reaction solution is adjusted to pH about 9 with aqueous ammonia, then extracted with ethyl acetate (50 mL × 3), the organic layers are combined, dried over sodium sulfate, and concentrated to obtain the crude product. The mixture is separated and purified using a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-3:1) to obtain a yellow solid, 3,6-dichloro-4-((1S,2S)-2-(methoxymethyl)cyclopropyl)pyridazine (12E) (120 mg, 18.1% yield). LC-MS, M / Z: 233.1[M+H] + .

[0164] Step 4. Synthesis of 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(methoxymethyl)cyclopropyl)pyridazine (12G) [ka] Under nitrogen protection, 3,6-dichloro-4-((1S,2S)-2-(methoxymethyl)cyclopropyl)pyridazine (12E) (120 mg, 0.515 mmol), sodium carbonate (164 mg, 1.544 mmol) and [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium (37.7 mg, 0.051 mmol) are dissolved in dioxane (5 mL) and water (5 mL), and the temperature is raised to 70° C., and a solution of 2,4-dimethoxypyrimidine-5-boronic acid (95 mg, 0.515 mmol) in dioxane (5 mL) and water (5 mL) is added dropwise, and the reaction is continued at 70° C. for 1 hour. The reaction mixture is diluted with water (50 mL), and then extracted with ethyl acetate (50 mL×3), and the organic layers are combined, dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by reversed-phase high performance liquid chromatography, the separation method was chromatography column: Phenomenex Luna C18 150×25mm×10μm, mobile phase: [water (0.01% trifluoroacetic acid)-acetonitrile], B%: 35%-65%, 10min, yellow solid 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(methoxymethyl)cyclopropyl)pyridazine (12G) (35mg, yield 20.2%) was obtained. LC-MS, M / Z: 337.1[M+H] + .

[0165] Step 5. Synthesis of 5-(6-chloro-5-((1S,2S)-2-(methoxymethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (12) [ka] Dissolve 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(methoxymethyl)cyclopropyl)pyridazine (12G) (35 mg, 0.104 mmol) in methanol (1 mL), add to aqueous hydrochloric acid (1 M, 0.416 mL), and heat to 50° C. for 20 hours. Freeze and dry the reaction solution to obtain a pale yellow solid, 5-(6-chloro-5-((1S,2S)-2-(methoxymethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (12) (24.8 mg, 77% yield). 1 H NMR (400 MHz, DMSO_d6) δ11.56~11.55(d, 1H), 11.52(s, 1H), 8.29~8.27 (d, 1H), 7.89 (s, 1H), 3.46~3.36 (m, 2H), 3.25(s, 3H), 2.07~2.05 (m, 1H), 1.52~1.49 (m, 1H), 1.21-1.06 (m, 2H). LC-MS, M / Z: 309.1[M+H] + .

[0166] Example 13: Preparation of target compound 13 5-(6-chloro-5-((1R,2S)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 13) [ka] The synthetic route to target compound 13 is shown below. [ka] Step 1, (R)-2-Bromosuccinic acid (13B) [ka] (R)-2-aminosuccinic acid (100.0 g, 751.3 mmol) is dissolved in concentrated sulfuric acid (269.7 mL) and water (1.8 L), potassium bromide (411.3 g, 3.46 mol) is added at 0° C., then an aqueous solution of sodium nitrite (93.3 g, 1.35 mol, 200 mL) is slowly added dropwise at 0° C., and the mixture is reacted at 25° C. for 4 hours. After the reaction is completed, the reaction solution is extracted with ethyl acetate (1500 mL x 2), the organic phases are combined, washed with saturated saline (2000 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which is then slurried with petroleum ether (500 mL) to obtain (R)-2-bromosuccinic acid (13B) (150 g, crude product).

[0167] Step 2, (R)-2-Bromobutane-1,4-diol (13C) [ka] (R)-2-bromosuccinic acid (13.0 g, 66.0 mmol) is dissolved in tetrahydrofuran (200 mL), then borane dimethylsulfide solution (10 M, 19.8 mL) is slowly added dropwise at 0° C., and the mixture is reacted at room temperature for 2 hours after the addition. After the reaction is completed, water (20 mL) is added dropwise at 0° C. to quench the reaction, and then solid potassium carbonate (30 g) is added, and the mixture is stirred for 1 hour, filtered, the filter cake is washed with tetrahydrofuran (50 mL×2), and the filtrate is concentrated to obtain (R)-2-bromobutane-1,4-diol (13C) (12.0 g, crude product).

[0168] Step 3, (S)-2-(2-(benzyloxy)ethyl)oxapropion ring (13D) [ka] Under nitrogen protection, add sodium hydride (7.10g, 177.5mmol, 60%) to tetrahydrofuran (60mL), then dissolve (R)-2-bromobutane-1,4-diol (12.0g, 71.0mmol) in tetrahydrofuran (60mL) and slowly add dropwise to the above solution, controlling the temperature at about 0°C. Next, dissolve benzyl bromide (17.0g, 99.4mmol) in tetrahydrofuran (30mL) and add to the reaction solution together with tetrabutylammonium iodide (2.62g, 7.10mmol), and react at 25°C for 5 hours. After the reaction is completed, the reaction mixture is quenched by adding water (200 mL), extracted with ethyl acetate (200 mL x 2), and the organic phases are combined, washed with saturated saline (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by separation on a silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-10:1) to obtain (S)-2-(2-(benzyloxy group)ethyl)oxapropion ring (13D) (9.50 g, yield 75.1%).

[0169] Step 4, (1R,2S)-ethyl 2-(2-(benzyloxy)ethyl)cyclopropaneformate (13E) [ka] Under nitrogen protection, sodium hydride (2.60g, 65.0mmol, 60%) is suspended in toluene (100mL), then triethyl phosphonoacetate (14.3g, 63.9mmol) is added dropwise at 0°C, and after the addition is completed, the mixture is stirred at 25°C for 1 hour, and (S)-2-(2-(benzyloxy group)ethyl)oxapropion ring (9.50g, 53.3mmol) is added to the reaction solution, and the temperature is raised to 130°C and the reaction is continued for 3 hours. The reaction mixture is diluted with water (100mL), extracted with ethyl acetate (100mL x 2), the organic layer phase is combined, the organic phase is washed with saturated saline solution (200mL), dried over sodium sulfate, and concentrated to obtain the crude product. The mixture is separated and purified using a silica gel column (petroleum ether:ethyl acetate (V / V) = 1:0-10:1) to obtain the yellow oily compound (1R,2S)-ethyl 2-(2-(benzyloxy)ethyl)cyclopropaneformate (13E) (10 g, yield 75.6%).

[0170] Step 5, (1R,2S)-ethyl 2-(2-hydroxyethyl)cyclopropaneformate (13F) [ka] Dissolve (1R,2S)-ethyl 2-(2-(benzyloxy)ethyl)cyclopropaneformate (9.00 g, 36.2 mmol) in ethanol (100 mL), add palladium on carbon (2.0 g, 10%) under nitrogen protection, flush with hydrogen gas three times, and react at 50 Psi pressure and 60 °C for 12 hours. Cool to room temperature, filter through diatomaceous earth to remove palladium on carbon, wash the filter cake three times with ethanol, and concentrate the filtrate to obtain the yellow oily compound (1R,2S)-ethyl 2-(2-hydroxyethyl)cyclopropaneformate (13F) (6.00 g, crude product).

[0171] Step 6. 2-((1S,2R)-2-(ethoxycarbonyl)cyclopropyl)acetic acid (13G) [ka] (1R,2S)-2-(2-hydroxyethyl)cyclopropaneformic acid ethyl ester (6.00 g, 37.9 mmol) is dissolved in acetonitrile (150 mL), and 2,2,6,6-tetramethylpiperidine oxide (477.1 mg, 3.03 mmol), sodium dihydrogen phosphate (7.28 g, 60.7 mmol), and disodium hydrogen phosphate (8.61 g, 60.7 mmol) are added in sequence at 25 ° C. Next, sodium hypochlorite solution (0.58 mL, 8%) and sodium chlorite (6.86 g, 75.9 mmol) are dissolved in water (75 mL) and slowly added dropwise to the reaction system at 0 ° C., and then stirred at 25 ° C. for 12 hours. The reaction system is diluted with water (200 mL), extracted with ethyl acetate (300 mL × 2), the organic layer phase is combined, saturated sodium carbonate aqueous solution (200 mL) is added, and the mixture is stirred for 10 minutes. The organic phase is separated, the aqueous phase is adjusted to pH = 2-3 with 6M hydrochloric acid solution, extracted with ethyl acetate (200mL x 2), the organic layers are combined, the organic phase is washed with saturated saline solution (200mL), dried over sodium sulfate, and concentrated to obtain the yellow oily compound 2-((1S,2R)-2-(ethoxycarbonyl)cyclopropyl)acetic acid (13G) (5.20g, yield 79.6%).

[0172] Step 7, (1R,2S)-ethyl 2-(2,2,2-trifluoroethyl)cyclopropaneformate (13H) [ka] 2-((1S,2R)-2-(ethoxycarbonyl)cyclopropyl)acetic acid (5.0 g, 25.5 mmol) is added to the autoclave, and sulfur tetrafluoride (9.0 g, 83.3 mmol) is added at -78 °C. The reaction system is heated to 70 °C in the autoclave and reacted for 16 hours. Dichloromethane (50 mL) is added to the reaction system, and the organic phase is washed with saturated aqueous sodium bicarbonate solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the yellow oily compound (1R,2S)-2-(2,2,2-trifluoroethyl)cyclopropaneformate ethyl (13H) (6.00 g, crude product), which is used directly in the next step.

[0173] Step 8, (1R,2S)-2-(2,2,2-trifluoroethyl)cyclopropanecarboxylic acid (13I) [ka] Dissolve (1R,2S)-2-(2,2,2-trifluoroethyl)cyclopropaneformic acid ethyl ester (6.00 g, 30.6 mmol) in tetrahydrofuran (50 mL) and water (25 mL), then add lithium hydroxide monohydrate (3.85 g, 91.8 mmol) and react at 50 ° C for 12 hours. After the reaction is completed, add water (50 mL), extract with dichloromethane (100 mL × 2), collect the aqueous phase, adjust the aqueous phase to pH = 3-4 with 6 M hydrochloric acid, then extract with dichloromethane (100 mL × 2), combine the organic phase, wash with saturated saline (100 mL), dry with anhydrous sodium sulfate, filter, and concentrate to obtain the brown oily compound (1R,2S)-2-(2,2,2-trifluoroethyl)cyclopropanecarboxylic acid (13I) (3.00 g, yield 58.3%).

[0174] Step 9. Synthesis of 3,6-dichloro-4-((1R,2S)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazine (13K) [ka] Dissolve 3,6-dichloropyridazine (2.40 g, 16.1 mmol) and (1R,2S)-2-(2,2,2-trifluoroethyl)cyclopropanecarboxylic acid (2.70 g, 16.1 mmol) in water (50 mL), then add concentrated sulfuric acid (2.45 mL) and heat to 70 ° C under nitrogen protection. Add aqueous silver nitrate (1.09 g, 6.42 mmol, 10.0 mL) quickly, add aqueous ammonium persulfate (11.0 g, 48.2 mmol, 20 mL) dropwise slowly, and continue reacting at 70 ° C for 1 hour. Adjust the reaction solution to about pH 9 with aqueous ammonia, extract with ethyl acetate (200 mL × 2), combine the organic layers, wash the organic phase with saturated saline (500 mL), dry with sodium sulfate, and concentrate to obtain the crude product. Separation by reverse phase Flash affords the brown oily compound 3,6-dichloro-4-((1R,2S)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazine (13K) (350 mg, 43.8% yield). LC-MS, M / Z: 271.1[M+H] + .

[0175] Step 10. Synthesis of 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1R,2S)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazine (13M) [ka] 3,6-Dichloro-4-((1R,2S)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazine (600mg, 2.21mmol) and 2,4-dimethoxypyrimidine-5-boronic acid (407mg, 2.21mmol) are dissolved in dioxane (10mL) and water (2mL), and sodium carbonate (704mg, 6.64mmol) and [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium (162mg, 221μmol) are added under nitrogen protection, and the temperature is raised to 50℃ and the reaction is carried out for 12 hours. The reaction mixture is diluted with water (20mL) and extracted with ethyl acetate (50mL×2), the organic phases are combined, the organic phase is washed with saturated saline solution (100mL), dried over sodium sulfate, and concentrated to obtain the crude product. The crude product is first purified by separation on a silica gel column (petroleum ether: ethyl acetate (V / V) = 50: 1-3: 1), and then separated by reversed phase high performance liquid chromatography (chromatography column: 3_Phenomenex Luna C18 75 x 30 mm x 3 μm, mobile phase: A = water + 0.05 volume hydrochloric acid (36.5%), B = acetonitrile, gradient: 45%-65%, 6.5 min), to obtain the compound 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1R,2S)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazine (13M) (300 mg, yield 32.7%) as a pale yellow solid. LC-MS, M / Z: 375.1[M+H] + .

[0176] Step 11: Synthesis of 5-(6-chloro-5-((1R,2S)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (13) [ka] 3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1R,2S)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazine (300 mg, 724 μmol) was dissolved in hydrochloric acid solution (1M, 10 mL), and the mixture was heated to 50°C and reacted for 12 hours. After the reaction system was concentrated to dryness, the crude product was first separated by reversed-phase high-performance liquid chromatography (chromatography column: 3_Phenomenex Luna C18 75×30 mm×3 μm, mobile phase: A=water+0.05 volume hydrochloric acid (36.5%), B=acetonitrile, gradient: 26%-46%, 6.5 min), and then separated by supercritical fluid chromatography (chromatography column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm, mobile phase: 0.1% aqueous ammonia in methanol, gradient: 45%-45%, 45 min) to obtain the white solid compound 5-(6-chloro-5-((1R,2S)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (13) (108.5 mg, yield 62.9%). SFC: Rt=1.645min, de%=100%, Detection method: Chromatography column: Chiralpak AD-3 50×4.6mm ID, 3μm, Mobile phase: A: CO2, B: 0.05% diethylamine in methanol, Elution gradient: 40% methanol (containing 0.05% diethylamine) and 60% carbon dioxide, Flow rate: 3mL / min, Detector: PDA, Column temperature: 35℃, Column pressure: 100 Bar 1 H NMR (400 MHz, CD3OD):δ 8.40 (s, 1H), 8.03 (s, 1H), 2.32-2.52 (m, 2H), 2.22-2.27 (m, 1H), 1.43-1.52 (m, 1H), 1.27-1.32 (m, 2H). LC-MS, M / Z: 347.0[M+H] + .

[0177] Example 14: Preparation of target compound 14 5-(6-chloro-5-((1R,2R)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 14) [ka] The synthetic route to target compound 14 is shown below. [ka] Step 1. Synthesis of (1R,2R)-2-((trifluoromethoxy)methyl)cyclopropane-1-carboxylate t-butyl ester (14B) [ka] Under nitrogen protection, (1R,2R)-t-butyl 2-(methylol)cyclopropane-1-carboxylate (14A) (4 g, 23.2 mmol), potassium fluoride (5.4 g, 93 mmol), selective fluorine reagent (12.3 g, 34.8 mmol) and silver trifluoromethanesulfonate (18 g, 69.6 mmol) were added in sequence to a light-shielded reaction bottle, and a solution of 2-fluoropyridine (6.8 g, 69.6 mmol) and trifluoromethyltrimethylsilane (9.9 g, 69.6 mmol) in ethyl acetate (50 mL) was added dropwise. After the addition was completed, the reaction was continued at room temperature for 18 h. Add water (100 mL) to dilute, separate the liquid, extract the aqueous phase with ethyl acetate (100 mL × 2), combine the organic layers, dry over anhydrous sodium sulfate, and concentrate. Separate and purify the residue with a silica gel column (petroleum ether: ethyl acetate (V / V) = 500:1) to obtain a colorless liquid, (1R,2R)-2-((trifluoromethoxy)methyl)cyclopropane-1-carboxylate t-butyl (14B) (2.2 g, yield 39.4%).

[0178] Step 2. Synthesis of (1R,2R)-2-((trifluoromethoxy)methyl)cyclopropane-1-carboxylic acid (14C) [ka] Dissolve (1R,2R)-2-((trifluoromethoxy)methyl)cyclopropane-1-carboxylate tert-butyl (14B) (2.2 g, 9.2 mmol) in hydrogen chloride dioxane (10 mL, 4 M) and react at room temperature for 20 h with stirring. Concentrate the reaction mixture to obtain (1R,2R)-2-((trifluoromethoxy)methyl)cyclopropane-1-carboxylate (14C) (1.6 g, 95% yield) as a yellow oil.

[0179] Step 3. Synthesis of 3,6-dichloro-4-((1R,2R)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazine (14E) [ka] Dissolve 3,6-dichloropyridazine (1.29 g, 8.69 mmol) and (1R,2R)-2-((trifluoromethoxy)methyl)cyclopropane-1-carboxylic acid (14C) (1.6 g, 8.69 mmol) in water (40 mL), add silver nitrate (0.74 g, 4.35 mmol), add concentrated sulfuric acid (2.2 mL), and heat to 70 ° C under nitrogen protection. Slowly add an aqueous solution of ammonium persulfate (6.6 g, 28.9 mmol, 40 mL) dropwise and continue reacting at 70 ° C for 2 hours. Adjust the reaction solution to about pH 9 with aqueous ammonia, extract with ethyl acetate (100 mL × 3), combine the organic layers, dry with sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by separation using a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-3:1) to obtain a pale yellow solid, 3,6-dichloro-4-((1R,2R)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazine (14E) (1.3 g, yield 52.1%). LC-MS, M / Z: 287.1[M+H] + .

[0180] Step 4. Synthesis of 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1R,2R)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazine (14G) [ka] Under nitrogen protection, 3,6-dichloro-4-((1R,2R)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazine (14E) (1.3 g, 4.53 mmol), 2,4-dimethoxypyrimidine-5-boronic acid (0.67 g, 3.62 mmol), sodium carbonate (1.44 g, 13.6 mmol) and [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium (0.33 g, 0.45 mmol) are dissolved in dioxane (20 mL) and water (20 mL), and the mixture is heated to 70° C. and reacted for 2 hours. The reaction mixture is diluted with water (100 mL) and extracted with ethyl acetate (150 mL×3), the organic layers are combined, dried over sodium sulfate and concentrated to obtain the crude product. The crude product is separated by reversed-phase high performance liquid chromatography, the separation method is chromatography column: Phenomenex Luna C18 150 x 25 mm x 10 μm, mobile phase: [water (0.01% trifluoroacetic acid)-acetonitrile], B%: 35%-65%, 10 min, and a pale yellow oily substance, 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1R,2R)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazine (14G) (60 mg, yield 3.4%) is obtained. LC-MS, M / Z: 391.1[M+H] + .

[0181] Step 5. Synthesis of 5-(6-chloro-5-((1R,2R)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (14) [ka] Dissolve 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1R,2R)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazine (14G) (60 mg, 0.15 mmol) in tetrahydrofuran (10 mL), add to aqueous hydrochloric acid (1M, 10 mL), and react for 20 hours at 50°C. Concentrate the organic solvent from the reaction mixture, filter, and collect and dry the white solid to obtain 5-(6-chloro-5-((1R,2R)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (14) (18 mg, 31.4% yield). 1 H NMR (400 MHz, DMSO_d6) δ11.52(s, 2H), 8.28(s, 1H), 7.94 (s, 1H), 4.22~4.17 (m, 2H), 2.26 (s, 1H), 1.66 (s, 1H), 1.29-1.21 (m, 2H). LC-MS, M / Z: 363.1[M+H] + .

[0182] Example 15: Preparation of target compound 15 6-(2,4-Dioxoxy-1H-pyrimidin-5-yl)-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine-3-methonitrile (target compound 15) [ka] The synthetic route to target compound 15 is shown below. [ka] Step 1. Synthesis of 6-(2,4-dioxoxy-1H-pyrimidin-5-yl)-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine-3-methonitrile (15) [ka] 5-(6-chloro-5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)-1H-pyrimidine-2,4-diketone (400 mg, 1.08 mmol) (see Example 4 for preparation method) is dissolved in N,N-dimethylformamide (10 mL), and zinc cyanide (152 mg, 1.30 mmol), tri(dibenzylacetone)dipalladium (98.9 mg, 0.108 mmol) and 1,1-bis(diphenylphosphine)dimetallocene (59.9 mg, 0.108 mmol) are added under nitrogen protection. The reaction is heated to 120° C. and reacted for 12 hours. The reaction solution is concentrated and then separated by high performance liquid phase chromatography (chromatography column: Phenomenex luna C18 150 x 40 mm x 15 μm, mobile phase: A = water + 0.225% volume formic acid (99.9%), B = acetonitrile, gradient: 22% - 52%, 10 min), to obtain a pale yellow solid compound 6-(2,4-dioxoxy-1H-pyrimidin-5-yl)-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine-3-methonitrile (15) (199.68 mg, yield 56.5%). 1 H NMR (400 MHz, CD3OD):δ 8.68 (s, 1H), 8.32 (s, 1H), 2.64-2.67(m, 1H),2.42-2.45 (m, 1H),1.69-1.72 (m, 1H), 1.57-1.67 (m, 1H). LC-MS, M / Z: 324.1 [M+H] + .

[0183] Example 16: Preparation of target compound 16 5-(6-chloro-5-((1S,2S)-2-(ethoxymethyl)cyclopropyl)pyridazin-3-yl)-1H-pyrimidine-2,4-diketone (target compound 16) [ka] The synthetic route to target compound 16 is shown below. [ka] Step 1, (1S,2S)-t-Butyl 2-(ethoxymethyl)cyclopropaneformate (16B) [ka] (1S,2S)-2-(methylol)cyclopropaneformate t-butyl 2g, 11.6mmol), iodoethane (3.62g, 23.2mmol, 2.18mL) and silver(I) oxide (5.38g, 23.2mmol) are dissolved in toluene (15mL), and then reacted at 70°C for 24 hours. After the reaction is completed, the reaction solution is filtered, washed with ethyl acetate (20mL x 2), filtered, and the filtrate is combined. Concentration is performed to obtain the yellow oily compound (1S,2S)-2-(ethoxymethyl)cyclopropaneformate t-butyl (16B) (2.00g, crude product).

[0184] Step 2, (1S,2S)-2-(ethoxymethyl)cyclopropanecarboxylic acid (16C) [ka] Dissolve (1S,2S)-2-(ethoxymethyl)cyclopropaneformate t-butyl (2.00 g, 9.33 mmol) in hydrogen chloride dioxane solution (4 M, 23.3 mL). React at 20°C for 2 hours. After completion of the reaction, concentrate the reaction solution to obtain (1S,2S)-2-(ethoxymethyl)cyclopropanecarboxylic acid (16C) (1.90 g, crude product).

[0185] Step 3, 3,6-dichloro-4-((1S,2S)-2-(ethoxymethyl)cyclopropyl)pyridazine (16E) [ka] (1S,2S)-2-(ethoxymethyl)cyclopropanecarboxylic acid (1.90g, 11.9mmol), 3,6-dichloropyridazine (1.79g, 12.0mmol) and sulfuric acid (3.30g, 33.6mmol, 1.79mL) are dissolved in water (15mL), and then reacted at 70°C for 30 minutes under nitrogen protection. Next, silver nitrate (816.1mg, 4.80mmol) is dissolved in water (2mL) and added to the reaction solution, and then ammonium persulfate (8.22g, 36.0mmol) is dissolved in water (20mL) and added dropwise to the reaction solution. Next, the reaction is continued at 70°C for 1 hour. After the reaction, the reaction solution was adjusted to pH 9 with aqueous ammonia, extracted with ethyl acetate (20 mL x 2), and the organic phases were combined, washed with saline (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by high-performance liquid chromatography (chromatography column: Phenomenex luna C 18 150 x 40 mm x 15 µm, mobile phase: A = water + 0.225% formic acid by volume (99%), B = acetonitrile, gradient: 18%-48%, 7.5 min) to obtain the yellow oily compound 3,6-dichloro-4-((1S,2S)-2-(ethoxymethyl)cyclopropyl)pyridazine (16E) (250 mg, 9.28% yield). LC-MS, M / Z: 247.1[M+H] + .

[0186] Step 4, 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(ethoxymethyl)cyclopropyl)pyridazine (16G) [ka] 3,6-Dichloro-4-((1S,2S)-2-(ethoxymethyl)cyclopropyl)pyridazine (250 mg, 765 μmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (140 mg, 765 μmol), [1,1-bis(diphenylphosphine)ferrocene)]dichloropalladium dichloromethane (62.5 mg, 76.5 μmol) and sodium carbonate (202 mg, 1.91 mmol) are dissolved in dioxane (3 mL) and water (0.5 mL), and the mixture is reacted at 50° C. for 2 hours under nitrogen protection. After the reaction is completed, the reaction solution is poured into water (10 mL), extracted with ethyl acetate (20 mL x 2), the organic phases are combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by high performance liquid phase chromatography. The separation method is (chromatography column: Phenomenex luna C18 150 x 40 mm x 15 μm, mobile phase: A = water + 0.225% volume formic acid (99%), B = acetonitrile, gradient: 47%-67%, 7 min), and the yellow oily compound 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(ethoxymethyl)cyclopropyl)pyridazine (16G) (80.0 mg, 21.2% yield) is obtained. LC-MS, M / Z: 351.1 [M+H] + .

[0187] Step 5. 5-(6-chloro-5-((1S,2S)-2-(ethoxymethyl)cyclopropyl)pyridazin-3-yl)-1H-pyrimidine-2,4-diketone (Target Compound 16) [ka] 3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(ethoxymethyl)cyclopropyl)pyridazine (80.0 mg, 175 μmol) is dissolved in hydrochloric acid (1 M, 2.00 mL) and reacted at 50° C. for 12 hours. After the reaction is completed, the reaction solution is concentrated and separated by high performance liquid phase chromatography (chromatography column: Phenomenex luna C18 150 x 40 mm x 15 μm, mobile phase: A = water + 0.225% volume formic acid (99%), B = acetonitrile, gradient: 18%-48%, 7 min), and the white solid compound 5-(6-chloro-5-((1S,2S)-2-(ethoxymethyl)cyclopropyl)pyridazin-3-yl)-1H-pyrimidine-2,4-diketone (16) (31.0 mg, yield 54.9%) is obtained. 1 H NMR (400 MHz, CD3OD): δ8.38 (s, 1H), 8.02 (s, 1H), 3.54-3.60 (m, 4H), 2.18-2.22 (m, 1H),1.59-1.61 (m, 1H), 1.18-1.26 (m, 5H). LC-MS, M / Z: 323.1 [M+H] + .

[0188] Example 17: Preparation of target compound 17 5-(6-chloro-5-((1S,2S)-2-(isopropoxymethyl)cyclopropyl)pyridazin-3-yl)-1H-pyrimidine-2,4-diketone (target compound 17) [ka] The synthetic route to target compound 17 is shown below. [ka] Step 1, (1S,2S)-2-(isopropoxymethyl)cyclopropaneformate t-butyl ester (17B) [ka] (1S,2S)-2-(methylol)cyclopropaneformate t-butyl (2.00 g, 11.6 mmol), isopropane bromide (2.86 g, 23.2 mmol, 2.18 mL) and silver(I) oxide (5.38 g, 23.2 mmol) are dissolved in toluene (15 mL) and reacted for 24 hours at 70° C. After the reaction is completed, the reaction solution is filtered, washed with ethyl acetate (20 mL×2), filtered, and the filtrates are combined and concentrated to obtain the yellow oily compound (1S,2S)-2-(isopropoxymethyl)cyclopropaneformate t-butyl (17B) (2.00 g, crude product).

[0189] Step 2, (1S,2S)-2-(isopropoxymethyl)cyclopropanecarboxylic acid (17C) [ka] Dissolve (1S,2S)-2-(isopropoxymethyl)cyclopropaneformate t-butyl (2.00 g, 9.33 mmol) in hydrogen chloride dioxane solution (4 M, 23.3 mL). React at 20°C for 2 hours. After completion of the reaction, concentrate the reaction solution to obtain (1S,2S)-2-(isopropoxymethyl)cyclopropanecarboxylic acid (17C) (1.90, crude product).

[0190] Step 3, 3,6-dichloro-4-((1S,2S)-2-(isopropoxymethyl)cyclopropyl)pyridazine (17E) [ka] (1S,2S)-2-(isopropoxymethyl)cyclopropanecarboxylic acid (1.90g, 12.0mmol), 3,6-dichloropyridazine (1.79g, 12.0mmol) and sulfuric acid (3.30g, 33.6mmol, 1.79mL) are dissolved in water (15mL) and reacted at 70℃ for 30 minutes under nitrogen protection. Silver nitrate (816.1mg, 4.80mmol) is dissolved in water (2mL) and added to the reaction solution, and ammonium persulfate (8.22g, 36.0mmol) is dissolved in water (20mL) and added dropwise to the reaction solution. Then, the reaction is carried out at 70℃ for 1 hour. After the reaction is completed, the reaction solution is adjusted to about pH = 9 with ammonia water, extracted with ethyl acetate (20mL x 2), the organic phases are combined, washed with brine (50mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by high performance liquid phase chromatography. The separation method is (chromatography column: Phenomenex luna C18 150 x 40mm x 15μm, mobile phase: A = water + 0.225% volume formic acid (99%), B = acetonitrile, gradient: 20%-55%, 7.5 minutes), and the yellow oily compound 3,6-dichloro-4-((1S,2S)-2-(isopropoxymethyl)cyclopropyl)pyridazine (17E) (250mg, 8.20% yield) is obtained. LC-MS, M / Z: 261.1[M+H] + .

[0191] Step 4, 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(isopropoxymethyl)cyclopropyl)pyridazine (17G) [ka] 3,6-Dichloro-4-((1S,2S)-2-(isopropoxymethyl)cyclopropyl)pyridazine (250 mg, 765 μmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (140 mg, 765 μmol), [1,1-bis(diphenylphosphine)ferrocene)]dichloropalladium dichloromethane (62.5 mg, 76.5 μmol) and sodium carbonate (202 mg, 1.91 mmol) are dissolved in dioxane (3 mL) and water (0.5 mL), and the mixture is reacted at 50° C. for 2 hours under nitrogen protection. After the reaction is completed, the reaction solution is poured into water (10 mL) and extracted with ethyl acetate (20 mL x 2). The organic phases are combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by separation on a silica gel column (petroleum ether: ethyl acetate (V / V) = 10:1-1:1) to obtain the yellow oily compound 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(isopropoxymethyl)cyclopropyl)pyridazine (17G) (100 mg, crude product). LC-MS, M / Z: 365.1 [M+H] + .

[0192] Step 5, 5-(6-chloro-5-((1S,2S)-2-(isopropoxymethyl)cyclopropyl)pyridazin-3-yl)-1H-pyrimidine-2,4-diketone (target compound 17) [ka] 3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(isopropoxymethyl)cyclopropyl)pyridazine (100 mg, 135 μmol) is dissolved in hydrochloric acid (1 M, 2.00 mL) and reacted at 50° C. for 12 hours. After the reaction is completed, the reaction solution is concentrated to obtain the product, which is then separated by high performance liquid phase chromatography (chromatography column: Phenomenex luna C18 150 x 40 mm x 15 μm, mobile phase: A = water + 0.225% volume formic acid (99%), B = acetonitrile, gradient: 22%-52%, 7 min), to obtain the yellow solid compound 5-(6-chloro-5-((1S,2S)-2-(isopropoxymethyl)cyclopropyl)pyridazin-3-yl)-1H-pyrimidine-2,4-diketone (17) (11.0 mg, yield 16.3%). 1 H NMR (400 MHz, CD3OD):δ8.38 (s, 1H), 8.02 (s, 1H), 3.66-3.69 (m, 1H), 3.59-3.62 (m, 1H),3.52-3.59 (m, 1H), 2.17-2.19 (m, 1H),1.57-1.58 (m, 1H),1.24-1.26 (m, 1H), 1.20-1.24 (m, 1H),1.18-1.19 (m, 3H),1.16-1.18 (m, 3H). LC-MS, M / Z: 337.1 [M+H] + .

[0193] Example 18: Preparation of target compound 18 5-(6-chloro-5-((1S,2R)-2-(2,2-difluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 18) [ka] The synthetic route to target compound 18 is shown below. [ka] Step 1, (1S,2R)-2-(2-((benzyloxy)ethyl)cyclopropaneformate t-butyl ester (18B) [ka] Under nitrogen protection, sodium hydride (1.46 g, 36.5 mmol, 60%) is suspended in toluene (50 mL), and 2-ethoxyphosphoryl t-butyl acetate (8.49 g, 33.7 mmol) is added dropwise at 0-10 ° C. After the addition is completed, the mixture is stirred at 25 ° C. for 1 hour, and (R)-2-(2-(benzyloxy group) ethyl) oxapropion ring (5.00 g, 28.1 mmol) is added to the reaction solution, and the mixture is heated to 130 ° C. and reacted for 3 hours. The reaction mixture is diluted with saturated ammonium chloride aqueous solution (40 mL), and then extracted with ethyl acetate (40 mL × 2), and the organic layer phase is combined, washed with saturated saline solution (20 mL), dried over sodium sulfate, and concentrated to obtain the crude product. Separate and purify with a silica gel column (petroleum ether:ethyl acetate (V / V) = 300:1-50:1) to obtain the yellow oily compound (1S,2R)-2-(2-((benzyloxy)ethyl)cyclopropaneformate tert-butyl (18B) (4.50 g, yield 58.0%).

[0194] Step 2, (1S,2R)-t-butyl 2-(2-hydroxyethyl)cyclopropaneformate (18C) [ka] Dissolve (1S,2R)-2-(2-((benzyloxy)ethyl)cyclopropaneformate t-butyl (4.5 g, 16.3 mmol) in ethanol (50 mL), add palladium carbon (1.4 g, 10%) under nitrogen protection, replace with hydrogen gas three times, and react at 50 Psi pressure and 60 °C for 24 hours. After the reaction is completed, filter the reaction solution through diatomaceous earth, wash the filter cake twice with ethanol, collect the filtrate, and concentrate to obtain the colorless oily compound (1S,2R)-2-(2-hydroxyethyl)cyclopropaneformate t-butyl (18C) (3.20 g, crude product).

[0195] Step 3, (1S,2R)-t-butyl 2-(2-oxyethylene)cyclopropaneformate (18D) [ka] Dissolve (1S,2R)-2-(2-hydroxyethyl)cyclopropaneformate t-butyl (3.10 g, 16.6 mmol) in dichloromethane (40 mL) and add Dice-Martin alkyl periodate (10.6 g, 25.0 mmol) in a batchwise manner at 0-10 °C under nitrogen protection, and react at 25 °C for 2 hours after addition. Quench the reaction mixture with saturated aqueous sodium sulfite solution (30 mL), then extract with dichloromethane (30 mL x 3), combine the organic phases, wash the organic phase with saturated brine (20 mL x 2), dry over sodium sulfate, and concentrate to obtain the crude product. Separate and purify with a silica gel column (petroleum ether:ethyl acetate (V / V) = 200:1-30:1) to obtain the colorless oily compound (1S,2R)-2-(2-oxyethylene)cyclopropaneformate t-butyl (18D) (2.20 g, yield 71.7%).

[0196] Step 4, (1S,2R)-2-(2,2-difluoroethyl)cyclopropaneformate t-butyl ester (18E) [ka] Dissolve (1S,2R)-2-(2-oxyethylene)cyclopropaneformate t-butyl (2.1 g, 11.4 mmol) in dichloromethane (20 mL) and add diethylaminosulfur trifluoride (4.04 g, 25.1 mmol) in batches at 0-10 °C under nitrogen protection. After addition, react at 25 °C for 1 hour. Quench the reaction mixture with saturated aqueous sodium bicarbonate solution (40 mL), extract with dichloromethane (30 mL × 2), combine the organic layer phase, wash the organic phase with saturated brine (10 mL × 2), dry with sodium sulfate, and concentrate to obtain the crude product. The mixture is separated and purified using a silica gel column (petroleum ether:ethyl acetate (V / V) = 200:1-30:1) to obtain the yellow oily compound (1S,2R)-t-butyl 2-(2,2-difluoroethyl)cyclopropaneformate (18E) (1.15 g, yield 48.9%).

[0197] Step 5, (1S,2R)-2-(2,2-difluoroethyl)cyclopropanecarboxylic acid (18F) [ka] (1S,2R)-2-(2,2-difluoroethyl)cyclopropaneformate t-butyl (650 mg, 3.15 mmol) is dissolved in hydrochloric acid dioxane solution (5 mL, 4 M) and reacted for 1 hour at 25° C. The reaction mixture is concentrated under reduced pressure to obtain the colorless oily compound (1S,2R)-2-(2,2-difluoroethyl)cyclopropanecarboxylic acid (18F) (475 mg, crude product).

[0198] Step 6, 3,6-dichloro-4-((1S,2R)-2-(2,2-difluoroethyl)cyclopropyl)pyridazine (18H) [ka] Dissolve 3,6-dichloropyridazine (466 mg, 3.13 mmol) and (1S,2R)-2-(2,2-difluoroethyl)cyclopropanecarboxylic acid (470 mg, 3.13 mmol) in water (4.0 mL), add concentrated sulfuric acid (467 μL), and heat to 70 ° C under nitrogen protection. Next, add an aqueous solution of silver nitrate (170 mg, 1.00 mmol, 4.4 mL) quickly, add an aqueous solution of ammonium persulfate (1.60 g, 6.99 mmol, 4.0 mL) slowly, and continue reacting at 70 ° C for 1 hour. Adjust the reaction solution to about pH 9 with aqueous ammonia, extract with ethyl acetate (20 mL × 3), combine the organic layers, wash the organic phase with saturated saline (10 mL × 2), dry with sodium sulfate, and concentrate to obtain the crude product. The crude product was separated together with the previous batch by reversed phase Flash to give 3,6-dichloro-4-((1S,2R)-2-(2,2-difluoroethyl)cyclopropyl)pyridazine (18H) (210 mg, 15.2% yield) as a yellow oil. LC-MS, M / Z (ESI): 253.0[M+H] + .

[0199] Step 7, 3-chloro-4-((1S,2R)-2-(2,2-difluoroethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine (18J) [ka] 3,6-Dichloro-4-((1S,2R)-2-(2,2-difluoroethyl)cyclopropyl)pyridazine (200 mg, 790.3 umol) and 2,4-dimethoxypyrimidine-5-boronic acid (145.4 mg, 790.3 umol) are dissolved in dioxane (8.0 mL) and water (2.0 mL), and sodium carbonate (251.3 mg, 2.37 mmol) and [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium (115.6 mg, 158.1 μmol) are added under nitrogen protection, and the mixture is heated to 50°C and reacted for 8 hours. The reaction mixture is concentrated under reduced pressure to obtain the crude product. The crude product was separated by reversed-phase high performance liquid chromatography (chromatographic column: 3_Phenomenex Luna C18 75×30 mm×3 μm, mobile phase: A=water+0.1% volumetric trifluoroacetic acid (99.9%), B=acetonitrile, gradient: 48%-68%, 7 min) to obtain the white solid compound 3-chloro-4-((1S,2R)-2-(2,2-difluoroethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine (18J) (95 mg, yield 33.7%). LC-MS, M / Z (ESI): 357.0[M+H] + .

[0200] Step 8, 5-(6-chloro-5-((1S,2R)-2-(2,2-difluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (18) [ka] 3-Chloro-4-((1S,2R)-2-(2,2-difluoroethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine (90 mg, 252.3 μmol) is added to an aqueous solution of hydrochloric acid (1 M, 2.0 mL), and the mixture is heated to 50° C. and reacted for 8 hours. After concentrating and drying the reaction solution, the crude product is first separated by reversed-phase high performance liquid chromatography (chromatography column: 3_Phenomenex Luna C18 75×30 mm×3 μm, mobile phase: A=water+0.1% volumetric trifluoroacetic acid (99%), B=acetonitrile, gradient: 30%-50%, 7 min), to obtain the white solid compound 5-(6-chloro-5-((1S,2R)-2-(2,2-difluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (18) (35.3 mg, yield 42.6%). 1 H NMR (400 MHz, DMSO_d6):δ 11.53 (s, 2H), 8.29 (s, 1H),7.90 (s, 1H), 6.02-6.30 (m, 1H), 2.05-2.12 (m, 3H), 1.13-1.25 (m, 3H). LC-MS, M / Z (ESI): 329.0[M+H] + .

[0201] Example 19: Preparation of target compound 19 5-(6-chloro-5-((1R,2S)-2-(2,2-difluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 19) [ka] The synthetic route to target compound 19 is shown below. [ka] Step 1, (1R,2S)-2-(2-((benzyloxy)ethyl)cyclopropaneformate t-butyl ester (19B) [ka] Under nitrogen protection, suspend sodium hydride (1.40 g, 35.0 mmol, 60%) in toluene (50 mL), add 2-ethoxyphosphoryl t-butyl acetate (7.06 g, 28.1 mmol) dropwise at 0-10 ° C, stir at 25 ° C for 1 hour after the dropwise addition is completed, add (S)-2-(2-(benzyloxy group) ethyl) oxapropion ring (5.00 g, 28.1 mmol) to the reaction solution, heat to 130 ° C and react for 3 hours. Dilute the reaction mixture with saturated ammonium chloride aqueous solution (40 mL), then extract with ethyl acetate (40 mL × 2), combine the organic layer phase, wash the organic phase with saturated saline (20 mL), dry with sodium sulfate, and concentrate to obtain the crude product. Separate and purify with a silica gel column (petroleum ether:ethyl acetate (V / V) = 1:0-10:1) to obtain the yellow oily compound (1R,2S)-2-(2-((benzyloxy)ethyl)cyclopropaneformate tert-butyl (19B) (5.00 g, yield 64.5%).

[0202] Step 2, (1R,2S)-t-butyl 2-(2-hydroxyethyl)cyclopropaneformate (19C) [ka] (1R,2S)-2-(2-((benzyloxy)ethyl)cyclopropaneformate t-butyl (4.50 g, 16.3 mmol) is dissolved in ethanol (50 mL), and under nitrogen protection, palladium carbon (1.40 g, 10%) is added, and the mixture is purged with hydrogen gas three times, and then reacted at 50 Psi pressure and 60° C. for 24 hours. After the reaction is completed, the temperature is lowered, and the mixture is filtered through diatomaceous earth, and the filter cake is washed with ethanol. The filtrate is collected and concentrated to obtain the colorless oily compound (1R,2S)-2-(2-hydroxyethyl)cyclopropaneformate t-butyl (19C) (2.80 g, crude product).

[0203] Step 3, (1R,2S)-t-butyl 2-(2-oxyethylene)cyclopropaneformate (19D) [ka] Dissolve (1R,2S)-2-(2-hydroxyethyl) t-butyl cyclopropaneformate (1.00 g, 5.37 mmol) in dichloromethane (10 mL) and add Dice-Martin alkyl periodate (3.42 g, 8.05 mmol) in batches at 0-10 °C under nitrogen protection. After addition, react at 25 °C for 2 hours. Quench the reaction mixture with saturated aqueous sodium sulfite solution (15 mL), extract with dichloromethane (10 mL x 2), combine the organic phases, wash the organic phase with saturated brine (30 mL x 2), dry over sodium sulfate, and concentrate to obtain the crude product. The mixture is separated and purified using a silica gel column (petroleum ether:ethyl acetate (V / V) = 200:1-30:1) to obtain the yellow oily compound (1R,2S)-t-butyl 2-(2-oxyethylene)cyclopropaneformate (19D) (730 mg, yield 73.8%).

[0204] Step 4, (1R,2S)-2-(2,2-difluoroethyl)cyclopropaneformate t-butyl ester (19E) [ka] Dissolve (1R,2S)-2-(2-oxyethylene)cyclopropaneformate t-butyl (730 mg, 3.96 mmol) in dichloromethane (12 mL) and add diethylaminosulfur trifluoride (1.41 g, 8.72 mmol) in batches at 0-10 °C under nitrogen protection. After addition, react at 25 °C for 1 hour. Quench the reaction mixture with saturated aqueous sodium bicarbonate solution (20 mL), extract with dichloromethane (15 mL × 3), combine the organic layer phase, wash the organic phase with saturated brine (20 mL × 2), dry over sodium sulfate, and concentrate to obtain the crude product. The product is purified by separation using a silica gel column (petroleum ether:ethyl acetate (V / V) = 100:1-10:1) to obtain the yellow oily compound (1R,2S)-2-(2,2-difluoroethyl)cyclopropaneformate t-butyl (19E) (510 mg, yield 62.4%).

[0205] Step 5, (1R,2S)-2-(2,2-difluoroethyl)cyclopropanecarboxylic acid (19F) [ka] (1R,2S)-2-(2,2-difluoroethyl)cyclopropaneformate t-butyl (500 mg, 2.42 mmol) was dissolved in hydrochloric acid in dioxane (8 mL, 4 M) and reacted for 2 hours at 25° C. The reaction mixture was concentrated under reduced pressure to obtain a yellow oily compound (1R,2S)-2-(2,2-difluoroethyl)cyclopropanecarboxylic acid (19F) (360 mg, crude product).

[0206] Step 6, 3,6-dichloro-4-((1R,2S)-2-(2,2-difluoroethyl)cyclopropyl)pyridazine (19H) [ka] 3,6-Dichloropyridazine (347 mg, 2.33 mmol) and (1R,2S)-2-(2,2-difluoroethyl)cyclopropanecarboxylic acid (350 mg, 2.33 mmol) are dissolved in water (3.5 mL), then concentrated sulfuric acid (363 μL) is added and the mixture is heated to 70 ° C under nitrogen protection. An aqueous solution of silver nitrate (170 mg, 1.00 mmol, 3.5 mL) is added quickly, and then an aqueous solution of ammonium persulfate (1.60 g, 6.99 mmol, 5.0 mL) is slowly added dropwise, and the reaction is continued at 70 ° C for 1 hour. The reaction solution is adjusted to about pH 9 with aqueous ammonia, extracted with ethyl acetate (20 mL × 3), the organic layers are combined, the organic phase is washed with saturated saline (20 mL × 2), dried over sodium sulfate, and concentrated to obtain the crude product. Separation by reverse phase Flash affords a yellow oily compound, 3,6-dichloro-4-((1R,2S)-2-(2,2-difluoroethyl)cyclopropyl)pyridazine (19H) (330 mg, 55.9% yield). LC-MS, M / Z (ESI): 253.0[M+H] + .

[0207] Step 7, 3-chloro-4-((1R,2S)-2-(2,2-difluoroethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine (19J) [ka] 3,6-Dichloro-4-((1R,2S)-2-(2,2-difluoroethyl)cyclopropyl)pyridazine (330 mg, 1.30 mmol) and 2,4-dimethoxypyrimidine-5-boronic acid (240 mg, 1.30 mmol) were dissolved in dioxane (10 mL) and water (2.0 mL). Under nitrogen protection, sodium carbonate (415 mg, 3.91 mmol) and [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium (191 mg, 111 μmol) were added, and the mixture was heated to 70 °C and reacted for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated by reversed-phase high-performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 150 x 40 mm x 15 μm, mobile phase: A = water + 0.225% by volume formic acid (99.9%), B = acetonitrile, gradient: 33%-63%, 11 min) to obtain the compound 3-chloro-4-((1R,2S)-2-(2,2-difluoroethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine (19J) (140 mg, 30.1% yield) as a yellow solid. LC-MS, M / Z (ESI): 357.1[M+H] + .

[0208] Step 8, 5-(6-chloro-5-((1R,2S)-2-(2,2-difluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (19) [ka] 3-Chloro-4-((1R,2S)-2-(2,2-difluoroethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine (130 mg, 364 μmol) is added to an aqueous solution of hydrochloric acid (1 M, 2.0 mL), and the mixture is heated to 50° C. and reacted for 8 hours. After concentrating and drying the reaction solution, the crude product is first separated by reversed-phase high performance liquid chromatography (chromatography column: Phenomenex Gemini-NX C18 150×25mm×10μm, mobile phase: A=water+0.225% volumetric formic acid (99%), B=acetonitrile, gradient: 19%-49%, 10 min), and then separated by supercritical fluid chromatography (chromatography column: DAICEL CHIRALPAK AD (250mm×30mm, 10μm), mobile phase: 0.1% ammonia water methanol solution, gradient: 70%-70%, 80 min), to obtain the white solid compound 5-(6-chloro-5-((1R,2S)-2-(2,2-difluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (19) (40.3mg, yield 49.4%). 1 H NMR (400 MHz, DMSO_d6):δ 11.53 (s, 2H), 8.29 (s, 1H),7.90 (s, 1H), 6.02-6.30 (m, 1H), 2.05-2.12 (m, 3H), 1.13-1.25 (m, 3H). LC-MS, M / Z (ESI): 329.0[M+H] + .

[0209] Example 20: Preparation of target compound 20 5-(5-((1S,2S)-2-(fluoromethyl)cyclopropyl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 20) [ka] The synthetic route to target compound 20 is shown below. [ka] Step 1. Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)-3-methylpyridazine (20B) [ka] Under nitrogen protection, 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazine (20A) (2.0 g, 6.16 mmol) (see Example 1 for preparation), 2,4,6-trimethyl-1,3,5,2,4,6-trioxytriborane in tetrahydrofuran (3.5 M, 4.93 mL, 17.24 mmol), cesium carbonate (6.02 g, 18.48 mmol) and [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium (0.451 g, 0.616 mmol) are dissolved in dioxane (40 mL) and water (10 mL), and the mixture is heated to 100° C. and reacted for 2 hours. The reaction mixture is diluted with water (100 mL), extracted with ethyl acetate (80 mL x 3), the organic layers are combined, dried over sodium sulfate, and concentrated to obtain the crude product. The crude product is separated by reversed-phase high performance liquid chromatography (HPLC) using a chromatography column of Phenomenex Luna C18 150 x 25 mm x 10 μm, mobile phase: [water (0.01% NH3.H2O)-acetonitrile], B%: 35%-65%, 10 min, and a pale yellow solid, 6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)-3-methylpyridazine (20B) (1.6 g, yield 85.0%), is obtained. LC-MS, M / Z: 305.1[M+H] + .

[0210] Step 2, 5-(5-((1S,2S)-2-(fluoromethyl)cyclopropyl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 20) [ka] 6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)-3-methylpyridazine (20B) (1.6 g, 5.26 mmol) is dissolved in tetrahydrofuran (10 mL), added to aqueous hydrochloric acid (1 M, 26.3 mL), heated to 50 °C, and reacted for 20 hours. The organic solvent in the reaction solution is concentrated, filtered to collect a white solid, and dried to obtain 5-(5-((1S,2S)-2-(fluoromethyl)cyclopropyl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 20) (1.1 g, 75.8% yield). 1 H NMR(400MHz,DMSO_d6) δ11.98~11.97(d,1H), 11.72(s, 1H), 8.40~8.39(d, 1H), 8.14(s, 1H), 4.64~4.31(m, 2H), 2.78(s, 3H), 2.26~2.20(m, 1H), 1.80~1.71(m, 1H), 1.36~1.21(m, 2H). LC-MS, M / Z: 277.3[M+H] + .

[0211] Example 21: Preparation of target compound 21 5-(6-Methyl-5-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 21) [ka] The synthetic route to target compound 21 is shown below. [ka] Step 1, Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-4-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazine (21B) [ka] Under nitrogen protection, 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazine (21A) (1.0 g, 2.56 mmol) (see Example 11 for the synthesis of the intermediate), 2,4,6-trimethyl-1,3,5,2,4,6-trioxytriborane in tetrahydrofuran (3.5 M, 2 mL, 7.17 mmol), cesium carbonate (2.5 g, 7.68 mmol) and [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium (0.187 g, 0.256 mmol) are dissolved in dioxane (20 mL) and water (5 mL), and the mixture is heated to 100° C. and reacted for 2 hours. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic layers were combined, dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by reversed-phase high performance liquid chromatography (column: Phenomenex Luna C18 150 x 25 mm x 10 μm, mobile phase: [water (0.01% NH3.H2O)-ACN], B%: 35%-65%, 10 min) to obtain 6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-4-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazine (21B) (0.8 g, 84.3% yield) as a pale yellow oil. LC-MS, M / Z: 371.1[M+H] + .

[0212] Step 2. Synthesis of 5-(6-methyl-5-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 21) [ka] 6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-4-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazine (21B) (0.8 g, 2.16 mmol) is dissolved in tetrahydrofuran (5 mL), added to aqueous hydrochloric acid (1 M, 10.8 mL), heated to 50 °C, and reacted for 20 hours. The organic solvent in the reaction solution is concentrated, filtered to collect a white solid, and dried to obtain 5-(6-methyl-5-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 21) (0.61 g, 82.5% yield). 1 H NMR (400 MHz, DMSO_d6) δ 11.85~11.83 (d, 1H), 11.67 (s, 1H), 8.36~8.35 (d, 1H), 8.05 (s, 1H), 4.26~4.12 (m, 2H), 2.74 (s, 3H), 2.27~2.22 (m, 1H), 1.72~1.67 (m, 1H), 1.34~1.25 (m, 2H). LC-MS, M / Z: 343.3 [M+H] + .

[0213] Example 22: Preparation of target compound 22 5-(6-Methyl-5-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 22) [ka] The synthetic route to target compound 22 is shown below. [ka] Step 1, 6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-4-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazine (22B) [ka] 3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazine (400 mg, 1.04 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxytriborane (893 μL, 3.13 mmol) and sodium carbonate (331 mg, 3.13 mmol) are dissolved in dioxane (12 mL) and water (3 mL), and [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium (152 mg, 208 μmol) is added under nitrogen protection, and the mixture is heated to 100 ° C. and reacted for 2 hours. After the reaction is completed, the reaction system is spin-dried to obtain the crude product. The mixture is separated and purified using a silica gel column (petroleum ether:ethyl acetate (V / V) = 2:1-1:2) to obtain the brown oily compound 6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-4-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazine (2) (400 mg, yield 75.6%). LC-MS, M / Z (ESI): 355.3 [M+H] +

[0214] Step 2, 5-(6-methyl-5-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (target compound 22) [ka] 6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-4-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazine (400 mg, 853 umol) is dissolved in tetrahydrofuran (2.00 mL), hydrochloric acid (1 M, 10.0 mL) is added, and the mixture is reacted at 50°C for 12 hours. After the reaction is completed, the reaction solution is concentrated and separated by reversed-phase high-performance liquid chromatography (chromatography column: Phenomenex Gemini-NX C18 75 mm x 30 mm x 3 μm, mobile phase: A = water + 0.225% volumetric formic acid (99%), B = acetonitrile, gradient: 12%-42%, 7 minutes), and after freeze-drying, the mixture is separated again by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm, solvent: 0.1% aqueous ammonia in methanol, gradient: 40%-40%, 45 min) to obtain the white solid compound 5-(6-methyl-5-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-diketone (22) (96.1 mg, yield 34.1%). LC-MS, M / Z (ESI): 326.9 [M+H] +

[0215] SFC: Rt=1.641min, de%=100%, Detection method: Column: Chiralpak AD-3 50×4.6mm ID, 3um, Mobile phase: A:CO2, B:0.05% diethylamine in methanol, Eluent: 40% methanol (containing 0.05% diethylamine) and 60% carbon dioxide, Flow rate: 3mL / min, Detector: PDA, Column temperature: 35℃, Column pressure: 100 Bar. 1 H NMR (400 MHz, CD3OD): δ 8.29 (s, 1H), 7.86 (s, 1H), 2.77 (s, 3H), 2.37-2.44 (m, 2H), 2.02-2.05 (m, 1H), 1.41-1.43 (m, 1H), 1.18-1.22 (m, 2H).

[0216] Test Example 1: In vitro inhibitory activity of compounds against recombinant human CD73 enzyme The test is carried out in Tris-MgCl2 buffer containing 25 mM Tris (Biosharp, 77-86-1) and 25 mM MgCl2 (Nanjing Chemical Reagent Co., Ltd., 7791-18-6). Human-CD73 (Novoprotein, C446) is prepared as a 3x mother solution with Tris-MgCl2 buffer, and added to a 96-well white board at 20 μL / well to a final concentration of 0.1 μg / mL. The final concentration of the compound is diluted with Tris-MgCl2 buffer to a 3x mother solution with an appropriate concentration gradient, and the compound is added to the above 96-well test white board at 20 μL / well. After uniform mixing, it is incubated at room temperature for 30 min. At the same time, a positive control group (no compound added) and a negative control group (no CD73 added) are prepared by adding Tris-MgCl2buffer to a 3x mother solution. AMP (Sigma, A1752-5G) was prepared to a 3x mother solution in a Tris-MgCl2 buffer, and added to the 96-well white board at 20 μL / well to a final concentration of 100 μM. The mixture was mixed evenly and incubated at 37°C for 60 min. For ATP, ATP (Sigma, A7699-1G) was prepared to a 7x mother solution in a Tris-MgCl2 buffer, and added to the 96-well white board at 10 μL / well to a final concentration of 100 μM. The mixture was mixed evenly and incubated for 5 min. The mixture was detected with an ATP-GLO kit (Promega, G7573).

[0217] The inhibition rate of different concentrations of compounds against Human-CD73 was calculated by the following formula, and then the IC of Human-CD73 inhibition by compounds was calculated by Prism software with compound concentration as the X-axis and inhibition rate as the Y-axis. 50 Calculate the value.

number

[0218] [Table 1]

[0219] The results of the in vitro enzyme test show that the compounds disclosed herein have good inhibitory effects on CD73 enzyme, and some compounds exhibit superior inhibitory effects on CD73 enzyme than the control compounds.

[0220] Test Example 2: Inhibitory activity of compounds against CD73 enzyme bound to the surface of human melanoma A375 cells Culture A375 (ATCC, CRL-1619) cells in DMEM medium (Gibco, 11995-040) containing 10% FBS (Gibco, 10099-141C) and 1% P / S (Thermo, 10378016). When the cells are in good condition, digest the cells with trypsin, remove the supernatant by centrifugation, collect the cells, wash them once with serum-free DMEM medium, resuspend them in serum-free DMEM medium, count them, and collect them at 1 × 10 4 / well, connect to a round-bottom 96-well plate at 60 μL / well, and set up a positive control (A375 + AMP) and a negative control (AMP only) at the same time. Compounds are diluted with serum-free DMEM medium to 5x mother solution with appropriate concentration gradient, and added to the cells of the above 96-well plate at 20μL / well, placed in an incubator and pre-incubated for 30min, AMP is prepared to 5x mother solution with serum-free DMEM, then the prepared AMP is added to the cells at 20μL / well, the final concentration is 200μM, and incubated at 37℃ for 16h, after incubation, the 96-well plate is centrifuged at 1500rpm for 3min, the supernatant is sucked up at 50μL / well into a new 96-well whiteboard, then 2μL of 25x ATP mother solution diluted with serum-free DMEM is added to each well, the final concentration is 100μM, and 50μL / well of CellTiter-Glo(R) Luminescent Cell Viability Assay reagent (Promega, G7573) is added, mixed uniformly, and then detected.

[0221] The inhibition rate of the compounds with different concentrations against CD73 binding to A375 was calculated by the following formula, and the compound concentration was plotted on the X-axis and the inhibition rate was plotted on the Y-axis. The IC 50Calculate the value.

number

[0222] [Table 2]

[0223] The test results show that the compounds disclosed herein have strong inhibitory activity against CD73 enzyme bound to the surface of A375 cells, and the inhibitory activity is far superior to that of positive compounds.

[0224] Test Example 3: Plasma protein binding rate of compound The equilibrium dialysis method (HTDialysis, HTD 96b) is used to detect the plasma protein binding rate of the compound. Prepare the compound in DMSO to a 0.5 mM preliminary solution, and dilute it 25 times with 0.05 M sodium phosphate buffer to a working solution of 20 μM. Take a blank 96-well plate and add 380 μL of plasma per well, then add 20 μL / well of working solution to the plasma and mix evenly, so that the final concentration of the compound is 1 μM, and each well contains 0.2% DMSO.

[0225] Add 100 µL of 0.05 M sodium phosphate buffer to the receiving side of each dialysis chamber (HTD 96b) and add 100 µL of plasma containing the compound to the donor side. After covering with the plastic lid, incubate at 37 °C with shaking for 5 h.

[0226] After the incubation, 25 μL of samples were taken from the supply side and the receiving side of the dialysis chamber, respectively, and placed in a blank 96-well plate. An equal volume of blank plasma was added to the supply side sample, and an equal volume of 0.05 M sodium phosphate buffer was added to the receiving side sample, respectively, and mixed uniformly. After adding 200 μL of acetonitrile solution containing internal standards to each well, the 96-well plate was vortexed at a speed of 600 rpm for 10 minutes and centrifuged at 5594 g for 15 minutes (Thermo Multifuge × 3R), and then 50 μL of the supernatant was transferred to a new 96-well plate and mixed with the sample and 50 μL of ultrapure water before LC-MS / MS analysis.

[0227] Calculate the plasma protein binding rate and free fraction using the following formula: % binding rate = 100 × ([supply side concentration] 5h - [Receiver concentration] 5h ) / [supply side concentration] 5h % free fraction = 100 - % bound fraction

[0228] [Table 3]

[0229] The results of the plasma protein binding test show that the compounds of the present disclosure have high plasma free fractions and exhibit superior drug formability to the control compounds.

[0230] Test Example 4: AMP-induced Human CD4 + Compound release activity on suppressing T cell proliferation Primary human CD4 cells were cultured in RPMI1640 (Shanghai Yuanpei Bioscience, L210KJ) medium containing 10% FBS (Gibco, 10099-141C) and 1% P / S (Thermo, 10378016). + T. On the first day of the study, CD4 + T (Allcells (Shanghai) Co., Ltd., PB009-2F-C) cells were reactivated and diluted to 3 × 10 4 / well, 50μL / well, connected according to duplicate wells. Dilute the compounds in 4× mother solution with appropriate concentration gradient in complete medium, add 50μL / well to the above cells, pre-incubate at 37℃ for 30min, prepare 4× IL-2 (Sino Biological, GMP-11848-HNAE) in complete medium, then resuspend CD3 / CD28 beads (Gibco, 11131D) in 4× IL-2 solution, add to the above cells at a dose of 50μL / well, so that the final concentration of IL-2 is 5U / ml, and each well contains 1μL of washed CD3 / CD28 beads, then incubate at 37℃ for 60min, and at the same time, prepare a positive control group (Human CD4 + T+ IL-2+CD3 / CD28 beads) and negative control group (Human CD4 + Set up a plate containing 100x AMP (T+ IL-2+CD3 / CD28 beads+AMP), dilute 4xAMP (Sigma, A1752-5G) in complete medium, add 50μL / well to the cells, final concentration is 0.3mM, continue to incubate at 37℃, add AMP again on the third day of the test, add 20μL / well to the plate, final concentration is 0.3mM, on the fifth day, measure the proliferation status of the cells with CCK8 kit (DojinDO, CK04).

[0231] The following formula is used to measure the CD4 AMP induction at different compound concentrations: + The inhibition rate of T cell proliferation was calculated, and the compound concentration was plotted on the X-axis and the inhibition rate on the Y-axis to determine whether the compound inhibited AMP-induced CD4 + ECs that release the inhibition of T cell proliferation 50 Calculate the value.

number

[0232] [Table 4]

[0233] As can be seen from the test results, the compounds disclosed herein inhibit AMP-induced CD4+ It significantly relieved the inhibition of T proliferation, and its activity was superior to that of positive compounds.

[0234] Test Example 5: Pharmacokinetics test For the mouse pharmacokinetics study, 20-25g male ICR mice were used and fasted overnight. Three mice were given oral intragastric administration (10mg / kg). Blood was collected before administration, 15 and 30 minutes after administration, and 1, 2, 4, 8, and 24 hours after administration. Three additional mice were given intravenous administration (3mg / kg) and blood was collected before administration, 15 and 30 minutes after administration, and 1, 2, 4, 8, and 24 hours after administration. The blood samples were centrifuged at 6800g and 2-8℃ for 6 minutes, and the plasma was collected and stored at -80℃. The plasma at each time point was taken, mixed with 3-5 times the amount of acetonitrile solution containing the internal standard, vortexed for 1 minute, and centrifuged at 13000 rpm for 10 minutes at 4℃, the supernatant was taken, mixed with 3 times the amount of water, and an appropriate amount of the mixture was taken for LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed with WinNonlin 7.0 software non-ventricular model.

[0235] In the dog pharmacokinetic study, male Beagle dogs weighing 8-10 kg were used and fasted overnight. Three Beagle dogs were given 5 mg / kg orally via intragastric administration. Three other Beagle dogs were given 1 mg / kg via intravenous injection. The rest of the procedure was the same as in the mouse pharmacokinetic study.

[0236] [Table 5]

[0237] The results of the mouse pharmacokinetic test show that the compounds of the present disclosure exhibit excellent pharmacokinetic properties, and in particular, compound 3, compound 4, compound 9 and compound 11 have significantly improved pharmacokinetic properties compared to the positive control phase.

[0238] [Table 6]

[0239] The results of the pharmacokinetic test in dogs show that all of the compounds disclosed herein have exposure levels equal to or higher than those of the control compounds, and in particular, the exposure levels of compounds 4 and 11 are far superior to those of the control compounds, exhibiting excellent pharmacokinetic properties and good drug formability.

[0240] Test Example 6: In vivo efficacy test of A375 melanoma Logarithmic growth phase A375 cells were collected and incubated with Mitomycin C for 2 h, then washed three times with PBS. After 5 days of co-culture of PBMCs and A375, PBMCs and freshly digested A375 cells were received and incubated at 5 × 10 5 4 x 10 PBMCs 6 A375 cells were inoculated subcutaneously into the right side of NCG mice at 0.2ml / mouse (containing 50% Matrigel). After inoculation, the mice were randomly divided into model and treatment groups according to their body weight, and the tumor size and animal body weight were measured and recorded before and during treatment. After the treatment, the difference in tumor size between the model and treatment groups was compared to determine the drug efficacy.

[0241] [Table 7]

[0242] The results of the in vivo efficacy test show that the compound disclosed herein, when used in combination with a PD-1 antibody (trepril monolide, Shanghai Junshi Bio-Pharmaceutical Technology Co., Ltd., batch number: 202001002), can significantly enhance the inhibitory effect of the PD-1 antibody on the growth of A375 melanoma, and the synergistic efficacy of compound 1 is better at the same dose than that of the positive compound (Figure 1).

[0243] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to and the benefit of patent application No. 202011225900.8 filed with the State Intellectual Property Office of China on November 5, 2020, and patent application No. 202110480100.9 filed with the State Intellectual Property Office of China on April 30, 2021, the entire contents of which are incorporated herein by reference.

Claims

1. A compound of formula I, a tautomer of said compound, a stereoisomer of said compound, a hydrate of said compound, a solvate of said compound, or a pharma- ceutically acceptable salt of said compound, 【Chemistry 1】 however, R １ is based on the following formula: 【Chemistry 2】 where R ａ are independently unsubstituted or substituted with 1 to 5 identical or different halogens. １ -C ６ selected from alkyl groups, R ２ is halogen and C １ -C ６ A compound of formula I, a tautomer of said compound, a stereoisomer of said compound, a hydrate of said compound, a solvate of said compound, or a pharma- ceutically acceptable salt of said compound, wherein said compound is selected from the group consisting of an alkyl group, an alkyl group, an aryl ...

2. A compound of formula I, a tautomer of said compound, a stereoisomer of said compound, a hydrate of said compound, a solvate of said compound, or a pharma- ceutically acceptable salt of said compound, 【Chemistry 3】 however, R １ is based on the following formula: 【Chemistry 4】 where R ａ are independently unsubstituted or substituted with 1 to 5 identical or different halogens. １ -C ６ selected from alkyl groups, R ２ is halogen and C １ -C ６ A compound of formula I, a tautomer of said compound, a stereoisomer of said compound, a hydrate of said compound, a solvate of said compound, or a pharma- ceutically acceptable salt of said compound, wherein said compound is selected from the group consisting of an alkyl group, an alkyl group, an aryl ...

3. R ａ C is not substituted １ -C ６ When it is an alkyl group, １ -C ６ The alkyl group is C １ -C ４ is an alkyl group, or R ａ C substituted with 1 to 5 identical or different halogens １ -C ６ When it is an alkyl group, １ -C ６ The alkyl group is C １ -C ４ is an alkyl group, or R ａ C substituted with 1 to 5 identical or different halogens １ -C ６ When it is an alkyl group, the halogen is F, Cl, Br or I; or R ａ C substituted with 1 to 5 identical or different halogens １ -C ６ A compound represented by formula I according to claim 1 or claim 2, characterized in that, when it is an alkyl group, the number of substitutions with said halogen is 1, 2 or 3, a tautomer of said compound, a stereoisomer of said compound, a hydrate of said compound, a solvate of said compound, or a pharma- ceutically acceptable salt of said compound.

4. R ａ Unsubstituted C １ -C ６ When it is an alkyl group, １ -C ６ the alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group or an isobutyl group, or R ａ C substituted with 1 to 5 identical or different halogens １ -C ６ When it is an alkyl group, １ -C ６ the alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group or an isobutyl group, or R ａ C substituted with 1 to 5 identical or different halogens １ -C ６ When it is an alkyl group, the halogen is F or Cl; or R ａ C substituted with 1 to 5 identical or different halogens １ -C ６ A compound represented by formula I according to claim 1 or claim 2, characterized in that when the alkyl group is an alkyl group, the number of the halogens substituted is 3, a tautomer of the compound, a stereoisomer of the compound, a hydrate of the compound, a solvate of the compound, or a pharma- ceutically acceptable salt of the compound.

5. R ２ is a halogen, said halogen is F, Cl, Br or I, or R ２ C １ -C ６ When it is an alkyl group, １ -C ６ The alkyl group is C １ -C ４ 3. A compound of formula I according to claim 1 or claim 2, characterized in that said alkyl group is an alkyl group, a tautomer of said compound, a stereoisomer of said compound, a hydrate of said compound, a solvate of said compound or a pharma- ceutically acceptable salt of said compound.

6. R ２ is a halogen, said halogen is Cl; or R ２ C １ -C ６ When it is an alkyl group, １ -C ６ 3. A compound of formula I according to claim 1 or claim 2, characterized in that the alkyl group is a methyl group, a tautomer of said compound, a stereoisomer of said compound, a hydrate of said compound, a solvate of said compound or a pharma- ceutically acceptable salt of said compound.

7. A partial structure in the formula I represented by the following formula: 【Chemistry 5】 is the structure of the formula 【Chemistry 6】 Or, the structure 【Chemistry 7】 3. The compound of formula I according to claim 1 or claim 2, wherein:

8. A partial structure in the formula I represented by the following formula: 【Chemistry 8】 is the structure of the formula 【Chemistry 9】 and However, the above R １ is based on the following formula: 【Chemistry 10】 where R ａ C is unsubstituted or substituted with one or more identical or different halogens １ -C ６ 3. A compound of formula I according to claim 1 or claim 2, characterized in that: R is an alkyl group; a tautomer of said compound; a stereoisomer of said compound; a hydrate of said compound; a solvate of said compound; or a pharma- ceutically acceptable salt of said compound.

9. R ａ is unsubstituted or substituted with 1 to 5 identical or different halogens; １ -C ４ selected from alkyl groups, R ２ is halogen and C １ -C ４ 9. The compound of formula I according to claim 8, characterized in that said compound is selected from the group consisting of alkyl groups, tautomers of said compounds, stereoisomers of said compounds, hydrates of said compounds, solvates of said compounds, and pharma- ceutically acceptable salts of said compounds.

10. A partial structure in the formula I represented by the following formula: 【Chemistry 11】 is the structure of the formula 【Chemistry 12】 and However, the above R １ is based on the following formula: 【Chemistry 13】 A compound of formula I according to claim 1 or claim 2, characterized in that it is selected from the group consisting of a tautomer of said compound, a stereoisomer of said compound, a hydrate of said compound, a solvate of said compound, and a pharma- ceutically acceptable salt of said compound.

11. R ２ is halogen and C １ -C ４ 11. The compound of formula I according to claim 10, characterized in that said compound is selected from the group consisting of alkyl groups, tautomers of said compounds, stereoisomers of said compounds, hydrates of said compounds, solvates of said compounds, and pharma- ceutically acceptable salts of said compounds.

12. The compound represented by formula I is a compound represented by formula II 【Chemistry 14】 or a compound of formula III 【Chemistry 15】 and however, R １ is based on the following formula: 【Chemistry 16】 Or, based on the formula 【Chemistry 17】 where R ａ are independently unsubstituted or substituted with 1 to 5 identical or different halogens. １ -C ６ 2. The compound of formula I according to claim 1, characterized in that said compound is selected from the group consisting of alkyl groups, tautomers of said compounds, stereoisomers of said compounds, hydrates of said compounds, solvates of said compounds, and pharma- ceutically acceptable salts of said compounds.

13. The compound represented by formula I is a compound represented by formula II 【Chemistry 18】 or a compound of formula III 【Chemistry 19】 and however, R １ is based on the following formula: 【Chemistry 20】 Or, based on the formula 【Chemistry 21】 where R ａ are independently unsubstituted or substituted with 1 to 5 identical or different halogens. １ -C ６ 3. The compound of formula I according to claim 1 or claim 2, characterized in that the compound is selected from the group consisting of alkyl groups, tautomers of the compound, stereoisomers of the compound, hydrates of the compound, solvates of the compound, and pharma- ceutically acceptable salts of the compound.

14. Compounds of Formula IV 【Chemical 22】 and R ２ is halogen and C １ -C ６ 3. The compound of formula I according to claim 1 or claim 2, characterized in that the compound is selected from the group consisting of alkyl groups, tautomers of the compound, stereoisomers of the compound, hydrates of the compound, solvates of the compound, and pharma- ceutically acceptable salts of the compound.

15. A compound of formula V: 【Chemistry 23】 and R ２ is halogen and C １ -C ６ 3. The compound of formula I according to claim 1 or claim 2, characterized in that the compound is selected from the group consisting of alkyl groups, tautomers of the compound, stereoisomers of the compound, hydrates of the compound, solvates of the compound, and pharma- ceutically acceptable salts of the compound.

16. A compound of formula VI: 【Chemistry 24】 and R ２ is halogen and C １ -C ６ 3. The compound of formula I according to claim 1 or claim 2, characterized in that the compound is selected from the group consisting of alkyl groups, tautomers of the compound, stereoisomers of the compound, hydrates of the compound, solvates of the compound, and pharma- ceutically acceptable salts of the compound.

17. The compounds represented by formula I are the following compounds 1 to 9, 11, 12, 18, 21 and 2 ２ 【Chemistry 25】 The compound represented by formula I according to claim 1, characterized in that it is any compound selected from the group consisting of a tautomer of said compound, a stereoisomer of said compound, a hydrate of said compound, a solvate of said compound, and a pharma- ceutically acceptable salt of said compound.

18. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 17, a tautomer of said compound, a stereoisomer of said compound, a hydrate of said compound, a solvate of said compound or a pharma- ceutically acceptable salt of said compound, and a pharma- ceutically acceptable excipient of said compound.

19. 20. The use of a compound of formula I according to any one of claims 1-17, a tautomer of said compound, a stereoisomer of said compound, a hydrate of said compound, a solvate of said compound, or a pharma- ceutically acceptable salt of said compound in combination with a PD-1 / PD-L1 / CTLA-4 antibody or a PD-1 / PD-L1 / CTLA-4 inhibitor in the manufacture of a medicament for treating cancer.

20. Use of a compound of formula I according to any one of claims 1-17, a tautomer of said compound, a stereoisomer of said compound, a hydrate of said compound, a solvate of said compound or a pharma- ceutically acceptable salt of said compound, or the pharmaceutical composition of claim 18 in the manufacture of a medicament for treating cancer.

21. 21. The use according to claim 19 or 20, wherein the cancer is bladder cancer, breast cancer, bile duct cancer, rectal cancer, colon cancer, gastric cancer, gallbladder cancer, glioblastoma, head and neck cancer, liver cancer, lung cancer, lymphoma, neuroangioblastoma, melanoma, ovarian cancer, pancreatic cancer, prostate cancer or renal cancer.

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