Pyrimidinedione compounds and uses thereof

Abstract

The present invention provides a novel compound that effectively inhibits CD73 activity, which is a compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, its preparation method, and its use in the preparation of drugs.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to a pyrimidinedione compound. More specifically, the present invention relates to a pyrimidinedione compound and a preparation method thereof, as well as use thereof in preparing medicines. Background Art

[0002] CD73, also known as extracellular 5'-nucleotidyl hydrolase, is an exonuclease belonging to the metallophosphatase superfamily. It is a peripheral glycoprotein that is primarily anchored to the plasma membrane via a glycosylphosphatidylinositol (GPI) moiety. It has a molecular weight of 70 kDa and is encoded by the NT5E gene. CD73 is widely expressed on the cell surface of various tissues, including the brain, lungs, heart, spleen, lymph nodes, kidneys, colon, vascular endothelium, and bone marrow. It is also expressed by various immune cells, including macrophages, neutrophils, myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), natural killer cells (NK cells), and regulatory T cells (Tregs) (Soleimani A et al., Biochimie, 2020, 176:21-30). CD73 is also highly expressed in various tumor cells, such as melanoma, breast cancer, pancreatic cancer, ovarian cancer, colon cancer, and prostate cancer (Gao Z et al., Biomed Res Int, 2014, 2014:460654). CD73 also exists in a soluble form (sCD73) in biological fluids including serum and retains holoenzyme activity.

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

[0004] CD73 is closely related to tumor growth, angiogenesis and metastasis. Under normal physiological conditions, the extracellular ADO level is between 20 and 300nM, but in the tumor microenvironment, it increases and is maintained at the micromolar level (30-100μM), and the high extracellular ADO concentration is mainly affected by the hydrolysis of AMP by CD73. Studies have shown that the level of soluble CD73 (sCD73) in the plasma of cancer patients is increased compared with that in healthy people (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 loss of A2AR signaling in NK cells can improve CD73. + Tumor metastasis, enhancing anti-tumor immune response (Young A et al., Cancer Cell. 2016; 30 (3): 391-403.). Compared with normal pancreatic tissue, CD73 is upregulated in pancreatic ductal carcinoma (PDAC) and is associated with tumor size, lymph node metastasis, metastasis and poor prognosis (Harvey Jerry B et al., Front Immunol, 2020, 11: 508.). In ORIC's preclinical studies, the CD73 selective inhibitor ORIC-533 significantly reduced the ADO concentration in the tumor microenvironment while reducing tumor volume. These research results all show that CD73 is upregulated in a variety of tumors, and inhibiting CD73 may reduce ADO concentration, thereby inhibiting tumor growth and metastasis.

[0005] In addition to being used alone, CD73 inhibitors can block tumor growth by relieving immunosuppression, and can also be combined with other targeted therapies and / or immunotherapy, and radiotherapy to increase anti-tumor effects. In several mouse tumor models, combined treatment with anti-CD73 and anti-PD-L1 (programmed death receptor-ligand 1) and / or anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) antibodies is more effective than treatment with anti-PD-L1 and / or anti-CTLA-4 antibodies alone (Allard B et al., Clin. Cancer Res., 2013, 19: 5626-35.); CD73 levels were found to be upregulated in melanoma patients receiving PD-1 immunotherapy, and after anti-PD-1 treatment, a unique population of CD73-high macrophages persisted in glioblastoma patients, and CD73 deficiency enhanced the efficacy of anti-PD-1 and anti-CTLA-4 in mouse glioblastoma models (Goswami et al., 2013, 19: 5626-35). S et al., Nat. Med., 2020, 26: 39-46.); Radiotherapy causes the destruction of some tumor cells, causing a large amount of intracellular ATP to be released to the extracellular space. Under the action of CD73 on the surface of tumor cells or free CD73, it is converted into adenosine, producing an immunosuppressive effect. This is considered to be one of the reasons for the poor prognosis of some patients after radiotherapy. Therefore, the combination of CD73 inhibitors and radiotherapy may produce a synergistic effect (Wennerberg E et al., Cancer Immunol Res, 2020, 8: 465-478.).

[0006] Currently, some anti-CD73 monoclonal antibodies (MEDI9447, BMS986179, SRF373 / NZV930, CPI-006 / CPX-006, TJ004309) and selective small molecule inhibitors (LY3475070, AB680) have entered the clinical stage, and some experiments have achieved encouraging early results (NCT02754141). CD73 inhibition may be a promising method for treating tumors. Summary of the Invention

[0007] The present invention aims to propose a new CD73 inhibitor that can be used to prepare drugs for treating tumor-related diseases.

[0008] In the first aspect of the present invention, a compound is provided, which is a compound represented by Formula I, and its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0009]

[0010] in,

[0011] m is 0, 1, 2, 3 or 4;

[0012] Middle R 1 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R a Substituted C1-C6 alkyl, or, unsubstituted or replaced by R a Substituted C1-C6 alkyl-O-; the R a Substituted C1-C6 alkyl, or, said R a In the substituted C1-C6 alkyl-O-, the substitutions independently refer to one or more of the following substituents: halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkyl-O-, -COOH, -C(=O)NH2; when there are multiple substituents, the substituents are the same or different; when m is not 0 or 1, R 1 are independently the same or different;

[0013] n is 0, 1, 2, or 3;

[0014] X is selected from N or C;

[0015] Z 1 , Z 2 are each independently selected from N or C;

[0016] Middle Y 1 , Y 2 , Y 3 are independently selected from N, C, O or S; the Y 1 , Y 2 , Y 3 Each independently represented by one or more R 2 replace;

[0017] R 2 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R b The substituted group, the R b The substitution may be one or more substitutions, and the R b Each is independently a substituent: halogen, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 alkyl-O-, C3-C6 cycloalkyl, 5-8 membered aryl, 5-8 membered heteroaryl, 4-8 membered heterocycloalkyl, or 3-9 membered heterocycloalkenyl; when there are multiple substituents, the substituents are the same or different; in the 5-8 membered heteroaryl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkyl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkenyl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.

[0018] In a preferred embodiment of the present invention, the compound represented by formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are:

[0019]

[0020] in,

[0021] m is 0, 1, 2, 3 or 4;

[0022] Middle R 1 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R a Substituted C1-C6 alkyl, or, unsubstituted or replaced by R a Substituted C1-C6 alkyl-O-; the R a Substituted C1-C6 alkyl, or, said R a In the substituted C1-C6 alkyl-O-, the substitutions independently refer to one or more of the following substituents: halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkyl-O-, -COOH, -C(=O)NH2; when there are multiple substituents, the substituents are the same or different; when m is not 0 or 1, R 1 are independently the same or different;

[0023] n is 0, 1, 2, or 3;

[0024] X is selected from N or C;

[0025] Z 1 , Z 2 are each independently selected from N or C;

[0026] Middle Y 1 , Y 2 , Y 3 are independently selected from N, C, O or S; the Y 1 , Y 2 , Y 3 Each independently represented by one or more R 2 replace;

[0027] R 2 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R bThe substituted group, wherein the substitution independently refers to one or more substitutions among the following substituents: C1-C6 alkyl, C1-C6 alkyl-O-, C3-C6 cycloalkyl, 5-8 membered aryl, 5-8 membered heteroaryl, 4-8 membered heterocycloalkyl, or 3-9 membered heterocycloalkenyl; when there are multiple substituents, the substituents are the same or different; in the 5-8 membered heteroaryl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkyl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkenyl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.

[0028] In a preferred embodiment of the present invention, the unsubstituted or R b In the substituted groups, the groups are each independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 5-8 membered aryl, 5-8 membered heteroaryl, 4-8 membered heterocycloalkyl or 4-8 membered heterocycloalkenyl.

[0029] In a preferred embodiment of the present invention, the for or Preferably

[0030] In a preferred embodiment of the present invention, It is a 5-membered heteroaryl group, a 5-membered heterocycloalkyl group or a 5-membered heterocycloalkenyl group, and is preferably a 5-membered heteroaryl group.

[0031] In a preferred embodiment of the present invention, when When it is a 5-membered heteroaryl group, the heteroatom of the heteroaryl group is N.

[0032] In a preferred embodiment of the present invention, when When it is a 5-membered heteroaryl group, the number of heteroatoms of the heteroaryl group is 1-3, preferably 1 or 2.

[0033] In a preferred embodiment of the present invention, In the case of R 1 When it is a halogen, the halogen is F, Cl, Br or I, preferably F or Cl.

[0034] In a preferred embodiment of the present invention, when R 1 When it is halogen, m is 1 or 2, preferably, m is 1.

[0035] In a preferred embodiment of the present invention, when R 1 is unsubstituted or replaced by R a Substituted C1-C6 alkyl, or, unsubstituted or replaced by R aIn the case of substituted C1-C6 alkyl-O-, the C1-C6 alkyl is independently a C1-C4 alkyl, preferably a methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl group.

[0036] In a preferred embodiment of the present invention, when R 1 is unsubstituted or replaced by R a Substituted C1-C6 alkyl or unsubstituted or R a In the case of substituted C1-C6 alkyl-O-, m is 1 or 2, preferably, m is 1.

[0037] In a preferred embodiment of the present invention, when R 1 To be R a Substituted C1-C6 alkyl or R a In the case of substituted C1-C6 alkyl-O-, the number of substitutions is independently 1-3.

[0038] In a preferred embodiment of the present invention, when R 1 To be R a Substituted C1-C6 alkyl, or, R a When it is substituted C1-C6 alkyl-O-, the substituents are each independently C1-C6 alkyl, or when it is C1-C6 alkyl-O-, the C1-C6 alkyl in the substituent is independently C1-C4 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

[0039] In a preferred embodiment of the present invention, R 1 are independently selected from unsubstituted or substituted R a Substituted C1-C4 alkyl or unsubstituted or R a Substituted C1-C4 alkyl-O-, wherein R a Substitution is one or more substitutions, the R a Each is independently selected from the following substituents: halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkyl-O-, -COOH, -C(=O)NH2.

[0040] In a preferred embodiment of the present invention, R 1 are independently selected from unsubstituted or substituted R a Substituted C1-C3 alkyl or unsubstituted or R a Substituted C1-C3 alkyl-O-, the R a Substitution is one or more substitutions, the R a Each is independently selected from the following substituents: halogen, hydroxy, cyano, amino, C1-C6 alkyl.

[0041] In a preferred embodiment of the present invention, R 1are independently selected from unsubstituted or substituted R a substituted methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, said R a Substitution is one or more substitutions, the R a Each is independently selected from the following substituents: halogen, hydroxy, cyano, amino, C1-C6 alkyl.

[0042] In a preferred embodiment of the present invention, R 1 are independently selected from unsubstituted or substituted R a Substituted methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, when R a When it is a halogen, the halogen is F, Cl, Br or I, preferably F or Cl.

[0043] In a preferred embodiment of the present invention, In which R1 is independently selected from unsubstituted or replaced by R a Substituted C1-C4 alkyl, said R a Substitution is one or more substitutions, the R a Each is independently selected from the following substituents: halogen, hydroxy, cyano, amino, C1-C6 alkyl; wherein m is 1 or 2, n is 0, preferably, m is 1 and n is 0.

[0044] In a preferred embodiment of the present invention, In the case of Y 1 、Y 2 、Y 3 Each independently represented by one or more R 2 When substituted, the R 2 The total number is 1 to 3.

[0045] In a preferred embodiment of the present invention, R 2 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R b Substituted C1-C6 alkyl, said R b Substitution is one or more substitutions, the R b Each is independently a substituent: halogen, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 alkyl-O-, C3-C6 cycloalkyl, 5-8 membered aryl, 5-8 membered heteroaryl, 4-8 membered heterocycloalkyl, or 3-9 membered heterocycloalkenyl; when there are multiple substituents, the substituents are the same or different; in the 5-8 membered heteroaryl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkyl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkenyl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.

[0046] In a preferred embodiment of the present invention, when R 2 When it is a halogen, the halogen is F, Cl, Br, or I, preferably F or Cl.

[0047] In a preferred embodiment of the present invention, R 2 are independently selected from unsubstituted or substituted R b Substituted C1-C6 alkyl, said R b Substitution is one or more substitutions, the R b Each is independently selected from the following substituents: halogen, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 alkyl-O-, C3-C6 cycloalkyl, 5-8 membered aryl, 5-8 membered heteroaryl, 4-8 membered heterocycloalkyl, or 3-9 membered heterocycloalkenyl; in the 5-8 membered heteroaryl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkyl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkenyl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.

[0048] In a preferred embodiment of the present invention, R 2 are independently selected from unsubstituted or substituted R b Substituted C1-C4 alkyl, said R b Substitution is one or more substitutions, the R b Each is independently selected from the following substituents: halogen, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 alkyl-O-, C3-C6 cycloalkyl.

[0049] In a preferred embodiment of the present invention, R 2 are independently selected from unsubstituted or substituted R b substituted methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, said R b Substitution is one or more substitutions, the R b Each is independently selected from the following substituents: halogen, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 alkyl-O-, C3-C6 cycloalkyl.

[0050] In a preferred embodiment of the present invention, when R 2 is unsubstituted or replaced by R b Substituted C1-C6 alkyl, or, unsubstituted or replaced by R b In the case of substituted C1-C6 alkyl-O-, the C1-C6 alkyl is independently C1-C4 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl. In a preferred embodiment of the present invention, when R2 is unsubstituted or replaced by R b In the case of a substituted C3-C6 cycloalkyl group, the C3-C6 cycloalkyl group is independently cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane or cyclobutane.

[0051] In a preferred embodiment of the present invention, when R 2 is unsubstituted or replaced by R b In the case of a substituted 5- to 8-membered aryl group, the 5- to 8-membered aryl group is independently phenyl or naphthyl, preferably phenyl.

[0052] In a preferred embodiment of the present invention, when R 2 is unsubstituted or replaced by R b In the case of a substituted 5- to 8-membered heteroaryl group, the 5- to 8-membered heteroaryl group is independently pyrrole, pyrazole, triazole, furan, oxazole, thiophene, thiazole, pyridine, pyrazine or pyrimidine, preferably pyrazole, furan, thiophene or pyridine.

[0053] In a preferred embodiment of the present invention, when R 2 is unsubstituted or replaced by R b In the case of substituted 4- to 8-membered heterocycloalkyl groups, the 4- to 8-membered heterocycloalkyl groups are independently azetidine, oxetane, tetrahydropyrrolidinyl, tetrahydrofuranyl, hexahydropyran or tetrahydro-2H-thiopyran 1,1-dioxide, preferably azetidine or oxetane.

[0054] In a preferred embodiment of the present invention, when R 2 is unsubstituted or replaced by R b When the substituted 4-8 membered heterocycloalkenyl group is a substituted 4-8 membered heterocycloalkenyl group, the 4-8 membered heterocycloalkenyl group is independently 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, or fluorodihydrofuranyl and its oxide, preferably dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl.

[0055] In a preferred embodiment of the present invention, when R 2 When it is a substituted C1-C6 alkyl, a substituted C3-C6 cycloalkyl, a substituted 5-8 membered aryl, a substituted 5-8 membered heteroaryl or a substituted 4-8 membered heterocycloalkyl, the number of substitutions is 3.

[0056] In a preferred embodiment of the present invention, when R 2It is a substituted C1-C6 alkyl, a substituted C3-C6 cycloalkyl, a substituted 5-8 membered aryl, a substituted 5-8 membered heteroaryl or a substituted 4-8 membered heterocycloalkyl, and when the substitutions are each independently halogen, the halogen is F, Cl, Br or I, preferably F or Cl.

[0057] In a preferred embodiment of the present invention, when R 2 is a substituted C1-C6 alkyl, a substituted C3-C6 cycloalkyl, a substituted 5-8 membered aryl, a substituted 5-8 membered heteroaryl or a substituted 4-8 membered heterocycloalkyl, wherein the substitution is one or more substitutions, each of which is independently selected from a C1-C4 alkyl group. Preferably, R 2 is a substituted methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl group.

[0058] In a preferred embodiment of the present invention, In, Z 1 , Z 2 are each independently selected from N or C,

[0059] When R 2 To be R b Substituted C1-C6 alkyl, R b Substituted C3-C6 cycloalkyl, R b substituted 5-8 membered aryl, R b substituted 5-8 membered heteroaryl or R b When the 4-8 membered heterocycloalkyl is substituted, the number of substitutions is 2 or 3.

[0060] In a preferred embodiment of the present invention, In, Z 1 , Z 2 are each independently selected from N or C;

[0061] When Y 1 、Y 2 、Y 3 Each independently represented by one or more R 2 When substituted, the R 2 The total number is 1 to 3, R 2 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R b Substituted C1-C6 alkyl, said R b Substitution is one or more substitutions, the R b Each is independently selected from the following substituents: halogen, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 alkyl-O-, C3-C6 cycloalkyl.

[0062] In a preferred embodiment of the present invention, when R2 When it is a halogen, the halogen is F, Cl, Br, or I, preferably F or Cl.

[0063] In a preferred embodiment of the present invention, R 2 is selected from hydrogen, -F, -Cl, -Br, amino, cyano, -CH3, -CF3, -CHF2 or -CH2CH3.

[0064] In a preferred embodiment of the present invention, the compound shown in formula I is

[0065]

[0066] X is selected from C or N;

[0067] The Z 1 , Z 2 、Y 1 、Y 2 、Y 3 As defined above.

[0068] In a preferred embodiment of the present invention, when for When R 2 In the Y 1 、Y 2 、Y 3 The replacement of

[0069] In a preferred embodiment of the present invention, when for When R 2 In the Y 1 、Y 2 、Y 3 The replacement of

[0070] In a preferred embodiment of the present invention, when for When R 2 In the Y 1 、Y 2 、Y 3 The replacement of

[0071] In a preferred embodiment of the present invention, when for When R 2 In the Y 1 、Y 2 、Y 3 The replacement of

[0072] In a preferred embodiment of the present invention, when for When R 2 In the Y 1 、Y 2 、Y 3 The replacement of

[0073] In a preferred embodiment of the present invention, when for When R 2 In the Y 1 、Y 2 、Y 3 The replacement of

[0074] In a preferred embodiment of the present invention, when for When for

[0075] In a preferred embodiment of the present invention, when for When for

[0076] In a preferred embodiment of the present invention, when for When for

[0077] In a preferred embodiment of the present invention, when for When for

[0078] In a preferred embodiment of the present invention, the for

[0079] In a preferred embodiment of the present invention, X is N or C.

[0080] In a preferred embodiment of the present invention, Selected from

[0081] In a preferred embodiment of the present invention, the for

[0082] In a preferred embodiment of the present invention, Selected from

[0083] In a preferred embodiment of the present invention, the compound structural formula is

[0084]

[0085] m is 0, 1, 2, 3 or 4;

[0086] Middle R 1 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R a Substituted C1-C6 alkyl, or, unsubstituted or replaced by R a Substituted C1-C6 alkyl-O-; the R a Substituted C1-C6 alkyl, or, said R a In the substituted C1-C6 alkyl-O-, the R a Substitution is one or more substitutions, the R a Each is independently selected from the following substituents: halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkyl-O-, -COOH, -C(=O)NH2; when m is not 0 or 1, R 1 are independently the same or different;

[0087] n is 0, 1, 2, or 3;

[0088] X is selected from N or C;

[0089] Middle Y 1 、Y 2 are independently selected from N, C, O or S; the Y 1 、Y 2 Each independently represented by one or more R 2 replace;

[0090] R 2 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R b The substituted group, the R b Substitution is one or more substitutions, the R bEach is independently selected from the following substituents: halogen, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 alkyl-O-, C3-C6 cycloalkyl, 5-8 membered aryl, 5-8 membered heteroaryl, 4-8 membered heterocycloalkyl, or 3-9 membered heterocycloalkenyl; in the 5-8 membered heteroaryl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkyl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkenyl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.

[0091] In a preferred embodiment of the present invention, the compound structural formula is

[0092]

[0093] m is 0, 1, 2, 3 or 4;

[0094] Medium R 1 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R a Substituted C1-C6 alkyl, or, unsubstituted or replaced by R a Substituted C1-C6 alkyl-O-; the R a Substituted C1-C6 alkyl, or, said R a In the substituted C1-C6 alkyl-O-, the R a Substitution is one or more substitutions, the R a Each is independently selected from the following substituents: halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkyl-O-, -COOH, -C(=O)NH2; when m is not 0 or 1, R 1 are independently the same or different;

[0095] n is 0, 1, 2, or 3;

[0096] X is selected from N or C;

[0097] Middle Y 1 、Y 3 are independently selected from N, C, O or S; the Y 1 、Y 3 Each independently represented by one or more R 2 replace;

[0098] R 2 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R b The substituted group, the R bSubstitution is one or more substitutions, the R b Each is independently selected from the following substituents: halogen, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 alkyl-O-, C3-C6 cycloalkyl, 5-8 membered aryl, 5-8 membered heteroaryl, 4-8 membered heterocycloalkyl, or 3-9 membered heterocycloalkenyl; in the 5-8 membered heteroaryl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkyl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkenyl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.

[0099] In a preferred embodiment of the present invention, the compound structural formula is

[0100]

[0101] m is 0, 1, 2, 3 or 4;

[0102] Middle R 1 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R a Substituted C1-C6 alkyl, or, unsubstituted or replaced by R a Substituted C1-C6 alkyl-O-; the R a Substituted C1-C6 alkyl, or, said R a In the substituted C1-C6 alkyl-O-, the R a Substitution is one or more substitutions, the R a Each is independently selected from the following substituents: halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkyl-O-, -COOH, -C(=O)NH2; when m is not 0 or 1, R 1 are independently the same or different;

[0103] n is 0, 1, 2, or 3;

[0104] X is selected from N or C;

[0105] Middle Y 1 、Y 2 、Y 3 are independently selected from N, C, O or S; the Y 1 、Y 2 、Y 3 Each independently represented by one or more R 2 replace;

[0106] R 2are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R b The substituted group, the R b Substitution is one or more substitutions, the R b Each is independently selected from the following substituents: halogen, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 alkyl-O-, C3-C6 cycloalkyl, 5-8 membered aryl, 5-8 membered heteroaryl, 4-8 membered heterocycloalkyl, or 3-9 membered heterocycloalkenyl; in the 5-8 membered heteroaryl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkyl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkenyl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.

[0107] In a preferred embodiment of the present invention, the compound structural formula is

[0108] m is 0, 1, 2, 3 or 4;

[0109] Medium R 1 are independently selected from hydrogen, halogen, Hydroxyl, cyano, amino, unsubstituted or replaced by R a Substituted C1-C6 alkyl, or, unsubstituted or replaced by R a Substituted C1-C6 alkyl-O-; the R a Substituted C1-C6 alkyl, or, said R a In the substituted C1-C6 alkyl-O-, the R a Substitution is one or more substitutions, the R a Each is independently selected from the following substituents: halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkyl-O-, -COOH, -C(=O)NH2; when m is not 0 or 1, R 1 are independently the same or different;

[0110] n is 0, 1, 2, or 3;

[0111] X is selected from N or C;

[0112] Z 2 Independently selected from N or C;

[0113] Middle Y 1 、Y 2 、Y 3 are independently selected from N, C, O or S; the Y 1 、Y 2 、Y3 Each independently represented by one or more R 2 replace;

[0114] R 2 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R b The substituted group, the R b Substitution is one or more substitutions, the R b Each is independently selected from the following substituents: halogen, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 alkyl-O-, C3-C6 cycloalkyl, 5-8 membered aryl, 5-8 membered heteroaryl, 4-8 membered heterocycloalkyl, or 3-9 membered heterocycloalkenyl; in the 5-8 membered heteroaryl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkyl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkenyl, the heteroatoms are selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.

[0115] In a preferred embodiment of the present invention, the compound represented by formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are selected from any one of the following compounds:

[0116]

[0117]

[0118] In the second aspect of the present invention, a pharmaceutical composition is provided, comprising a therapeutically effective dose of the above-mentioned compound, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs and a pharmaceutically acceptable excipient.

[0119] According to a specific embodiment of the present invention, the pharmaceutical composition of the present invention can be included in the above-mentioned compound of therapeutically effective dose, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug and pharmaceutically acceptable pharmaceutical carrier, diluent or excipient are mixed and prepared into a pharmaceutical preparation, so as to be suitable for oral or parenteral administration. Methods of administration include, but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and oral routes. The preparation can be applied by any route, for example, by infusion or push injection, by the route of absorption through the epithelium or mucocutaneous membrane (such as oral mucosa or rectum, etc.). Administration can be systemic or local. Examples of oral administration preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, etc. The preparation can be prepared by methods known in the art and include carriers, diluents or excipients conventionally used in the field of pharmaceutical preparations.

[0120] In a third aspect of the present invention, the present invention provides the use of the above-mentioned compound, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug in combination with a PD-1 / PD-L1 antibody or a PD-1 / PD-L1 inhibitor in the preparation of a medicament for treating a disease associated with CD73, wherein the medicament can be used to treat 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, medulloblastoma, melanoma, ovarian cancer, pancreatic cancer, prostate cancer or kidney cancer.

[0121] In a fourth aspect, the present invention proposes the use of the above-mentioned compound, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the above-mentioned pharmaceutical composition in the preparation of drugs for treating CD73-related diseases.

[0122] According to a specific embodiment of the present invention, the use of the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition in the preparation of a drug for treating a disease related to CD73, the drug can be used to treat cancer. These cancers include, for example, bladder cancer, breast cancer, bile duct cancer, colorectal cancer, colon cancer, gastric cancer, gallbladder cancer, neuroblastoma, head and neck cancer, liver cancer, lung cancer, lymphoma, medulloblastoma, melanoma, ovarian cancer, pancreatic cancer, prostate cancer or kidney cancer.

[0123] Terms and Definitions

[0124] Unless otherwise specified, the terms and definitions used in this application, including the specification and claims, are as follows.

[0125] Those skilled in the art will understand that, according to the conventions used in the art, in the structural formula of this application, Used to depict chemical bonds, which are the points where a moiety or substituent is attached to a core or backbone structure.

[0126] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0127] The term "pharmaceutically acceptable salts" refers to salts of pharmaceutically acceptable non-toxic acids or bases, including salts of inorganic acids and bases, and organic acids and bases.

[0128] In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts that may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or that may be useful in the identification, characterization, or purification of the compounds of the present invention.

[0129] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0130] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or cohesiveness, making the formulation more suitable for direct compression.

[0131] The term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the present invention are prepared by modifying functional groups within the compound. These modifications can be removed by conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl group or an amino group within a compound of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group or a free amino group, respectively.

[0132] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0133] Depending on the choice of raw materials and methods, the compounds of the present invention may exist in the form of one of the possible isomers or a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are the symbols used to specify the rotation of plane polarized light caused by the compound, where (–) or L indicates that the compound is left-handed. Compounds prefixed with (+) or D are right-handed. With respect to a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of the isomers are often referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Many geometric isomers of alkenes, C=N double bonds, etc. can also exist in the compounds described herein, and all such stable isomers are contemplated by the present invention. When the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in either the cis- or trans- configuration.

[0134] When bonds to chiral carbon atoms in formulae of the present invention are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon atoms and the enantiomerically pure compounds and mixtures thereof are encompassed within the scope of the formulae. The diagrammatic representations of racemates and enantiomerically pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter.

[0135] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. Compounds of the invention containing asymmetrically substituted carbon atoms can be separated in optically active form or racemic form. Resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid that is an optically active, salified organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include α-methyl-benzylamine (e.g., S and R forms or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. The resolution of the racemic mixture can also be carried out by eluting on a column filled with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High performance liquid chromatography (HPLC) can also be used to carry out supercritical fluid chromatography (SFC). The selection of specific methods and elution conditions, chromatographic column selection can be selected by those skilled in the art according to the structure of the compound and test results. Further, optically pure starting materials or reagents of known configuration can also be used to obtain any enantiomer or diastereomer of the compound described in the present invention through stereoorganic synthesis.

[0136] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture with physical and chemical properties consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0137] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0138] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0139] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0140] 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, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any chemically feasible basis.

[0141] The term "C1-C6 alkyl" is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl radical is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or isomers thereof. In particular, the radical has 1, 2 or 3 carbon atoms ("C1-C3 alkyl"), for example methyl, ethyl, n-propyl or isopropyl.

[0142] The term "C1-C6 alkoxy" is understood to mean -O-(C1-C6 alkyl), which means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein "C1-C6 alkyl" has the above definition, such as methoxy, ethoxy, 1-propoxy, 2-propoxy, and 1-butoxy.

[0143] The term "C3-C6 cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0144] The term "4-8 membered heterocyclyl" or "4-8 membered heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring having 4 to 8 atoms, wherein 1, 2, 3, 4 or 5 ring atoms are selected from N, O and S, and unless otherwise specified, they may be attached via carbon or nitrogen, wherein -CH 2- The group is optionally replaced by -C(O)-; and wherein, unless otherwise indicated to the contrary, the ring nitrogen atom or the ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide or the ring nitrogen atom is optionally quaternized; wherein the -NH in the ring is optionally substituted by acetyl, formyl, methyl or methylsulfonyl; and the ring is optionally substituted by one or more halogens. It should be understood that when the total number of S atoms and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. If the heterocyclic group is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic ring or an aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclic group is monocyclic, it must not be aromatic. Examples of heterocyclic groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one, and 2,5-dioxoimidazolidinyl.

[0145] The term "4-8 membered heterocycloalkenyl" is understood to mean a non-aromatic monocyclic or polycyclic group containing 4 to 8 ring atoms, preferably 5 to 6 ring atoms, wherein the 4-8 membered heterocycloalkenyl 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 inclusion of aza, oxa or thia in the radical name means that at least one nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The nitrogen or sulfur atom of the 4-8 membered heterocycloalkenyl group may optionally be oxidized to the corresponding N-oxide, S-oxide or S-dioxide. Preferred 4- to 8-membered heterocycloalkenyl groups include, but are not limited to, 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, and oxides thereof. "4- to 8-membered heterocycloalkenyl" may also include two available hydrogen atoms on the same carbon atom of the ring being simultaneously substituted with a single group =O (i.e., forming a carbonyl group).

[0146] The term "5-8 membered aryl" is understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 5-8 carbon atoms, particularly a ring having 6 carbon atoms ("C6 aryl"), such as phenyl. When the 5-8 membered aryl is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the position of substitution, and for example, substitution may be in the ortho, para, or meta position.

[0147] The term "5- to 8-membered heteroaryl" is understood to mean a monovalent monocyclic, bicyclic or tricyclic aromatic ring radical having 5 to 8 ring atoms, in particular 5 or 6 carbon atoms, and containing 1 to 5 heteroatoms independently selected from N, O and S. Preference is given to monovalent monocyclic, bicyclic or tricyclic aromatic ring radicals containing 1 to 3 heteroatoms independently selected from N, O and S, and which may additionally be benzo-fused in each case. In particular, the heteroaryl radical is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like.

[0148] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0149] Additionally, it should be noted that, unless otherwise expressly stated, the term "independently" used in the present invention should be broadly construed to mean that the individual entities described are independent of one another and may independently represent the same or different specific groups. More specifically, the term "independently" can mean that specific options expressed by identical symbols in different groups do not affect each other, or that specific options expressed by identical symbols in the same group do not affect each other.

[0150] Beneficial effects

[0151] According to an embodiment of the present invention, the present invention provides CD73 inhibitors with novel structure, excellent pharmacokinetic properties, and good efficacy or drugability, which can be used to effectively treat CD73-related diseases and conditions.

[0152] The compounds of the present invention have a good inhibitory effect on the CD73 enzyme and good in vitro efficacy. In addition, the results of mouse experiments show that the compounds of the present invention exhibit excellent pharmacokinetic properties and good drugability.

[0153] In addition, the present invention has a significant effect of inhibiting the growth of CT-26 colorectal cancer when used alone or in combination with PD-1 antibody, and the compound of the present invention has a significant effect of inhibiting the growth of E.G7-OVA T cell lymphoma when used alone or in combination with PD-1 antibody.

[0154] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention. DETAILED DESCRIPTION

[0155] Below, the scheme of the present invention will be explained in conjunction with embodiment.It will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.In the embodiment, if specific technology or conditions are not indicated, the technology or conditions described in the literature in this area or the product instructions are used.The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained by commercial purchase.

[0156] Unless otherwise specified, the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10 -6 The solvents for NMR measurements are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and tetramethylsilane (TMS) is the internal standard.

[0157] The abbreviations of the present invention are defined as follows:

[0158] M: molar concentration, such as 1M hydrochloric acid means 1 mol / L hydrochloric acid solution

[0159] DMA: N,N-dimethylacetamide

[0160] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphonate

[0161] DIPEA: also written as DIEA, diisopropylethylamine, also known as N,N-diisopropylethylamine

[0162] DMF: N,N-dimethylformamide

[0163] LC-MS: Liquid chromatography-mass spectrometry

[0164] DMSO: dimethyl sulfoxide

[0165] HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

[0166] EGTA: Ethylene glycol bis(2-aminoethyl ether) tetraacetic acid

[0167] TLC: Thin layer chromatography

[0168] IC 50 : Half-maximal inhibitory concentration refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0169] Preparation 1:

[0170] The synthetic route of intermediate 1D is as follows:

[0171]

[0172] Step 1: Synthesis of ethyl (1S,2S)-2-((benzyloxy)methyl)cyclopropane-1-carboxylate

[0173]

[0174] Under nitrogen, sodium hydride (58.5 g, 1.46 mol, 60% content) was suspended in toluene (3000 mL). Triethyl phosphoacetate (327.7 g, 1.46 mol) was then added dropwise at 0°C. After the addition was complete, the mixture was stirred at 25°C for 1 hour. (S)-(+)-glycidyl benzyl ether (200 g, 1.22 mol) was then added to the reaction solution. The temperature was raised to 130°C and the reaction was allowed to proceed for 12 hours. The reaction mixture was diluted with water (5000 mL) and then extracted with ethyl acetate (2000 mL x 2). The organic layers were combined, washed with saturated brine (2000 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 50:1-10:1) to give a red oily substance (1S,2S)-2-((benzyloxy)methyl)cyclopropane-1-carboxylic acid ethyl ester (180 g, yield 63%).

[0175] 1 H NMR (400MHz, CDCl3) δ7.18-7.25(m,5H),4.42(s,2H),4.00-4.04(m,2H),3.33-3.37(m,1H),3 .24-3.28(m,1H),1.62-1.66(m,1H),1.46-1.49(m,1H),1.06-1.16(m,4H),0.75-0.78(m,1H).

[0176] Step 2: Synthesis of ethyl (1S,2S)-2-(hydroxymethyl)cyclopropane-1-carboxylate

[0177]

[0178] Ethyl (1S,2S)-2-((benzyloxy)methyl)cyclopropane-1-carboxylate (120 g, 512.2 mmol) was dissolved in ethanol (1200 mL). Under nitrogen, palladium on carbon (30.0 g, 10% content) was added. The atmosphere was then replaced with hydrogen three times, and the mixture was allowed to react at 50°C under 50 psi for 24 hours. The mixture was cooled to room temperature and filtered through celite. The filter cake was washed three times with ethanol, and the filtrate was concentrated to obtain ethyl (1S,2S)-2-(hydroxymethyl)cyclopropane-1-carboxylate (65.0 g, 85% yield) as a yellow oil.

[0179] Step 3: Synthesis of ethyl (1S,2S)-2-formylcyclopropane-1-carboxylate

[0180]

[0181] Ethyl (1S,2S)-2-(hydroxymethyl)cyclopropane-1-carboxylate (100 g, 693.6 mmol) was dissolved in dichloromethane (1500 mL). Dess-Martin periodinane (353.0 g, 832.4 mmol) was slowly added at 0°C, and the mixture was allowed to react at 25°C for 12 hours. After completion of the reaction, the reaction solution was poured into aqueous sodium carbonate (500 mL) and aqueous sodium sulfite (500 mL), then extracted with dichloromethane (2000 mL x 2). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford ethyl (1S,2S)-2-formylcyclopropane-1-carboxylate (67.0 g, 68% yield) as a yellow oil.

[0182] Step 4: Synthesis of ethyl (1S,2S)-2-(difluoromethyl)cyclopropane-1-carboxylate

[0183]

[0184] Ethyl (1S,2S)-2-formylcyclopropane-1-carboxylate (95 g, 668.3 mmol) was dissolved in dichloromethane (1200 mL), and diethylaminosulfur trifluoride (237.0 g, 194 mL, 1.47 mol) was added dropwise at 0°C, followed by stirring at 25°C for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (1000 mL), then extracted with dichloromethane (500 mL × 2), and the organic layers were combined, washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate, and concentrated to give ethyl (1S,2S)-2-(difluoromethyl)cyclopropane-1-carboxylate (95 g, crude) as a yellow oil, which was used directly in the next step.

[0185] 1 H NMR (400MHz, CDCl3) δ5.62-5.91(m,1H),4.16(q,2H),1.88-1.96(m,2H),1.26-1.30(m,4H),1.12-1.16(m,1H)

[0186] Step 5: Synthesis of (1S,2S)-2-(difluoromethyl)cyclopropane-1-carboxylic acid

[0187]

[0188] Ethyl (1S,2S)-2-(difluoromethyl)cyclopropane-1-carboxylate (95.0 g, 578.7 mmol) was dissolved in methanol (500 mL) and water (100 mL). Sodium hydroxide (69.5 g, 1.74 mmol) was then added and the mixture was allowed to react at 25°C for 12 hours. After completion of the reaction, the reaction solution was concentrated, water (500 mL) was added, and the mixture was extracted with methyl tert-butyl ether (500 mL x 2). The aqueous phase was collected and adjusted to pH 3 with 1M hydrochloric acid. The aqueous phase was then extracted with ethyl acetate (500 mL x 3). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford (1S,2S)-2-(difluoromethyl)cyclopropane-1-carboxylic acid (47.0 g, 60% yield) as a yellow oil.

[0189] 1 H NMR (400MHz, CDCl3) δ9.52(br.s,1H),5.65-5.94(m,1H),1.89-1.94(m,2H),1.34-1.37(m,1H),1.23-1.27(m,1H).

[0190] Step 6: Synthesis of 1,3-dioxoisoindolin-2-yl (1S,2S)-2-(difluoromethyl)cyclopropane-1-carboxylate

[0191]

[0192] (1S,2S)-2-(Difluoromethyl)cyclopropane-1-carboxylic acid (20.0 g, 146.9 mmol) and 4-dimethylaminopyridine (1.80 g, 14.7 mmol) were dissolved in dichloromethane (200 mL). N,N-diisopropylcarbodiimide (22.3 g, 176.4 mmol) was added dropwise at 0°C. The mixture was stirred at 0°C for 0.5 hours, followed by the addition of N-hydroxyphthalimide (28.8 g, 176.4 mmol). The mixture was reacted at 25°C for 12 hours. After completion of the reaction, water (200 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (200 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was separated and purified by silica gel column (100% dichloromethane) to give 1,3-dioxoisoindolin-2-yl (1S,2S)-2-(difluoromethyl)cyclopropane-1-carboxylate (33 g, yield 79.8%) as a white solid.

[0193] Step 7: Synthesis of 2-((1S,2S)-2-(difluoromethyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0194]

[0195] Dissolve 1,3-dioxoisoindolin-2-yl (1S,2S)-2-(difluoromethyl)cyclopropane-1-carboxylate (33.0 g, 117.4 mmol) and bis(oxonadole) borate (59.6 g, 237.7 mmol) in ethyl acetate (400 mL). Heat to 85°C under nitrogen. Add ethyl isonicotinate (8.87 g, 8.06 mL, 58.7 mmol) dropwise. Then, react at 85°C under nitrogen for 12 hours. After completion of the reaction, concentrate the reaction solution, slurry the residue with petroleum ether:ethyl acetate (v / v) = 50:1 (300 mL), filter through celite, wash the filter cake with petroleum ether:ethyl acetate (v / v) = 50:1 (200 mL), and concentrate the filtrate to obtain the crude product. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:1-20:1) to give a yellow oily substance 2-((1S,2S)-2-(difluoromethyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10 g, 39% yield).

[0196] 1 H NMR (400MHz, CDCl3) δ5.30-5.60(m,1H),1.41-1.49(m,1H),1.22(s,12H),0.80-0.87(m,2H),0.11-1.13(m,1H).

[0197] Example 1: Preparation of target compound 1

[0198] 5-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-a]pyrimidin-7-yl)pyrimidine-2,4(1H,3H)-dione

[0199]

[0200] The synthetic route of target compound 1 is as follows:

[0201]

[0202] Step 1: Synthesis of 5,7-dichloroimidazo[1,2-a]pyrimidine

[0203]

[0204] Dissolve imidazo[1,2-a]pyrimidine-5,7-diol (2.00 g, 13.2 mmol) in phosphorus oxychloride (20 mL) and react at 100°C for 4 hours. The reaction solution was concentrated and then slowly added to an ice-water mixture (50 mL). The pH was adjusted to 9 with saturated sodium bicarbonate aqueous solution, followed by extraction with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 5,7-dichloroimidazo[1,2-a]pyrimidine (2.2 g, 88.4% yield) as a yellow solid, which was used directly in the next step.

[0205] 1 H NMR (400MHz, DMSO-d6) δ8.09(d,1H),7.88(d,1H),7.72(s,1H).

[0206] LC-MS, M / Z(ESI):188.0[M+H] +

[0207] Step 2: Synthesis of 5-chloro-7-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-a]pyrimidine

[0208]

[0209] Under nitrogen protection, 5,7-dichloroimidazo[1,2-a]pyrimidine (2.20 g, 11.7 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (2.15 g, 11.7 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (856.2 mg, 1.17 mmol), and sodium carbonate (3.10 g, 29.3 mmol) were dissolved in 1,4-dioxane (50 mL) and water (10 mL). The mixture was then reacted at 25°C under nitrogen protection for 10 hours. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1-1:1) to give a yellow solid 5-chloro-7-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-a]pyrimidine (1.50 g, yield 43.9%).

[0210] LC-MS, M / Z(ESI):292.1[M+H] +

[0211] Step 3: Synthesis of 5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-7-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-a]pyrimidine

[0212]

[0213] Under nitrogen protection, 5-chloro-7-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-a]pyrimidine (500 mg, 1.71 mmol), 2-((1S,2S)-2-(difluoromethyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (747.5 g, 3.43 mmol), dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II) (121.4 mg, 0.171 mmol), and cesium carbonate (1.40 g, 4.29 mmol) were dissolved in 1,4-dioxane (30 mL) and water (6 mL), and then reacted at 100 ° C under nitrogen protection for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (100 mL) and then extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain a crude product. The product was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-1:1) to obtain 5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-7-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-a]pyrimidine (250 mg, crude) as a yellow solid, which was used directly in the next step.

[0214] LC-MS, M / Z(ESI):348.1[M+H] +

[0215] Step 4: Synthesis of 5-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-a]pyrimidin-7-yl)pyrimidine-2,4(1H,3H)-dione

[0216]

[0217] 5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-7-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-a]pyrimidine (250 mg, 0.720 mmol) was dissolved in a 1 M aqueous hydrochloric acid solution (5 mL) and heated to 75°C for 2 hours. The reaction solution was concentrated and purified by HPLC (column: 3-Phenomenex Luna C18 75 × 30 mm × 3 μm; solvent: A = water + 0.05 vol% hydrochloric acid (36.5%), B = acetonitrile; gradient: 0%-15% over 7 minutes) to obtain 5-(5-(((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-a]pyrimidin-7-yl)pyrimidine-2,4(1H,3H)-dione (30 mg, 12% yield) as a yellow solid.

[0218] 1 H NMR(400MHz,CD3OD)δ8.77(s,1H),8.48(s,1H),8.25(d,1H),8.12(d,1H),5.89-6.19 (m,1H),2.83-2.87(m,1H),2.13-2.19(m,1H),1.67-1.72(m,1H),1.56-1.60(m,1H).

[0219] LC-MS, M / Z(ESI):320.1[M+H] +

[0220] Example 2: Preparation of target compound 2

[0221] 5-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione

[0222]

[0223] The synthetic route of target compound 2 is as follows:

[0224]

[0225] Step 1: Synthesis of 3,6-dichloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyridazine

[0226]

[0227] Dissolve 3,6-dichloropyridazine (6.60 g, 44.3 mmol) and (1S,2S)-2-(difluoromethyl)cyclopropane-1-carboxylic acid (6.03 g, 44.3 mmol) in water (150 mL). Add concentrated sulfuric acid (6.74 mL) and heat to 70°C under nitrogen. Then, quickly add an aqueous solution of silver nitrate (4.20 g, 24.7 mmol, 7.5 mL), followed by the slow dropwise addition of an aqueous solution of ammonium persulfate (30.3 g, 132.9 mmol, 75 mL). Continue the reaction at 70°C for 2 hours. Adjust the pH of the reaction mixture to approximately 9 with aqueous ammonia, then extract with ethyl acetate (500 mL x 2). Combine the organic layers, wash with saturated brine (500 mL), dry over anhydrous sodium sulfate, and concentrate to yield the crude product. The residue was separated and purified using a reverse phase column (0.1% trifluoroacetic acid) to give 3,6-dichloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyridazine (5.00 g, 46.4% yield) as a yellow oil.

[0228] 1H NMR (400MHz, CDCl3) δ7.10(s,1H),5.79-6.08(m,1H),2.39-2.45(m,1H),1.68-1.75(m,1H),1.51-1.54(m,1H),1.22-1.25(m,1H).

[0229] LC-MS, M / Z(ESI):239.0[M+H] +

[0230] Step 2: Synthesis of 3-chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine

[0231]

[0232] 3,6-Dichloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyridazine (5.00 g, 20.9 mmol) and (2,4-dimethoxypyrimidin-5-yl)boronic acid (3.85 g, 20.9 mmol) were dissolved in 1,4-dioxane (50 mL) and water (10 mL). Sodium carbonate (6.65 g, 62.7 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (1.53 g, 2.09 mmol) were added under nitrogen protection. The temperature was raised to 70°C and the reaction was allowed to react for 1 hour. The reaction mixture was diluted with water (50 mL) and then extracted with ethyl acetate (100 mL*3). The organic phases were combined, washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated to obtain a crude product. The product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-2:1) to give a yellow oily compound 3-chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine (4.5 g, yield 48%).

[0233] LC-MS, M / Z(ESI):343.1[M+H] +

[0234] Step 3: Synthesis of 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine-3-carbonitrile

[0235]

[0236] Under the protection of nitrogen, 3-chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine (1.00 g, 2.31 mmol), tris(dibenzylideneacetone)dipalladium (211.0 mg, 230.5 μmol) and zinc cyanide (270.6 mg, 2.31 mmol) were added to N,N-dimethylformamide (10.0 mL), and then reacted at 120 ° C for 12 hours. After completion of the reaction, the reaction solution was added to water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was washed twice with saturated brine (50 mL), and then dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, which was separated and purified on a silica gel column (petroleum ether: ethyl acetate (V / V) = 20:1-3:1) to give a yellow oily substance, 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine-3-carbonitrile (600.0 mg, yield 78.1%).

[0237] LC-MS, M / Z(ESI):334.1[M+H] +

[0238] Step 4: Synthesis of (4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-yl)methanamine

[0239]

[0240] 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine-3-carbonitrile (600.0 mg, 1.80 mmol) and aqueous ammonia (2.52 g, 18.0 mmol, 25% content) were dissolved in methanol (10.0 mL). Under nitrogen protection, Raney nickel (240.0 mg) was added, and the atmosphere was replaced with hydrogen three times. The mixture was then reacted at 50 psi at 30°C for 5 hours. After completion of the reaction, the Raney nickel was removed by filtration through celite, and the filter cake was washed three times with methanol. The filtrate was concentrated to obtain (4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-yl)methanamine (160.0 mg, 25.0% yield) as a yellow oil.

[0241] LC-MS, M / Z(ESI):338.1[M+H] +

[0242] Step 5: Synthesis of 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,5-b]pyridazine

[0243]

[0244] (4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-yl)methanamine (160.0 mg, 415.0 μmol) was dissolved in trimethyl orthoformate (6.00 mL) and reacted at 80°C for 2 hours. After completion of the reaction, the reaction solution was concentrated to obtain 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,5-b]pyridazine (80.0 mg, 50.1% yield) as a yellow oil.

[0245] LC-MS, M / Z(ESI):348.1[M+H] +

[0246] Step 6: Synthesis of 5-(4-(((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione

[0247]

[0248] 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,5-b]pyridazine (80.0 mg, 280.9 μmol) was dissolved in hydrochloric acid (1 M, 3.12 mL) and reacted at 50°C for 12 hours. After completion of the reaction, the reaction mixture was lyophilized to obtain a crude product. The crude product was added to methanol (2.00 mL) and stirred for 30 minutes, slurried, and purified. The crude product was filtered and the filter cake was dried to obtain 5-(4-(((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione (13.7 mg, 17.1% yield) as a gray solid.

[0249] 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H),11.57(s,1H),9.41(s,1H),8.03-8.06(m,2H),7. 16(s,1H),5.89-6.18(m,1H),2.58-2.61(m,1H),2.07-2.49(m,1H),1.42-1.48(m,2H).

[0250] LC-MS, M / Z(ESI):320.1[M+H] +

[0251] Example 3: Preparation of target compound 3

[0252] 5-(8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

[0253]

[0254] The synthetic route of target compound 3 is as follows:

[0255]

[0256] Step 1: Synthesis of 6-chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine

[0257]

[0258] 8-Bromo-6-chloroimidazo[1,2-b]pyridazine (100 mg, 430.17 μmol) and 2-((1S,2S)-2-(difluoromethyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (187.60 mg, 860.34 μmol) were dissolved in 1,4-dioxane (6 mL) and water (2 mL). Cesium carbonate (420.5 mg, 1.29 mmol) and dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II) (60.9 mg, 86.0 μmol) were added under nitrogen. The temperature was raised to 100°C and the reaction was allowed to react for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated and purified using a silica gel column (petroleum ether:ethyl acetate (V / V) = 20:1-3:1) to obtain a yellow oil. The crude product was then separated and purified by reverse-phase high-performance liquid chromatography (column: Zhongpu RD-C18 150 × 25 mm × 3 μm; solvent: A = water + 0.05% trifluoroacetic acid (99%), B = acetonitrile; gradient: 25%-55% over 10 minutes) to obtain 6-chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine (30 mg, 36.4% yield) as a yellow oil.

[0259] LC-MS, M / Z(ESI):266.1[M+Na] +

[0260] Step 2: Synthesis of 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

[0261]

[0262] 6-Chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine (30 mg, 114.59 μmol) and (2,4-dimethoxypyrimidin-5-yl)boronic acid (42.16 mg, 229.17 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.5 mL). Sodium carbonate (30.36 mg, 286.46 μmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (16.77 mg, 22.92 μmol) were added under nitrogen. The temperature was raised to 100°C and the reaction was allowed to react for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 2). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated and purified on a silica gel plate (petroleum ether:ethyl acetate (V / V) = 3:2) to give a white solid compound 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (25 mg, yield 46.4%).

[0263] LC-MS, M / Z(ESI):348.1[M+H] +

[0264] Step 3: Synthesis of 5-((8-(1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

[0265]

[0266] 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (25 mg, 53.2 μmol) was dissolved in aqueous hydrochloric acid (1 M, 1.06 mL), and the mixture was heated to 70° C. and reacted for 12 hours. The reaction system was spin-dried, and the crude product was separated and purified by reverse-phase high-performance liquid chromatography (column: Phenomenex luna C18 150×25mm×10μm; solvent: A=water+0.05vol% hydrochloric acid (36.5%), B=acetonitrile; gradient: 1%-30%, 10 minutes) to give a white solid 5-(8-(1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (7.32 mg, 42.3% yield).

[0267] 1H NMR(400MHz,DMSO-d6)δ11.60-11.56(m,2H),8.39(s,1H),8.02(d,1H),7.96(s,1H),7.61(s,1H) ,5.93-6.23(m,1H),2.71-2.75(m,1H),2.36-2.45(m,1H),1.61-1.65(m,1H),1.46-1.51(m,1H).

[0268] LC-MS, M / Z(ESI):320.1[M+H] +

[0269] Example 4: Preparation of target compound 4

[0270] 5-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)pyrimidine-2,4(1H,3H)-dione

[0271]

[0272] The synthetic route of target compound 4 is as follows:

[0273]

[0274] Step 1: Synthesis of 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine

[0275]

[0276] 4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine (300 mg, 1.48 mmol), sodium carbonate (157.4 mg, 1.48 mmol), and (2,4-dimethoxypyrimidin-5-yl)boronic acid (327.78 mg, 1.78 mmol) were dissolved in 1,4-dioxane (8 mL) and water (2 mL). Under nitrogen, [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (108.6 mg, 148.5 μmol) was added. The atmosphere was then replaced with nitrogen three times and allowed to react at 100°C for 2 hours. After completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by slurrying with ethyl acetate (2 mL) and filtered to give a yellow solid 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (260 mg, 57.6% yield).

[0277] 1 H NMR (400MHz, CDCl3) δ9.08(s,1H),8.07(s,1H),7.77(s,1H),4.15(s,3H),4.11(s,3H),4.09(s,3H).

[0278] LC-MS, M / Z(ESI):306.1[M+H] +

[0279] Step 2: Synthesis of 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine

[0280]

[0281] 4-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (100 mg, 327.8 μmol), sodium carbonate (69.5 mg, 655.6 μmol), and 2-((1S,2S)-2-(difluoromethyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (85.8 mg, 363.4 μmol) were dissolved in 1,4-dioxane (3 mL) and water (1 mL). Dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II) (21.1 mg, 29.8 μmol) was added under nitrogen. The atmosphere was then replaced with nitrogen three times and reacted at 100°C for 2 hours. After completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel plate (ethyl acetate:petroleum ether (V / V) = 3:1) to obtain 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (88.0 mg, 74.3% yield) as a white solid.

[0282] LC-MS, M / Z(ESI):362.1[M+H] +

[0283] Step 3: Synthesis of 5-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)pyrimidine-2,4(1H,3H)-dione

[0284]

[0285] 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (64.9 mg, 179.8 μmol) and hydrochloric acid solution (1 M, 1.41 mL) were dissolved in methanol (1.50 mL) and stirred at 70°C for 8 hours. After completion of the reaction, the crude product was separated and purified by reverse-phase high performance liquid chromatography (column: 3_Phenomenex Luna C18 75×30 mm×3 μm; solvent: A = water + 0.05 vol% hydrochloric acid (36.5%), B = acetonitrile; gradient: 17%-37%, 7 min) to give a yellow solid 5-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)pyrimidine-2,4(1H,3H)-dione (4.28 mg, 7% yield).

[0286] 1 H NMR(400MHz,DMSO-d6)δ11.51(s,1H),11.41(s,1H),8.34(d,1H),8.18(s,1H),7.80(s,1H) ,5.86-6.16(m,1H),4.02(s,3H),2.62-2.65(m,1H),2.01-2.03(m,1H),1.41-1.46(m,2H).

[0287] LC-MS, M / Z(ESI):334.1[M+H] +

[0288] Example 5: Preparation of target compound 5

[0289] 5-(8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-methylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

[0290]

[0291] The synthetic route of target compound 5 is as follows:

[0292]

[0293] Step 1: Synthesis of 8-bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine

[0294]

[0295] Under dark conditions, bromoacetone (2.3 g, 16.8 mmol) was added to a flask containing 4-bromo-6-chloropyridazin-3-amine (0.5 g, 2.4 mmol) and the mixture was allowed to react overnight at 90°C. The mixture was cooled to room temperature, and petroleum ether (10 mL) was added. The mixture was filtered, and the filter cake was washed with petroleum ether (10 mL x 3). The filter cake was collected and dried to obtain 8-bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine (0.5 g, 85% yield) as a yellow solid.

[0296] LC-MS, M / Z (ESI): 245.9 [M+H] +

[0297] Step 2: Synthesis of 6-chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-methylimidazo[1,2-b]pyridazine

[0298]

[0299] Under nitrogen protection, a mixture of 8-bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine (420 mg, 1.704 mmol), dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II) (241 mg, 0.341 mmol) and potassium phosphate (1085 mg, 5.11 mmol) in 1,4-dioxane (15 mL) and water (5 mL) was heated to 80 ° C and stirred for ten minutes. 2-((1S,2S)-2-(difluoromethyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (409 mg, 1.874 mmol) was added and the reaction was carried out at 80 ° C for three hours. The mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified on a silica gel plate to give a yellow solid 6-chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-methylimidazo[1,2-b]pyridazine (140 mg, yield 31.9%).

[0300] LC-MS, M / Z (ESI): 258.1 [M+H] +

[0301] Step 3: Synthesis of 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylimidazo[1,2-b]pyridazine

[0302]

[0303] Under nitrogen protection, 6-chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-methylimidazo[1,2-b]pyridazine (140 mg, 0.543 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (300 mg, 1.630 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (39.8 mg, 0.054 mmol), sodium carbonate (173 mg, 1.630 mmol) were added to 1,4-dimethoxypyrimidin-5-ylboronic acid (300 mg, 1.630 mmol). A mixed solution of oxadiazole (8 mL) and water (2 mL) was heated to 100°C and reacted at this temperature for 3 h. After cooling to room temperature, water (30 mL) was added and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified on a silica gel plate to give a solid 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylimidazo[1,2-b]pyridazine (20 mg, yield 10.2%).

[0304] Step 4: Synthesis of 5-(8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-methylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

[0305]

[0306] 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylimidazo[1,2-b]pyridazine (20 mg, 0.055 mmol) was dissolved in methanol (3 mL), 1M dilute hydrochloric acid (1 mL, 1 mmol) was added, and the reaction was stirred at room temperature overnight. The mixture was concentrated, and the residue was lyophilized to obtain 5-(8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-methylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (12.2 mg, 66.1% yield) as a pale yellow solid.

[0307] 1 H NMR(400MHz,DMSO-d6)δ11.70(d,1H),11.56(s,1H),8.29(s,1H),8.04(d,1H),7.70(s,1 H),6.11(td,1H),2.86–2.74(m,1H),2.49(d,3H),2.32–2.18(m,1H),1.56–1.42(m,2H).

[0308] LC-MS, M / Z (ESI): 334.1 [M+H] +

[0309] Example 6: Preparation of target compound 6

[0310] 5-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-5-methylimidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione

[0311]

[0312] The synthetic route of target compound 6 is as follows:

[0313]

[0314] Step 1: Synthesis of 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-(1-ethoxyvinyl)pyridazine

[0315]

[0316] 3-Chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine (1.00 g, 1.90 mmol) and tributyl(1-ethoxyvinyl)stannane (822 mg, 2.28 mmol) were dissolved in N,N-dimethylformamide (20 mL) solution, and ditriphenylphosphine palladium dichloride (133 mg, 190 μmol) was added under nitrogen protection, and the temperature was raised to 110 ° C for 3 hours. Saturated potassium fluoride solution (50 mL) was added to the reaction system, stirred at room temperature for 30 minutes, then extracted with ethyl acetate (50 mL × 2), the organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated to give a dark brown oily substance 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-(1-ethoxyvinyl)pyridazine (1.00 g, crude product).

[0317] LC-MS, M / Z(ESI):379.2[M+H] +

[0318] Step 2: Synthesis of 1-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-yl)ethan-1-one

[0319]

[0320] 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-(1-ethoxyvinyl)pyridazine (0.90 g, 2.38 mmol) was dissolved in tetrahydrofuran (20 mL), and 0.5 M aqueous hydrochloric acid (20 mL) was added. The mixture was reacted at 25°C for 12 hours. After completion of the reaction, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This crude product was separated using a reverse phase column (0.1% trifluoroacetic acid) to afford 1-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-yl)ethan-1-one (400 mg, 48.0% yield) as a brown solid.

[0321] 1 H NMR(400MHz, CDCl3)δ8.50(s,1H),7.67(s,1H),5.75(td,1H),4.11(s,3H),4.00(s,3H), 2.91(s,3H),2.08-2.13(m,1H),1.71-1.80(m,1H),1.32-1.37(m,1H),1.15-1.21(m,1H).

[0322] LC-MS, M / Z(ESI):351.1[M+H] +

[0323] Step 3: Synthesis of 1-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-yl)ethan-1-amine

[0324]

[0325] 1-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-yl)ethan-1-one (300 mg, 856 μmol) and ammonium acetate (660 mg, 8.56 mmol) were dissolved in methanol (10 mL), sodium cyanoborohydride (80.7 mg, 1.28 mmol) was added, and the mixture was reacted at 25°C for 12 hours. After completion of the reaction, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated using a reverse phase column (0.1% trifluoroacetic acid system) to give 1-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-yl)ethan-1-amine (150 mg, 50% yield) as a yellow oil.

[0326] LC-MS, M / Z(ESI):352.1[M+H] +

[0327] Step 4: Synthesis of 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)-5-methylimidazo[1,5-b]pyridazine

[0328]

[0329] 1-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-yl)ethan-1-amine (130 mg, 370 μmol) was dissolved in trimethyl orthoformate (1.5 mL), heated to 110°C, and reacted for 12 hours. The reaction system was spin-dried to obtain 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)-5-methylimidazo[1,5-b]pyridazine (130 mg, crude) as a yellow oil.

[0330] LC-MS, M / Z(ESI):362.1[M+H] +

[0331] Step 5:

[0332] 5-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-5-methylimidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione

[0333]

[0334] 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)-5-methylimidazo[1,5-b]pyridazine (130 mg, crude product) was dissolved in aqueous hydrochloric acid (1 M, 5 mL), and the mixture was heated to 50° C. and reacted for 12 hours. The reaction solution was concentrated and then isolated and purified by reverse-phase high performance liquid chromatography (column: 3_Phenomenex Luna C18 75×30 mm×3 μm; solvent: A = water + hydrochloric acid (0.05%), B = acetonitrile; gradient: 5%-25% over 6.5 minutes) to obtain 5-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-5-methylimidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione (28.86 mg, 23.4% yield over two steps) as a yellow solid.

[0335] 1 H NMR (400MHz, CD3OD) δ9.63(s,1H),8.25(s,1H),7.45(s,1H),5.99(td,1H),2.87(s,3H),2.71-2.76(m,1H),2.01-2.06(m,1H),1.43-1.49(m,2H).

[0336] LC-MS, M / Z(ESI):334.1[M+H] +

[0337] Example 7: Preparation of target compound 7

[0338] 5-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-7-(trifluoromethyl)imidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione

[0339]

[0340] The synthetic route of target compound 7 is as follows:

[0341]

[0342] Step 1: Synthesis of 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)-7-(trifluoromethyl)imidazo[1,5-b]pyridazine

[0343]

[0344] Dissolve (4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-yl)methanamine (530 mg, 1.57 mmol), triethylamine (635.9 mg, 6.28 mmol), and 4-dimethylaminopyridine (19.2 mg, 157.1 μmol) in 8 ml of dichloromethane. Add trifluoroacetic anhydride (1.65 g, 7.86 mmol) dropwise at 0°C, and allow to react at 25°C for 2 hours. After completion of the reaction, concentrate the reaction solution to obtain the crude product. The product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 20:1-5:1) to give a yellow oily compound 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)-7-(trifluoromethyl)imidazo[1,5-b]pyridazine (350 mg, yield 53.6%).

[0345] LC-MS, M / Z(ESI):416.1[M+H] +

[0346] Step 2: Synthesis of 5-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-7-(trifluoromethyl)imidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione

[0347]

[0348] 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)-7-(trifluoromethyl)imidazo[1,5-b]pyridazine (350 mg, 842.7 μmol) was dissolved in hydrochloric acid (1 M, 3 mL) and reacted at 50°C for 12 hours. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. The crude product was purified by slurrying with methanol (10 mL) and water (50 mL) and filtered to obtain 5-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-7-(trifluoromethyl)imidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione (99.2 mg, 30.4% yield) as a gray solid.

[0349] 1 HNMR(400MHz,DMSO-d6)δ11.58(s,2H),7.97(s,1H),7.87(s,1H),7.29(s,1H) ;5.88–6.18(m,1H),2.65-2.67(m,1H),2.05–2.08(m,1H),1.46-1.48(m,2H).

[0350] LC-MS, M / Z(ESI):388.1[M+H] +

[0351] Example 8: Preparation of target compound 8

[0352] 5-(4-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione

[0353]

[0354] The synthetic route of target compound 8 is as follows:

[0355]

[0356] Step 1: Synthesis of (S)-2-chloro-3-methylbutan-1-ol

[0357]

[0358] (S)-2-chloro-3-methylbutanoic acid (30.0 g, 0.22 mmol) was dissolved in tetrahydrofuran (300 mL). Lithium aluminum tetrahydride (9.17 g, 0.24 mmol) was slowly added at 0-10°C. After addition, the mixture was stirred at 25°C for 1 hour, then heated to 50°C and reacted for 1 hour. After completion of the reaction, the reaction solution was cooled to 0-10°C, and water (9 mL), 15% aqueous sodium hydroxide solution (9 mL), and water (27 mL) were added in sequence. The mixture was then filtered through celite, the filter cake was washed with tetrahydrofuran (100 mL x 3), and the filtrate was concentrated to obtain the crude product. Purification by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1-2:1) afforded (S)-2-chloro-3-methylbutan-1-ol as a yellow oil (8.4 g, 31% yield).

[0359] 1 H NMR (400MHz, CDCl3) δ3.91-3.94(m,1H),3.74-3.82(m,2H),2.06-2.09(m,1H),1.99-2.05(m,1H),1.04(dd,6H).

[0360] Step 2: Synthesis of (R)-2-isopropyloxirane

[0361]

[0362] Potassium hydroxide (52.1 g, 0.93 mol) was dissolved in water (50 mL) and cooled to 0-5°C. (S)-2-chloro-3-methylbutan-1-ol (25.0 g, 0.20 mol) was then added dropwise. The mixture was then allowed to react at 25°C for 1 hour. After completion of the reaction, the reaction solution was distilled at 25°C using a water pump. The fractions were cooled in a dry ice-ethanol bath and collected to obtain (R)-2-isopropyloxirane (16.0 g, 91.1% yield) as a yellow oil.

[0363] 1 H NMR (400MHz, CDCl3) δ2.71-2.74(m,2H),2.52-2.54(m,1H),1.47-1.53(m,1H),1.04(d,3H),0.97(d,3H).

[0364] Step 3: Synthesis of ethyl (1S,2R)-2-isopropylcyclopropane-1-carboxylate

[0365]

[0366] Triethyl phosphoacetate (14.3 g, 63.8 mmol) was dissolved in 1,4-dioxane (20 mL). Then, n-butyllithium (2.5 M, 30.2 mL) was added dropwise at 0°C. After the addition was complete, the reaction mixture was stirred at 25°C for 0.5 hours. The mixture was then transferred to a sealed container and a solution of (R)-2-isopropyloxirane (5.00 g, 58.1 mmol) in 1,4-dioxane (10 mL) was added. The container was tightened and the temperature was raised to 145°C for 12 hours. After the reaction was complete, the reaction system was cooled, water (100 mL) was added, and the mixture was extracted with methyl tert-butyl ether (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield ethyl (1S,2R)-2-isopropylcyclopropane-1-carboxylate (7.0 g, 80.8% yield) as a yellow oil.

[0367] 1 H NMR (400MHz, CDCl3) δ4.09-4.13(m,2H),1.36-1.39(m,1H),1.19-1.27(m,5H),1.09-1.13(m,1H),0.96-0.99(m,6H),0.69-0.75(m,1H).

[0368] Step 4: Synthesis of (1S,2R)-2-isopropylcyclopropane-1-carboxylic acid

[0369]

[0370] Ethyl (1S,2R)-2-isopropylcyclopropane-1-carboxylate (7.00 g, 44.8 mmol) was dissolved in 1,4-dioxane (60 mL) and water (60 mL). Sodium hydroxide (17.9 g, 448.1 mmol) was then added and the mixture was allowed to react at 100°C for 7 hours. After completion of the reaction, the mixture was extracted with methyl tert-butyl ether (100 mL × 2). The aqueous phase was collected and adjusted to pH 1-2 with concentrated hydrochloric acid. The mixture was then extracted with methyl tert-butyl ether (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford (1S,2R)-2-isopropylcyclopropane-1-carboxylic acid (6.40 g, crude) as a yellow oil, which was used directly in the next step.

[0371] 1 H NMR (400MHz, CDCl3) δ1.56-1.60(m,1H),1.45-1.50(m,1H),1.37-1.40(m,1H),1.21-1.27(m,1H),1.60-1.85(m,6H),0.97-1.02(m,1H).

[0372] Step 5: Synthesis of 3,6-dichloro-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine

[0373]

[0374] 3,6-Dichloropyridazine (6.27 g, 42.1 mmol) and (1S,2S)-2-(difluoromethyl)cyclopropane-1-carboxylic acid (5.39 g, 42.1 mmol) were dissolved in water (100 mL). Concentrated sulfuric acid (5.39 mL) was then added and the temperature was raised to 70°C under nitrogen. An aqueous solution of silver nitrate (3.57 g, 21.0 mmol, 25 mL) was then quickly added, followed by an aqueous solution of ammonium persulfate (28.8 g, 126.2 mmol, 50 mL) added dropwise. The reaction was continued at 70°C for 1 hour. After completion of the reaction, the pH of the reaction mixture was adjusted to approximately 9 with aqueous ammonia, and then extracted with ethyl acetate (200 mL x 2). The organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1-3:1) to give 3,6-dichloro-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine (3.20 g, yield 32.9%) as a yellow oil.

[0375] LC-MS, M / Z(ESI):231.0[M+H] +

[0376] Step 6: Synthesis of 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine

[0377]

[0378] 3,6-Dichloro-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine (2.10 g, 9.09 mmol) and 2,4-dimethoxypyrimidine-5-boronic acid (1.67 g, 9.09 mmol) were dissolved in 1,4-dioxane (10 mL) and water (3 mL). Sodium carbonate (2.89 g, 27.3 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (664.8 mg, 0.91 mmol) were added under nitrogen protection. The temperature was raised to 100°C and the reaction was allowed to react for 2 hours. The reaction mixture was diluted with water (100 mL) and then extracted with ethyl acetate (150 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-2:1) to give a yellow oily substance, 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine (2.00 g, yield 65.7%).

[0379] LC-MS, M / Z(ESI):335.1[M+H] +

[0380] Step 7: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine-3-carbonitrile

[0381]

[0382] Under the protection of nitrogen, 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine (2.00 g, 5.97 mmol), tris(dibenzylideneacetone)dipalladium (547.0 mg, 597.4 μmol) and zinc cyanide (2.00 g, 17.0 mmol) were added to N,N-dimethylformamide (30 mL), and then reacted at 100 ° C for 3 hours. After completion of the reaction, the reaction solution was added to water (30 mL), and extracted with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine (50 mL), and then the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified on a silica gel column (petroleum ether: ethyl acetate (V / V) = 10:1-3:1) to give a yellow oily product 6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine-3-carbonitrile (1.90 g, crude product), which was used directly in the next step.

[0383] LC-MS, M / Z(ESI):326.2[M+H] +

[0384] Step 8: Synthesis of (6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-yl)methanamine

[0385]

[0386] 6-(2,4-Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine-3-carbonitrile (1.90 g, 5.84 mmol) was dissolved in methanol (30.0 mL). Under nitrogen, Raney nickel (1.50 g, 17.5 mmol) was added. The mixture was then replaced with hydrogen three times and allowed to react at 50°C for 10 hours at 50 psi. After completion of the reaction, the Raney nickel was removed by filtration through celite, and the filter cake was washed three times with methanol. The filtrate was concentrated to obtain a crude product, which was then purified by reverse-phase column chromatography (0.1% HCl) to afford (6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-yl)methanamine (500 mg, crude) as a yellow oil, which was used directly in the next step.

[0387] LC-MS, M / Z(ESI):330.2[M+H] +

[0388] Step 9: Synthesis of 2-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,5-b]pyridazine

[0389]

[0390] (6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-yl)methanamine (240.0 mg, 728.6 μmol) was dissolved in trimethyl orthoformate (6.00 mL) and reacted at 110°C for 12 hours. After completion of the reaction, the reaction solution was concentrated to obtain 2-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,5-b]pyridazine (280.0 mg, crude) as a yellow oil, which was used directly in the next step.

[0391] LC-MS, M / Z(ESI):340.2[M+H] +

[0392] Step 10: Synthesis of 5-(4-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione

[0393]

[0394] 2-(2,4-Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,5-b]pyridazine (200 mg, 589.3 μmol) was dissolved in hydrochloric acid (1 M, 5 mL) and reacted at 50°C for 10 hours. After completion of the reaction, the reaction solution was directly concentrated to obtain a crude product, which was then separated and purified by reverse-phase high performance liquid chromatography (column: 3_Phenomenex Luna C18 75×30 mm×3 μm; solvent: A = water + 0.05 vol% hydrochloric acid (36.5%), B = acetonitrile; gradient: 12%-32%, 6.5 minutes) to obtain a yellow solid 5-(4-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione (85 mg, 43.6% yield).

[0395] 1 H NMR (400MHz, CD3OD) δ9.71(d,1H),8.35(d,1H),8.26(s,1H),7.38(s,1H),2.10-2.15(m,1H),1.25-1.39(m,4H),1.09(t,6H).

[0396] LC-MS, M / Z(ESI):312.1[M+H] +

[0397] Example 9: Preparation of target compound 9

[0398] 5-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-7-methylimidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione (target product 9)

[0399]

[0400] The synthetic route of target compound 9 is as follows:

[0401]

[0402] Step 1: Synthesis of 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)-7-methylimidazo[1,5-b]pyridazine (9A)

[0403]

[0404] (4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-yl)methanamine (150 mg, 444.7 μmol) was dissolved in trimethyl orthoacetate (5 mL) and a catalytic amount of acetic acid (50 μL) was added. The mixture was reacted at 130°C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude yellow oily compound 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)-7-methylimidazo[1,5-b]pyridazine (9A) (160 mg, crude), which was used directly in the next step.

[0405] LC-MS, M / Z(ESI):362.1[M+H] +

[0406] Step 2: Synthesis of 5-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-7-methylimidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione (9)

[0407]

[0408] 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)-7-methylimidazo[1,5-b]pyridazine (160 mg) was dissolved in hydrochloric acid (1 M, 1 mL) and reacted at 50°C for 12 hours. After the reaction was completed, the reaction solution was separated by reverse-phase high performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3μm; solvent: A = water + 0.05% by volume hydrochloric acid (36.5%), B = acetonitrile; gradient: 4%-24%, 6.5 minutes) to obtain a yellow solid compound 5-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-7-methylimidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione (9) (44.6 mg, two-step yield 30.1%).

[0409] 1 HNMR(400MHz,DMSO-d6)δ11.79-11.80(m,1H),11.60(s,1H),7.29(s,1H),8.16-8.18(m,1H),7.29 (s,1H),5.90-6.20(m,1H),2.85(s,3H),2.54-2.60(m,1H),2.05-2.18(m,1H),1.42-1.49(m,2H).

[0410] LC-MS, M / Z(ESI):334.1[M+H] +

[0411] Example 10: Preparation of target compound 10

[0412] 5-(8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (target compound 10)

[0413]

[0414] The synthetic route of target compound 10 is as follows:

[0415]

[0416] Step 1: Synthesis of 1,3-dioxoisoindole-2-yl (1S,2R)-2-isopropylcyclopropane-1-carboxylate (10A)

[0417]

[0418] Dissolve (1S,2R)-2-isopropylcyclopropane-1-carboxylic acid (4.86 g, 37.9 mmol) and 4-dimethylaminopyridine (463.3 mg, 3.79 mmol) in dichloromethane (100 mL). Add N,N-diisopropylcarbodiimide (5.74 g, 45.5 mmol) dropwise at 0°C. Stir at 0°C for 0.5 hours, then add N-hydroxyphthalimide (7.42 g, 45.5 mmol). React at 25°C for 12 hours. After completion of the reaction, quench the reaction with water (200 mL) and extract with dichloromethane (200 mL x 2). The organic phases are combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was separated and purified by silica gel column (100% dichloromethane) to obtain a yellow solid compound 1,3-dioxoindole-2-yl (1S, 2R)-2-isopropylcyclopropane-1-carboxylate (2) (10 g, yield 96.5%).

[0419] 1 H NMR (400MHz, CDCl3) δ7.88-7.90(m,2H),7.77-7.80(m,2H),1.73-1.77(m,1H),1.47 -1.53(m,1H),1.37-1.42(m,1H),1.18-1.26(m,1H),1.06-1.10(m,4H),1.03(d,3H).

[0420] Step 2: Synthesis of 2-((1S,2S)-2-isopropylcyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10B)

[0421]

[0422] Dissolve 1,3-dioxoindole-2-yl (1S,2R)-2-isopropylcyclopropane-1-carboxylate (10.0 g, 36.6 mmol) and bis(oxonadole) borate (18.6 g, 73.2 mmol) in ethyl acetate (100 mL). Heat to 85°C under nitrogen. Add ethyl isonicotinate (2.77 g, 2.51 mL, 18.3 mmol) dropwise. Then, react at 85°C under nitrogen for 12 hours. After completion of the reaction, concentrate the reaction solution, and slurry the residue with 300 mL of petroleum ether:ethyl acetate (v / v) = 50:1. Filter through celite, wash the filter cake with 200 mL of petroleum ether:ethyl acetate (v / v) = 50:1, and concentrate the filtrate to obtain the crude product. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 50:1-10:1) to give a yellow oily compound 2-((1S,2S)-2-isopropylcyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10B) (2.60 g, yield 33.8%).

[0423] 1 H NMR(400MHz, CDCl3)δ1.22(s,12H),0.96-1.01(m,6H),0.81-0.85(m,1H),0. 74-0.78(m,1H),0.62-0.66(m,1H),0.41-0.45(m,1H),-0.39--0.34(m,1H).

[0424] Step 3: Synthesis of 6-chloro-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-amine (10C)

[0425]

[0426] 4-Bromo-6-chloropyridazin-3-amine (500 mg, 2.40 mmol) and 2-((1S,2S)-2-isopropylcyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.01 g, 4.80 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL). Cesium carbonate (1.95 g, 6.00 mmol) and bis(di-tert-butyl-(4-dimethylaminophenyl)phosphine)palladium dichloride (169.8 mg, 0.239 mmol) were added under nitrogen. The temperature was raised to 100°C and the reaction was allowed to react for 12 hours. The reaction mixture was diluted with water (100 mL) and then extracted with ethyl acetate (100 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1-1:1) to give a yellow solid compound 6-chloro-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-amine (10C) (150 mg, yield 29.5%).

[0427] LC-MS, M / Z(ESI):212.1[M+H] +

[0428] Step 4: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-amine (10D)

[0429]

[0430] 6-Chloro-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-amine (150 mg, 0.708 mmol) and (2,4-dimethoxypyrimidin-5-yl)boronic acid (195.5 mg, 1.06 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL). Under nitrogen, sodium carbonate (187.8 mg, 1.77 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (51.8 mg, 70.8 μmol) were added. The temperature was raised to 90°C and the reaction was allowed to react for 2 hours. The reaction mixture was diluted with water (25 mL) and then extracted with ethyl acetate (50 mL × 2). The organic layers were combined, washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain a crude product. The residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1-1:10) to give a yellow solid compound 6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-amine (10D) (200 mg, yield 89.5%).

[0431] LC-MS, M / Z(ESI):316.2[M+H] +

[0432] Step 5: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazine (10E)

[0433]

[0434] 6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-amine (200 mg, 0.634 mmol) was dissolved in 1,4-dioxane (10 mL). Chloroacetaldehyde (622.3 mg, 40% aqueous solution, 3.17 mmol) was added and the mixture was heated to 100°C for 2 hours. The reaction mixture was concentrated to obtain 6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazine (10E) (200 mg, crude) as a yellow solid. The crude product was used directly in the next step.

[0435] LC-MS, M / Z(ESI):340.1[M+H] +

[0436] Step 6: 5-(8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (target compound 10)

[0437]

[0438] 6-(2,4-Dimethoxypyrimidin-5-yl)-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazine (200 mg, 0.589 mmol) was dissolved in hydrochloric acid (1 M, 5 mL), and the mixture was heated to 70° C. and reacted for 2 hours. The reaction solution was concentrated and then separated by reverse-phase high performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3μm; solvent: A = water + 0.05vol% HCl (36.5%), B = acetonitrile; gradient: 10%-30%, 6.5 minutes) to obtain a white solid compound 5-(8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (10) (135 mg, two-step yield 68%).

[0439] 1H NMR (400MHz, CD3OD) δ8.44(d,1H),8.32(s,1H),8.22(d,1H),7.98(s,1H),2.21-2.25(m,1H),1.42-1.48(m,1H),1.32-1.39(m,3H),1.11(dd,6H).

[0440] LC-MS, M / Z(ESI):312.2[M+H] +

[0441] Example 11: Preparation of target compound 11

[0442] 5-(3-chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (target compound 11)

[0443]

[0444] The synthetic route of target compound 11 is as follows:

[0445]

[0446] Step 1: Synthesis of 6-chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyridazin-3-amine (11B)

[0447]

[0448] 4-Bromo-6-chloropyridazin-3-amine (750 mg, 3.60 mmol) and 2-((1S,2S)-2-(difluoromethyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.57 g, 7.20 mmol) were dissolved in 1,4-dioxane (15 mL) and water (3 mL). Cesium carbonate (3.52 g, 10.8 mmol) and bis(di-tert-butyl-(4-dimethylaminophenyl)phosphine)palladium dichloride (255 mg, 360 μmol) were added under nitrogen. The temperature was raised to 90°C and the reaction was allowed to react for 12 hours. The reaction mixture was diluted with water (20 mL) and then extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 20:1-1:1) to give a yellow oily compound 6-chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyridazin-3-amine (11B) (420 mg, yield 53%).

[0449] LC-MS, M / Z(ESI):220.1[M+H] +

[0450] Step 2: Synthesis of 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-amine (11C)

[0451]

[0452] 6-Chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyridazin-3-amine (400 mg, 1.82 mmol) and (2,4-dimethoxypyrimidin-5-yl)boronic acid (369 mg, 2.0 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL). Sodium carbonate (579 mg, 5.46 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (133 mg, 182 μmol) were added under nitrogen. The temperature was raised to 70°C and the reaction was allowed to react for 2 hours. The reaction mixture was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL × 2). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1-10:1) to give a yellow solid compound 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-amine (11C) (320 mg, yield 51.7%).

[0453] LC-MS, M / Z(ESI):324.0[M+H] +

[0454] Step 3: Synthesis of 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (11D)

[0455]

[0456] 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-amine (150 mg, 464 μmol) was dissolved in 1,4-dioxane (3 mL), and chloroacetaldehyde (137 mg, 40% aqueous solution, 696 μmol) was added. The mixture was heated to 90°C and reacted for 2 hours. The reaction solution was concentrated to obtain 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (11D) (170 mg, crude) as a brown solid. The crude product was used directly in the next step.

[0457] LC-MS, M / Z(ESI):348.0[M+H] +

[0458] Step 4: Synthesis of 3-chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (11E)

[0459]

[0460] 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (150 mg, 432 μmol) was dissolved in N,N-dimethylformamide (10 mL), and N-chlorosuccinimide (58 mg, 432 μmol) was added. The mixture was reacted at 25°C for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 2). The organic layers were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated to afford 3-chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (11E) as a yellow solid (200 mg, 65.7% yield).

[0461] LC-MS, M / Z(ESI):382.0[M+H] +

[0462] Step 5: Synthesis of 5-(3-chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (11)

[0463]

[0464] 3-Chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (190 mg, 288 μmol) was dissolved in hydrochloric acid (1 M, 10 mL) and stirred at 50°C for 3 hours. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. The crude product was separated by reverse-phase high performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3μm; solvent: A=water+0.05vol%HCl(36.5%), B=acetonitrile; gradient: 20%-40%, 6.5 minutes) to give a light yellow solid compound 5-(3-chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (11) (57.5 mg, yield 55.5%).

[0465] 1H NMR(400MHz,CD3OD)δ8.36(s,1H),8.35(s,1H),8.14(s,1H),5.91-6.20(m,1H ),2.70-2.74(m,1H),2.24-2.28(m,1H),1.65-1.68(m,1H),1.52-1.55(m,1H).

[0466] LC-MS, M / Z(ESI):354.0[M+H] +

[0467] Example 12: Preparation of target compound 12

[0468] 5-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione (12)

[0469]

[0470] The synthetic route of target compound 12 is as follows:

[0471]

[0472] Step 1: Synthesis of ethyl 3-((1S,2S)-2-(difluoromethyl)cyclopropyl)-3-oxopropanoate (12A)

[0473]

[0474] Triethylamine (66.8 g, 659.8 mmol), magnesium chloride (27.9 g, 293.9 mmol) and potassium monoethyl malonate (37.5 g, 220.4 mmol) were added to acetonitrile (600 mL) at 25°C, and then stirred at 25°C for 3 hours. At the same time, (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid (20.0 g, 146.9 mmol) and 1,1-carbonyldiimidazole (35.7 g, 220.4 mmol) were added to acetonitrile (400 mL) and stirred at 25°C for 3 hours. The latter reaction solution (400 mL) was then added dropwise to the previous reaction solution (600 mL) at 0°C, and the reaction solution was stirred at 25°C for 14 hours. After the reaction was completed, water (200 mL) was added to the reaction solution, followed by extraction with ethyl acetate (200 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 10:1-5:1) to obtain ethyl 3-((1S,2S)-2-(difluoromethyl)cyclopropyl)-3-oxopropanoate (12A) (5.80 g, 19.14% yield) as a yellow oil.

[0475] LC-MS, M / Z (ESI): 205.0 [MH] +

[0476] Step 2: Synthesis of 3-((1S,2S)-2-(difluoromethyl)cyclopropyl)-3-oxopropanoic acid (12B)

[0477]

[0478] At 25°C, ethyl 3-((1S,2S)-2-(difluoromethyl)cyclopropyl)-3-oxopropanoate (5.80 g, 28.1 mmol) was added to a 2M aqueous sodium hydroxide solution (57.9 mL), and then stirred at 25°C for 12 hours. After the reaction was completed, 1M aqueous hydrochloric acid solution was added dropwise to the reaction solution to adjust the pH to 2-3, and then extracted with ethyl acetate (100 mL×2). The organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude yellow oily compound 3-((1S,2S)-2-(difluoromethyl)cyclopropyl)-3-oxopropanoic acid (12B) (3.34 g, crude).

[0479] LC-MS, M / Z (ESI): 177.0 [MH] +

[0480] Step 3: Synthesis of 3-((1S,2S)-2-(difluoromethyl)cyclopropyl)-3-oxo-N-(1H-pyrrol-1-yl)propionamide (12C)

[0481]

[0482] At 25 ° C, 3-((1S, 2S)-2-(difluoromethyl)cyclopropyl)-3-oxopropanoic acid (2.39 g, 13.4 mmol) was added to N, N-dimethylformamide (100 mL), and then 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (5.56 g, 14.6 mmol), N, N-diisopropylethylamine (4.72 g, 36.5 mmol) and 1-aminopyrrole (1.00 g, 12.2 mmol) were added thereto, and then stirred at 25 ° C for 12 hours. After completion of the reaction, water (100 mL) was added to the reaction solution, and then extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-5:1) to give a yellow oily compound 3-((1S,2S)-2-(difluoromethyl)cyclopropyl)-3-oxo-N-(1H-pyrrol-1-yl)propionamide (12C) (1.20 g, yield 40.7%).

[0483] LC-MS, M / Z (ESI): 241.0 [MH] +

[0484] Step 4: Synthesis of 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazin-2(1H)-one (12D)

[0485]

[0486] 3-((1S,2S)-2-(difluoromethyl)cyclopropyl)-3-oxo-N-(1H-pyrrol-1-yl)propionamide (1.20 g, 4.95 mmol) was added to acetic acid (24.0 mL) and dioxane (72.0 mL) at 25°C, followed by stirring at 100°C for 12 hours. After completion of the reaction, water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1-2:1) to give a yellow oily compound 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazin-2(1H)-one (12D) (516 mg, yield 46.5%).

[0487] LC-MS, M / Z(ESI):225.0[M+H] +

[0488] Step 5: Synthesis of 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazin-2-yl trifluoromethanesulfonate (12E)

[0489]

[0490] At 25 ° C, 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazin-2(1H)-one (250 mg, 1.12 mmol) and triethylamine (338.5 mg, 3.35 mmol) were added to dichloromethane (3.00 mL), and then trifluoromethanesulfonic anhydride (629.2 mg, 2.23 mmol) was added dropwise to the reaction solution at 0 ° C, and the mixture was stirred at 0 ° C for 30 minutes. After the reaction was completed, water (50 mL) was added to the reaction solution, and then extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude yellow oily compound 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazin-2-yl trifluoromethanesulfonate (12E) (317.8 mg, yield 80.0%).

[0491] LC-MS, M / Z(ESI):357.0[M+H] +

[0492] Step 6: Synthesis of 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrrolo[1,2-b]pyridazine (12F)

[0493]

[0494] 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazin-2-yl trifluoromethanesulfonate (317.8 mg, 892.0 μmol), 2,4-dimethoxypyrimidine-5-boronic acid (180.5 mg, 981.2 μmol), sodium carbonate (236.4 mg, 2.23 mmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (65.3 mg, 89.2 μmol) were added to dioxane (3.5 mL) and water (0.7 mL) at 25°C. The mixture was then stirred at 100°C for 2 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, which was then extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified on a preparative plate (petroleum ether:ethyl acetate = 2:1) to give a green oily compound 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrrolo[1,2-b]pyridazine (12F) (150 mg, 48.6% yield).

[0495] LC-MS, M / Z(ESI):347.1[M+H] +

[0496] Step 7: Synthesis of 5-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione (12)

[0497]

[0498] 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrrolo[1,2-b]pyridazine (150 mg, 433.1 μmol) was added to a 1 M aqueous hydrochloric acid solution (4.33 mL) at 25° C., followed by stirring at 50° C. for 12 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain a crude product, which was then separated by reverse-phase high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150×25mm×10μm; solvent: A=water+0.225vol% formic acid (99%), B=acetonitrile; gradient: 22%-55%, 11 minutes) to obtain the target compound 5-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione (12) (15.1 mg, yield 10.8%).

[0499] 1 H NMR (400MHz, DMSO-d6): δ11.34(br d,2H),7.91(s,1H),7.83(dd,1H),6.8-6.9(m,2H),6.68(dd,1H),5.84-6.14(m,1H),2.49-2.50(m,1H),1.84-1.92(m,1H),1.20-1.28(m,2H).

[0500] LC-MS, M / Z(ESI):319.0[M+H] + .

[0501] Example 13: Preparation of target compound 13

[0502] 5-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrimidine-2,4(1H,3H)-dione (target compound 13)

[0503]

[0504] The synthetic route of target compound 13 is as follows:

[0505]

[0506] Step 1: Synthesis of 2-chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyrrolo[2,1-f][1,2,4]triazine (13B)

[0507]

[0508] 2,4-Dichloropyrrolo[2,1-f][1,2,4]triazine (500 mg, 2.66 mmol), 2-[(1S,2S)-2-(difluoromethyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (638 mg, 2.93 mmol) and potassium phosphate (1.69 g, 7.98 mmol) were dissolved in dioxane (10 mL) and water (0.5 mL). Dichlorobis(triphenylphosphine)palladium(II) (187 mg, 266 μmol) was added under nitrogen protection at 25 °C and stirred at 80 °C for 12 hours. The reaction system was dried by rotary evaporation, and the crude product was separated and purified by reverse phase flash chromatography (0.05% HCl) to obtain a yellow oily compound 2-chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyrrolo[2,1-f][1,2,4]triazine (13B) (450 mg, yield 21.6%).

[0509] LC-MS, M / Z(ESI):244.1[M+H] +

[0510] Step 2: Synthesis of 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazine (13B)

[0511]

[0512] 2-Chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyrrolo[2,1-f][1,2,4]triazine (450 mg, 1.72 mmol), 2,4-dimethoxypyrimidine-5-boronic acid (348 mg, 1.89 mmol) and sodium carbonate (547 mg, 5.16 mmol) were dissolved in dioxane (10 mL) and water (2 mL). Under nitrogen protection at 25 ° C, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (281 mg, 344 μmol) was added and stirred at 80 ° C for 12 hours. The reaction system was spin-dried, and the crude product was purified by reverse phase Flash (0.05% HCl) to obtain a dark brown oily compound 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazine (13C) (200 mg, yield 27.6%).

[0513] LC-MS, M / Z(ESI):348.3[M+H] +

[0514] Step 3: Synthesis of 5-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrimidine-2,4(1H,3H)-dione (13)

[0515]

[0516] 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazine (200 mg, 474 μmol) was dissolved in aqueous hydrochloric acid (1 M, 10 mL) and reacted at 50° C. for 12 hours. The reaction solution was concentrated and then separated by reverse-phase high performance liquid chromatography (chromatographic column: 3_Phenomenex LunaC18 75×30mm×3μm; solvent: A=water+0.05% volume hydrochloric acid (36.5%), B=acetonitrile; gradient: 20%-40%, 6.5 minutes) to obtain a light yellow solid compound 5-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrimidine-2,4(1H,3H)-dione (13) (11.6 mg, yield 7.33%).

[0517] 1 H NMR (400MHz, CD3OD): δ8.56(s,1H),8.27(s,1H),7.65(d,1H),7.22-7.24(m, 1H),6.02(td,1H),3.03-3.07(m,1H),2.48-2.52(m,1H),1.77-1.83(m,2H).

[0518] LC-MS, M / Z(ESI):320.1[M+H] +

[0519] Example 14: Preparation of target compound 14

[0520] 5-(2-chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (target compound 14)

[0521]

[0522] The synthetic route of target compound 14 is as follows:

[0523]

[0524] Step 1: Synthesis of 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-2-ol (14A)

[0525]

[0526] 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-amine (1.00 g, 2.98 mmol), disodium hydrogen phosphate (1.14 g, 8.05 mmol), and tert-butyl N-(2-chloroacetyl)aminomethyl ester (980 mg, 5.07 mmol) were dissolved in N,N-dimethylacetamide (20 mL) and reacted at 100°C for 12 hours. After completion of the reaction, water (100 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude yellow solid compound 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-2-ol (14A) (200 mg, yield 13.9%) was then purified by reverse phase Flash (0.05% TFA) to give the crude yellow solid compound 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-2-ol (14A) (200 mg, yield 13.9%).

[0527] 1 H NMR (400MHz, CDCl3): δ8.71(s,1H),7.40(s,1H),7.02(s,1H),5.84-6.13(m,1H),4.08(s,3 H),4.10(s,3H),2.69-2.73(m,1H),2.05(br.s,1H),1.60-1.64(m,1H),1.24-1.28(m,1H).

[0528] LC-MS, M / Z(ESI):364.1[M+H] +

[0529] Step 2: 5-(2-chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (target compound 14)

[0530]

[0531] 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-2-ol (200 mg, 435 μmol) was dissolved in 1 M aqueous hydrochloric acid solution (2 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 reverse-phase high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150×40 mm×15 μm; mobile phase: A = water + 0.05% volume hydrochloric acid (36.5%), B = acetonitrile; gradient: 22%-52%, 10 minutes) to obtain a white solid compound 5-(2-chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (target compound 14) (0.37 mg, yield 0.1%).

[0532] 1 H NMR (400MHz, CD3OD): δ8.12(s,1H),8.09(s,1H),7.59(s,1H),5.76-6.05(m,1H ),2.66-2.69(m,1H),2.27-2.29(m,1H),1.56-1.60(m,1H),1.51-1.53(m,1H).

[0533] LC-MS, M / Z(ESI):354.1[M+H] + .

[0534] Example 15: Preparation of target compound 15

[0535] 5-(3-chloro-8-((1S,2S)-2-(fluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (target compound 15)

[0536]

[0537] The synthetic route of target compound 15 is as follows:

[0538]

[0539] Step 1: Synthesis of 6-chloro-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazin-3-amine (15B)

[0540]

[0541] 4-Bromo-6-chloropyridazin-3-amine (600 mg, 2.88 mmol) and 2-((1S,2S)-2-(fluoromethyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.15 g, 5.76 mmol) were dissolved in dioxane (24 mL) and water (6 mL). Cesium carbonate (2.81 g, 8.64 mmol) and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (204 mg, 288 μmol) were added under nitrogen protection. The reaction mixture was reacted at 100°C for 12 hours. The reaction mixture was diluted with water (20 mL) and then extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain a crude product. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 20:1-1:1) to give 6-chloro-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazin-3-amine (15B) (160 mg, 27.6% yield) as a yellow oily compound.

[0542] LC-MS, M / Z(ESI):202.6[M+H] +

[0543] Step 2: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazin-3-amine (15C)

[0544]

[0545] 6-Chloro-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazin-3-amine (150 mg, 0.74 mmol) and (2,4-dimethoxypyrimidin-5-yl)boronic acid (205 mg, 1.12 mmol) were dissolved in dioxane (6 mL) and water (1.5 mL). Sodium carbonate (237 mg, 2.23 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (54 mg, 74 μmol) were added under nitrogen and reacted at 80°C for 4 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The organic layers were combined, washed with saturated brine (30 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1-0:1) to give a yellow solid compound 6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazin-3-amine (15C) (230 mg, yield 78%).

[0546] LC-MS, M / Z(ESI):306.3[M+H] +

[0547] Step 3: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(fluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine (15D)

[0548]

[0549] 6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazin-3-amine (230 mg, 753 μmol) was dissolved in dioxane (6 mL), and chloroacetaldehyde (370 mg, 40% aqueous solution, 1.83 mmol) was added. The mixture was reacted at 100°C for 5 hours. The reaction solution was concentrated to obtain 6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(fluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine (15D) (250 mg, crude) as a brown solid. The crude product was used directly in the next step.

[0550] LC-MS, M / Z(ESI):330.3[M+H] +

[0551] Step 4: Synthesis of 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(fluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine (15E)

[0552]

[0553] 6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(fluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine (250 mg, 759 μmol) was dissolved in N,N-dimethylformamide (5 mL), and N-chlorosuccinimide (44 mg, 759 μmol) was added. The mixture was reacted at 25°C for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 2). The organic layers were combined, washed with saturated brine (50 mL × 3), dried over sodium sulfate, and concentrated to afford 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(fluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine (15E) as a yellow solid (100 mg, 36.2% yield).

[0554] LC-MS, M / Z(ESI):364.7[M+H] +

[0555] Step 5: Synthesis of 5-(3-chloro-8-((1S,2S)-2-(fluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (15)

[0556]

[0557] 3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(fluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine (100 mg, 500 μmol) was dissolved in hydrochloric acid solution (1 M, 10 mL) and reacted at 100°C for 12 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was adjusted to alkalinity by adding saturated sodium carbonate and filtered. The filter cake was added with methanol (10 mL) and heated under reflux to obtain a pale yellow solid compound 5-(3-chloro-8-((1S,2S)-2-(fluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (15) (32 mg, 32.9% yield).

[0558] 1 H NMR (400MHz, DMSO) δ11.51-11.55(m,2H),8.01(s,1H),7.84(s,1H),7.48(s,1H),4.32-4.61(m,2H),1.12(s,1H),1.03(s,1H),1.21-1.57(m,2H).

[0559] LC-MS, M / Z(ESI):336.7[M+H] + .

[0560] Example 16: Preparation of target compound 16

[0561] 5-(2,3-dichloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (target compound 16)

[0562]

[0563] The synthetic route of target compound 16 is as follows:

[0564]

[0565] Step 1: Synthesis of 2,3-dichloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (16A)

[0566]

[0567] 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (100 mg, 288 μmol) was dissolved in N,N-dimethylformamide (2 mL), and N-chlorosuccinimide (58 mg, 432 μmol) was added. The mixture was reacted at 50°C for 16 hours. The reaction mixture was diluted with water (10 mL), then extracted with ethyl acetate (20 mL×2). The organic layers were combined, washed with saturated brine (20 mL×3), dried over sodium sulfate, and concentrated to obtain a crude product, which was separated by reverse-phase high performance liquid chromatography (chromatographic column: 3_Phenomenex Luna C18 75×30 mm×3 μm; mobile phase: A=water+0.05 volume% NH4HCO336.5%), B=acetonitrile; gradient: 20%-40%, 6.5 minutes) to obtain a light yellow solid compound: 2,3-dichloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (16A) (40 mg, yield 33.6%).

[0568] LC-MS, M / Z(ESI):416.0[M+H] +

[0569] Step 2: Synthesis of 5-(2,3-dichloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (16)

[0570]

[0571] 2,3-Dichloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (40 mg, 96 μmol) was dissolved in a hydrochloric acid solution (1 M, 10 mL) and reacted at 50°C for 16 hours. After completion of the reaction, the reaction solution was concentrated to obtain a light yellow solid compound 5-(2,3-dichloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (16) (20 mg, 53.6% yield).

[0572] 1H NMR(400MHz,DMSO-d6)δ11.56(t,2H),8.00(d,1H),7.62(s,1H),6.16-5.87(m,1 H),2.66-2.60(m,1H),2.48-2.44(m,1H),1.60-1.58(m,1H),1.57-1.42(m,1H).

[0573] LC-MS, M / Z(ESI):388.0[M+H] + .

[0574] Example 17: Preparation of target compound 17

[0575] 5-(8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (target compound 17)

[0576]

[0577] The synthetic route of target compound 17 is as follows:

[0578]

[0579] Step 1: Synthesis of 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine (17A)

[0580]

[0581] 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-amine (150 mg, 463 μmol) and 3-bromo-1,1,1-trifluoro-propan-2-one (106 mg, 556 μmol) were dissolved in dioxane (2.00 mL) and reacted at 50°C for 12 hours. After completion of the reaction, the reaction solution was concentrated to afford the crude compound 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine (17A) (180 mg, crude) as a yellow oil.

[0582] LC-MS, M / Z(ESI):416.1[M+H] +

[0583] Step 2: 5-(8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (target compound 17)

[0584]

[0585] 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazine (180 mg, 433 μmol) was dissolved in 1 M aqueous hydrochloric acid solution (1 mL) and reacted at 50° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated by reverse-phase high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150×40 mm×15 μm; solvent: A = water + 0.05% by volume hydrochloric acid 36.5%), B = acetonitrile; gradient: 30%-50%, 6.5 minutes) to obtain a white solid compound 5-(8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (17) (63.2 mg, yield 37.5%).

[0586] 1 H NMR(400MHz,CD3OD)δ8.50(s,1H),8.16(s,1H),7.69(s,1H),5.77-6.07(m,1H ),2.74-2.76(m,1H),2.36-2.39(m,1H),1.64-1.66(m,1H),1.50-1.54(m,1H).

[0587] LC-MS, M / Z(ESI):388.1[M+H] + .

[0588] Example 18: Preparation of target compound 18

[0589] 5-(4-((1S,2R)-2-isopropylcyclopropyl)-5-methylimidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione (target compound 18)

[0590]

[0591] The synthetic route of target compound 18 is as follows:

[0592]

[0593] Step 1: 6-(2,4-dimethoxypyrimidin-5-yl)-3-(1-ethoxyvinyl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine (18A)

[0594]

[0595] 3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine (650 mg, 1.94 mmol), tributyl (1-ethoxyvinyl)stannane (842 mg, 2.33 mmol) and dichlorobis(triphenylphosphine)palladium(II) (136 mg, 194 μmol) were dissolved in N,N-dimethylformamide (6 mL) and reacted at 110 °C under nitrogen protection for 3 hours. After completion of the reaction, the reaction solution was poured into an aqueous solution of potassium fluoride (10 mL), and then extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 20:1-5:1) to give a yellow oily compound 6-(2,4-dimethoxypyrimidin-5-yl)-3-(1-ethoxyvinyl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine (700 mg, 97.3% yield).

[0596] LC-MS, M / Z(ESI):371.1[M+H] +

[0597] Step 2: 1-(6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-yl)ethan-1-one (18B)

[0598]

[0599] 6-(2,4-dimethoxypyrimidin-5-yl)-3-(1-ethoxyvinyl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine (700 mg, 1.89 mmol) was dissolved in tetrahydrofuran (3 mL), and hydrochloric acid (0.5 M, 3.78 mL) was added dropwise. The mixture was reacted at 20°C for 2 hours. After completion of the reaction, the pH of the reaction solution was adjusted to 9 with aqueous sodium bicarbonate solution, and then extracted with dichloromethane (20 mL × 2). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product 1-(6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-yl)ethan-1-one (18B) (350 mg, crude).

[0600] LC-MS, M / Z(ESI):343.1[M+H] +

[0601] Step 3: 1-(6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-yl)ethan-1-amine (18C)

[0602]

[0603] 1-(6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-yl)ethan-1-one (280 mg, 817 μmol) and ammonium acetate (630 mg, 8.18 mmol) were dissolved in methanol (3 mL), and then reacted at 20 ° C for 12 hours. Sodium cyanoborohydride (77.0 mg, 1.23 mmol) was added and then reacted at 20 ° C for 30 minutes. After completion of the reaction, the reaction solution was poured into an aqueous solution of sodium carbonate (10 mL), extracted with ethyl acetate (20 mL×2), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was then separated by reverse-phase high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150×40 mm×15 μm; solvent: A=water+0.225% volume formic acid (99%), B=acetonitrile; gradient: 15%-45%, 10 minutes) to obtain a yellow oily compound 1-(6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-yl)ethan-1-amine (18C) (80.0 mg, 29.5% yield).

[0604] LC-MS, M / Z(ESI):344.1[M+H] +

[0605] Step 4: 2-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)-5-methylimidazo[1,5-b]pyridazine (18D)

[0606]

[0607] 1-(6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-yl)ethan-1-amine (80.0 mg, 203 μmol) was dissolved in trimethyl orthoformate (108 mg, 1.02 mmol) and reacted at 100°C for 2 hours. After completion of the reaction, the reaction solution was concentrated to obtain a crude yellow oily compound, 2-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)-5-methylimidazo[1,5-b]pyridazine (18D) (80.0 mg, crude).

[0608] LC-MS, M / Z(ESI):354.1[M+H] +

[0609] Step 5: 5-(4-((1S,2R)-2-isopropylcyclopropyl)-5-methylimidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione (target compound 18)

[0610]

[0611] 2-(2,4-Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)-5-methylimidazo[1,5-b]pyridazine (80.0 mg, 226 μmol) was dissolved in hydrochloric acid (1 M, 1.13 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 reverse-phase high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150×40 mm×15 μm; solvent: A = water + 0.225% volume formic acid (99%), B = acetonitrile; gradient: 14%-34%, 6.5 minutes) to obtain a yellow solid compound 5-(4-((1S,2R)-2-isopropylcyclopropyl)-5-methylimidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione (target compound 18) (11.0 mg, yield 14.9%).

[0612] 1 H NMR (400MHz, CD3OD): δ9.31(s,1H),8.18(s,1H),7.20(s,1H),2.84(s,3H), 2.16-2.20(m,1H),1.33-1.35(m,2H),1.28-1.30(m,2H),1.07-1.12(m,6H).

[0613] LC-MS, M / Z(ESI):326.1[M+H] + .

[0614] Example 19: Preparation of target compound 19

[0615] 5-(8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-ethylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (target compound 19)

[0616]

[0617] The synthetic route of target compound 19 is as follows:

[0618]

[0619] Step 1: Synthesis of 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-ethylimidazo[1,2-b]pyridazine (19A)

[0620]

[0621] 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-amine (200 mg, 618 μmol) and 1-bromobutan-2-one (140 mg, 928 μmol) were dissolved in dioxane (6 mL) and stirred at 60°C for 12 hours. The reaction system was spin-dried to obtain 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-ethylimidazo[1,2-b]pyridazine (19A) (300 mg, crude) as a yellow oil, which was used directly in the next step.

[0622] LC-MS, M / Z(ESI):376.1[M+H] +

[0623] Step 2: Synthesis of 5-(8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-ethylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (19)

[0624]

[0625] 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-ethylimidazo[1,2-b]pyridazine (270 mg, 719 μmol) was dissolved in aqueous hydrochloric acid (1 M, 5 mL), and the mixture was heated to 50° C. and reacted for 12 hours. The reaction solution was concentrated and then separated by high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150×25mm×10μm; solvent: A=water+0.05% volume hydrochloric acid (36.5%), B=acetonitrile; gradient: 2%-32%, 10 minutes) to obtain a light yellow solid compound 5-(8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-ethylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (19) (85.5 mg, yield 33.6%).

[0626] 1 H NMR (400MHz, CD3OD): δ8.30(s,1H),8.28(s,1H),8.05(s,1H),6.07(td,1H),2.99-3.0 5(m,2H),2.71-2.73(m,1H),2.22-2.23(m,1H),1.64-1.68(m,1H),1.45-1.50(m,4H).

[0627] LC-MS, M / Z(ESI):348.1[M+H] + .

[0628] Example 20: Preparation of target compound 20

[0629] 5-(3-chloro-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (target compound 20)

[0630]

[0631] The synthetic route of target compound 20 is as follows:

[0632]

[0633] Step 1: Synthesis of 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazine (20A)

[0634]

[0635] 6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazine (269.0 mg, 792.1 μmol) was dissolved in N-dimethylformamide (3 mL), and N-chlorosuccinimide (105.1 mg, 792.1 μmol) was added dropwise. The mixture was allowed to react at 25°C for 1 hour. After completion of the reaction, the reaction solution was concentrated to obtain the crude compound 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazine (20A) (350.0 mg, crude) as a yellow oil.

[0636] LC-MS, M / Z(ESI):374.1[M+H] +

[0637] Step 2: 5-(3-chloro-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (target compound 20)

[0638]

[0639] 3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazine (350.0 mg, 936.2 μmol) was dissolved in 1 M aqueous hydrochloric acid solution (4 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 reverse-phase high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150×40 mm×15 μm; mobile phase: A = water + 0.05% volume hydrochloric acid (36.5%), B = acetonitrile; gradient: 30%-50%, 6.5 minutes) to obtain a yellow solid compound 5-(3-chloro-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (target compound 20) (138.0 mg, yield 42.1%).

[0640] 1 H NMR (400MHz, CD3OD): δ8.31(s,1H),8.22(s,1H),7.89(s,1H),2.24-2.26(m,1H ),1.38-1.40(m,1H),1.36-1.38(m,1H),1.32-1.35(m,2H),1.07-1.11(m,6H).

[0641] LC-MS, M / Z(ESI):346.1[M+H] + .

[0642] Example 21: Preparation of target compound 21

[0643] 5-(7-amino-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione (target compound 21)

[0644]

[0645] The synthetic route of target compound 21 is as follows:

[0646]

[0647] Step 1: Synthesis of 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,5-b]pyridazin-7-amine (21A)

[0648]

[0649] (4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-((2,4-dimethoxypyrimidin-5-yl)pyridazin-3-yl)methanamine (80.0 mg, 237.2 μmol) was dissolved in ethanol (2.00 mL) and water (0.50 mL). Cyanogen bromide (37.6 mg, 355.2 μmol) was added and stirred for 30 minutes. Then, diisopropylethylamine (91.9 mg, 711.4 μmol) was added and reacted at 25°C for 1 hour. After completion of the reaction, the reaction solution was concentrated to give the crude yellow oily compound 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,5-b]pyridazin-7-amine (21A) (100 mg, crude).

[0650] LC-MS, M / Z(ESI):363.1[M+H] +

[0651] Step 2: 5-(7-amino-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione (target compound 21)

[0652]

[0653] 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,5-b]pyridazin-7-amine (50.0 mg, 215 μmol) was dissolved in 1 M aqueous hydrochloric acid solution (1 mL) and reacted at 50° C. for 12 hours. After completion of the reaction, the reaction solution was concentrated to obtain a crude product, which was separated by reverse-phase high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150×40 mm×15 μm; mobile phase: A = water + 0.05% volume hydrochloric acid (36.5%), B = acetonitrile; gradient: 8%-68%, 6.5 minutes) to obtain a yellow solid compound 5-(7-amino-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,5-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione (target compound 21) (7.00 mg, yield 7.91%).

[0654] 1 H NMR (400MHz, CD3OD): δ8.27(s,1H),7.45(s,1H),7.12(s,1H),5.75-6.04(m,1H),2.36-2.38(m,1H),1.96-1.99(m,1H),1.42-1.46(m,2H).

[0655] LC-MS, M / Z(ESI):335.1[M+H] + .

[0656] Example 22: Preparation of target compound 22

[0657] 5-(3-chloro-8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (target compound 22)

[0658]

[0659] The synthetic route of target compound 22 is as follows:

[0660]

[0661] Step 1: Synthesis of 1,3-dioxoisoindole-2-yl (1S,2S)-2-(trifluoromethyl)cyclopropane-1-carboxylate (22B)

[0662]

[0663] Dissolve (1S,2S)-2-(trifluoromethyl)cyclopropanecarboxylic acid (15.0 g, 97.4 mmol) and 4-dimethylaminopyridine (1.19 g, 9.73 mmol) in dichloromethane (150 mL). Add N,N-diisopropylcarbodiimide (14.7 g, 116.8 mmol) dropwise at 0°C. Stir at 0°C for 0.5 hours, then add N-hydroxyphthalimide (19.1 g, 116.8 mmol). React at 20°C for 12 hours. After completion of the reaction, quench the reaction with water (500 mL) and extract with dichloromethane (500 mL x 2). Combine the organic phases, wash with saturated brine (500 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. The residue was separated and purified by silica gel column (100% dichloromethane) to obtain a yellow solid compound 1,3-dioxoindole-2-yl (1S,2S)-2-(trifluoromethyl)cyclopropane-1-carboxylate (22B) (24.0 g, yield 82.4%).

[0664] 1 H NMR (400MHz, CDCl3): δ7.89-7.92(m,2H),7.81-7.83(m,2H),2.39-2.42(m,2H),1.58-1.61(m,2H).

[0665] Step 2: Synthesis of 4,4,5,5-tetramethyl-2-((1S,2S)-2-(trifluoromethyl)cyclopropyl)-1,3,2-dioxaborolane (22C)

[0666]

[0667] 1,3-Dioxoindole-2-yl (1S,2S)-2-(trifluoromethyl)cyclopropane-1-carboxylate (24.0 g, 80.2 mmol) and bis-xanacol boronate (40.7 g, 160 mmol) were dissolved in ethyl acetate (250 mL) and heated to 85°C under nitrogen. Ethyl isonicotinate (6.06 g, 40.1 mmol) was added dropwise, and the mixture was allowed to react at 85°C under nitrogen for 12 hours. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. Purification by silica gel column chromatography (petroleum ether) afforded the yellow oily compound 4,4,5,5-tetramethyl-2-((1S,2S)-2-(trifluoromethyl)cyclopropyl)-1,3,2-dioxaborolane (22C) (5.00 g, 26.4% yield).

[0668] 1H NMR (400MHz, CDCl3): δ1.68-1.70(m,1H),1.19-1.26(m,12H),0.87-0.88(m,1H),0.84-0.86(m,1H),0.32-0.32(m,1H).

[0669] Step 3: Synthesis of 6-chloro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-amine (22D)

[0670]

[0671] 4-Bromo-6-chloropyridazin-3-amine (1.00 g, 4.80 mmol) and 4,4,5,5-tetramethyl-2-((1S,2S)-2-(trifluoromethyl)cyclopropyl)-1,3,2-dioxaborolane (2.26 g, 9.59 mmol) were dissolved in dioxane (15 mL) and water (3 mL). Cesium carbonate (4.69 g, 14.4 mmol) and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (340 mg, 480 μmol) were added under nitrogen protection. The temperature was raised to 100°C and the reaction was allowed to react for 12 hours. The reaction mixture was concentrated to obtain a crude product. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1-1:1) to give a yellow oily compound 6-chloro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-amine (22D) (180 mg, 7.22% yield).

[0672] LC-MS, M / Z(ESI):238.3[M+H] +

[0673] Step 4: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-amine (22E)

[0674]

[0675] 6-Chloro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-amine (170 mg, 654 μmol) and (2,4-dimethoxypyrimidin-5-yl)boronic acid (144 mg, 785 μmol) were dissolved in dioxane (5 mL) and water (1 mL). Sodium carbonate (208 mg, 1.96 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (107 mg, 131 μmol) were added under nitrogen protection, and the temperature was raised to 80°C for 1 hour. The reaction mixture was concentrated to obtain a crude product, which was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1-0:1) to obtain a yellow solid compound 6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-amine (22E) (100 mg, 44.8% yield).

[0676] LC-MS, M / Z(ESI):342.3[M+H] +

[0677] Step 5: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine (22F)

[0678]

[0679] 6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-amine (100 mg, 293 μmol) was dissolved in dioxane (2 mL), and chloroacetaldehyde (115 mg, 40% aqueous solution, 586 μmol) was added. The mixture was heated to 90°C and reacted for 1 hour. The reaction solution was concentrated to obtain 6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine (22F) (120 mg, crude) as a yellow solid. The crude product was used directly in the next step.

[0680] LC-MS, M / Z(ESI):366.1[M+H] +

[0681] Step 6: Synthesis of 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine (22G)

[0682]

[0683] 6-(2,4-Dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine (100 mg, 274 μmol) was dissolved in N,N-dimethylformamide (3 mL), and N-chlorosuccinimide (36.6 mg, 274 μmol) was added. The mixture was reacted at 25°C for 1 hour. The reaction mixture was diluted with water (20 mL) and then extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by reverse-phase high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C1875×30mm×3μm; solvent: A=water+0.225% volume formic acid (99.0%), B=acetonitrile; gradient: 52%-82%, 7 minutes) to obtain a yellow oily compound 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine (22G) (15 mg, 13.7% yield).

[0684] LC-MS, M / Z(ESI):400.0[M+H] +

[0685] Step 7: Synthesis of 5-(3-chloro-8-(((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (22)

[0686]

[0687] 3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine (15 mg, 37.5 μmol) was dissolved in tetrahydrofuran (0.5 mL). Hydrochloric acid solution (1 M, 0.5 mL) was added and stirred at 50°C for 2 hours. After completion of the reaction, the reaction solution was concentrated to obtain the crude product. The crude product was separated by reverse-phase high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: A = water + 0.225% by volume formic acid (99.0%), B = acetonitrile; gradient: 25%-55%, 7 minutes) to obtain a white solid compound 5-(3-chloro-8-(((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (22) (2.64 mg, yield 18.7%).

[0688] 1 H NMR (400MHz, CD3OD): δ8.20(s,1H),7.72(s,1H),7.68(s,1H),2.88-2.90(m,1H),2.75-2.77(m,1H),1.76-1.78(m,1H),1.51-1.65(m,1H).

[0689] LC-MS, M / Z(ESI):372.2[M+H] +

[0690] Example 23: Preparation of target compound 23

[0691] 5-(8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (target compound 23)

[0692]

[0693] The synthetic route of target compound 23 is as follows:

[0694]

[0695] Step 1: Synthesis of 5-(8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (23)

[0696]

[0697] Dissolve 6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine (20 mg, 54.8 μmol) in tetrahydrofuran (0.5 mL). Add hydrochloric acid solution (1 M, 0.5 mL) and stir at 50°C for 2 hours. After completion of the reaction, concentrate the reaction solution to obtain the crude product. The crude product was separated by reverse-phase high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: A = water + 0.225% by volume formic acid (99.0%), B = acetonitrile; gradient: 5%-35%, 7 minutes) to obtain a white solid compound 5-(8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (23) (6.99 mg, yield 37.4%).

[0698] 1H NMR (400MHz, CD3OD): δ8.12(s,1H),8.11(s,1H),7.71(s,1H),7.56(s,1H), 2.89-2.94(m,1H),2.67-2.70(m,1H),1.67-1.71(m,1H),1.61-1.65(m,1H).

[0699] LC-MS, M / Z(ESI):338.1[M+H] + .

[0700] Example 24: Preparation of target compound 24

[0701] 5-(8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (target compound 24)

[0702]

[0703] The synthetic route of target compound 24 is as follows:

[0704]

[0705] Step 1: Synthesis of 6-chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropane)imidazole[1,2-b]pyrazine (24B)

[0706]

[0707] 6-Chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyridazin-3-amine (2.00 g, 8.88 mmol) was dissolved in dioxane (30 mL). Chloroacetaldehyde (2.61 g, 13.3 mmol, 40% aqueous solution) was added at 25°C, followed by stirring at 90°C for 2 hours. The reaction mixture was spin-dried to dryness, and the crude product was purified by reverse-phase flash chromatography (0.05% HCl) to afford 6-chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropane)imidazole[1,2-b]pyrazine (24B) as a yellow oil (1.50 g, 69.3% yield).

[0708] 1 H NMR (400MHz, CDCl3): δ7.89(d,1H),7.70(d,1H),6.76(s,1H),5.91(td,1H), 2.65-2.66(m,1H),2.61-2.64(m,1H),1.78-1.81(m,1H),1.50-1.54(m,1H).

[0709] LC-MS, M / Z(ESI):244.1[M+H] +

[0710] Step 2: Synthesis of 6-chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazine (24C)

[0711]

[0712] Dissolve 6-chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropane)imidazole[1,2-b]pyrazine (700 mg, 2.87 mmol) in N,N-dimethylformamide (15 mL). Add 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.22 g, 3.45 mmol) at 25°C, and stir at 80°C for 12 hours. Add ethyl acetate (50 mL) to the reaction system, and wash the organic phase with saturated brine (50 mL x 5), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. The crude product was purified by reverse phase flash chromatography (0.05% HCl) to give 6-chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazine (24C) (100 mg, 13.3% yield) as a yellow oil.

[0713] 1 H NMR (400MHz, CDCl3): δ7.32(d,1H),6.74(s,1H),5.91(td,1H),2.61-2.62(m,1H),2.59-2.60(m,1H),1.79-1.81(m,1H),1.51-1.54(m,1H).

[0714] LC-MS, M / Z(ESI):262.1[M+H] +

[0715] Step 3: Synthesis of 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine (24D)

[0716]

[0717] 6-Chloro-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazine (100 mg, 379 μmol) and 2,4-dimethoxypyrimidine-5-boronic acid (76.7 mg, 417 μmol) were dissolved in dioxane (5 mL) and water (1 mL). Sodium carbonate (121 mg, 1.14 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (61.9 mg, 75.8 μmol) were added under nitrogen protection. The temperature was raised to 80°C and the reaction was allowed to react for 12 hours. The reaction system was spin-dried to obtain a crude product. The crude product was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1-1:1) to give a white solid compound 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine (24D) (100 mg, yield 65.2%).

[0718] LC-MS, M / Z(ESI):366.1[M+H] +

[0719] Step 4: Synthesis of 5-(8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (24)

[0720]

[0721] 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine (100 mg, 247 μmol) was dissolved in aqueous hydrochloric acid (1 M, 5 mL), and the temperature was raised to 50° C. to react for 12 hours. The reaction solution was concentrated and then separated by high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75×30mm×3μm; mobile phase: A=water+0.225% volume formic acid (99.0%), B=acetonitrile; gradient: 15%-45%, 7 minutes) to obtain a light yellow solid compound 5-(8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (24) (43.4 mg, yield 50.6%).

[0722] 1H NMR (400MHz, CD3OD): δ8.16(s,1H),7.54(s,1H),7.40(d,1H),5.92(td,1H), 2.69-2.74(m,1H),2.27-2.31(m,1H),1.58-1.60(m,1H),1.49-1.53(m,1H).

[0723] LC-MS, M / Z(ESI):338.1[M+H] + .

[0724] Example 25: Preparation of target compound 25

[0725] 5-(3-Bromo-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (target compound 25)

[0726]

[0727] The synthetic route of target compound 25 is as follows:

[0728]

[0729] Step 1: Synthesis of 3-bromo-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (25A)

[0730]

[0731] 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (50.0 mg, 144 μmol) was dissolved in N,N-dimethylformamide (1.00 mL). N-bromosuccinimide (25.6 mg, 144 μmol) was added at 25°C, and the mixture was stirred at 25°C for 1 hour. Water (50 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 3-bromo-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (25A) (60 mg, crude) as a yellow oil.

[0732] LC-MS, M / Z(ESI):426.0[M+H] +

[0733] Step 2: Synthesis of 5-(3-bromo-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (25)

[0734]

[0735] 3-Bromo-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (60.0 mg, 141 μmol) was dissolved in a 1 M aqueous hydrochloric acid solution (3 mL) and the mixture was heated to 50°C for 12 hours. The reaction solution was concentrated and then separated by high-performance liquid chromatography (HPLC) using a 3-Phenomenex Luna C18 column (75 × 30 mm × 3 μm); solvent: A = water + 0.05% by volume hydrochloric acid (36.5%), B = acetonitrile; gradient: 22% to 42% over 6.5 minutes) to obtain a pale yellow solid compound. The reaction mixture was then heated to 50°C in methanol (2 mL) and recrystallized to give 5-(3-bromo-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (25) as a white solid (7 mg, 9% yield).

[0736] 1 H NMR (400MHz, CD3OD): δ8.35(s,1H),8.34(s,1H),8.13(s,1H),6.04(td,1H), 2.70-2.73(m,1H),2.25-2.28(m,1H),1.62-1.66(m,1H),1.52-1.54(m,1H).

[0737] LC-MS, M / Z(ESI):398.0[M+H] + .

[0738] Example 26: Preparation of target compound 26

[0739] 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazine-3-carbonitrile (target compound 26)

[0740]

[0741] The synthetic route of target compound 26 is as follows:

[0742]

[0743] Step 1: Synthesis of 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazine-3-carbonitrile (26)

[0744]

[0745] 5-(3-Bromo-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (110 mg, 276 μmol) was dissolved in N,N-dimethylformamide (5 mL). Zinc cyanide (38.9 mg, 332 μmol), tris(dibenzylideneacetone)dipalladium (25.3 mg, 27.6 μmol) and 1,1-bis(diphenylphosphino)ferrocene (15.3 mg, 27.6 μmol) were added under nitrogen protection, and the temperature was raised to 120 °C for 12 hours. The reaction solution was concentrated and then separated by high performance liquid chromatography (HPLC) using a column: Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: A = water + 0.225% by volume formic acid (99.0%), B = acetonitrile; gradient: 20%-50%, 7 minutes) to obtain a pale yellow solid compound 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazine-3-carbonitrile (26) (20.1 mg, 19.1% yield).

[0746] 1 H NMR (400MHz, CD3OD): δ8.30(s,1H),8.24(s,1H),7.89(s,1H),5.93(td,1H), 2.74-2.79(m,1H),2.38-2.42(m,1H),1.68-1.70(m,1H),1.52-1.56(m,1H).

[0747] LC-MS, M / Z(ESI):345.0[M+H] +

[0748] Example 27: Preparation of target compound 27

[0749] 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carbonitrile (target compound 27)

[0750]

[0751] The synthetic route of target compound 27 is as follows:

[0752]

[0753] Step 1: Ethyl 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxylate (27A)

[0754]

[0755] 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-amine (700.0 mg, 2.17 mmol), ethyl 3-bromo-2-oxopropanoate (928.0 mg, 4.76 mmol), and sodium carbonate (688.5 mg, 6.50 mmol) were dissolved in N,N-dimethylformamide (7 mL) and reacted at 40°C for 12 hours. After completion of the reaction, the reaction solution was poured into water, filtered, and the filter cake was collected and dried to obtain the crude yellow solid compound ethyl 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxylate (27A) (880.0 mg, crude).

[0756] LC-MS, M / Z(ESI):420.1[M+H] +

[0757] Step 2: 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxylic acid (27B)

[0758]

[0759] Ethyl 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxylate (400.0 mg, 953.2 μmol) and sodium hydroxide (38.1 mg, 953.2 μmol) were dissolved in tetrahydrofuran (4 mL) and reacted at 25°C for 2 hours. After completion of the reaction, the reaction solution was adjusted to pH 4 with 1 M hydrochloric acid and then extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxylic acid (27B) (200 mg, crude).

[0760] LC-MS, M / Z(ESI):392.1[M+H] +

[0761] Step 3: 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxamide (27C)

[0762]

[0763] 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxylic acid (190.0 mg, 485.1 μmol), N,N-diisopropylethylamine (188.2 mg, 1.46 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (276.3 mg, 728.3 μmol) were dissolved in N,N-dimethylformamide (2 mL) and reacted at 25°C for 30 minutes. Then, ammonium chloride (31.1 mg, 582.3 μmol) was added to the reaction solution and reacted at 25°C for 1 hour. After the reaction is completed, the reaction solution is poured into water and extracted with ethyl acetate (50 mL × 2). The organic phases are combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude yellow oily compound 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxamide (220 mg, crude).

[0764] LC-MS, M / Z(ESI):391.1[M+H] +

[0765] Step 4: 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxamide (27D)

[0766]

[0767] 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxamide (200 mg, 512.3 μmol) was dissolved in 1 M aqueous hydrochloric acid (2 mL) and reacted at 50°C for 12 hours. After completion of the reaction, the reaction solution was concentrated to obtain the crude yellow oily compound 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxamide (27D) (150 mg, crude).

[0768] LC-MS, M / Z(ESI):363.1[M+H] +

[0769] Step 5: 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carbonitrile (target compound 27)

[0770]

[0771] 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxamide (140.0 mg, 386.2 μmol), triethylamine (78.2 mg, 772 μmol) and trifluoroacetic anhydride (162 mg, 772 μmol) were dissolved in tetrahydrofuran (2 mL) and reacted at 25°C for 1 hour. After completion of the reaction, the reaction solution was concentrated to obtain the product, which was then separated by reverse-phase high performance liquid chromatography (chromatographic column: Phenomenexluna C18 150×40 mm×15 μm; solvent: A = water + 0.225% by volume formic acid (99%), B = acetonitrile; gradient: 22%-52%, 7 minutes) to obtain a white solid compound 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carbonitrile (target compound 27) (12.0 mg, 8.71% yield).

[0772] 1H NMR (400MHz, DMSO_d6): δ11.44(s,1H),9.11(s,1H),8.05(s,1H),7.69(s,1H),5.89-6. 18(m,1H),2.66-2.67(m,1H),2.32-2.33(m,1H),1.64-1.65(m,1H),1.45-1.48(m,1H).

[0773] LC-MS, M / Z(ESI):345.1[M+H] + .

[0774] Example 28: Preparation of target compound 28

[0775] 5-(2-(difluoromethyl)-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (28)

[0776]

[0777] The synthetic route of target compound 28 is as follows:

[0778]

[0779] Step 1: Synthesis of (8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-2-yl)methanol (28A)

[0780]

[0781] At room temperature, 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester (100 mg, 238.5 μmol) was added to tetrahydrofuran (1.00 mL), and then lithium aluminum tetrahydride (18.1 mg, 476.9 μmol) was added to the reaction solution in batches at 0°C under nitrogen protection, followed by stirring at 45°C for 2 hours. After completion of the reaction, ice water (0.1 mL) and 1M aqueous sodium hydroxide solution (0.1 mL) were added dropwise to the reaction solution, followed by addition of anhydrous sodium sulfate, and then filtered. The filter cake was washed with ethyl acetate (25 mL), and the filtrate was concentrated to obtain a crude product. The crude product was purified by preparative plate (petroleum ether: ethyl acetate = 1:5) to give a yellow solid compound (8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-2-yl)methanol (28A) (20.0 mg, yield 22.2%).

[0782] LC-MS, M / Z(ESI):378.0[M+H] +

[0783] Step 2: Synthesis of 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carbaldehyde (28B)

[0784]

[0785] At room temperature, (8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-2-yl)methanol (20.0 mg, 53.0 μmol) was added to dichloromethane (0.50 mL), and then Dess-Martin periodinane (24.7 mg, 58.3 μmol) was added to the reaction solution in batches under nitrogen protection at 0°C, and then stirred at 25°C for 1 hour. After the reaction was completed, saturated aqueous sodium thiosulfate solution (25 mL) was added dropwise to the reaction solution, and then extracted with ethyl acetate (25 mL×2). The organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by preparative plate (petroleum ether: ethyl acetate = 1:1) to give yellow oily compound 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carbaldehyde (28B) (15.0 mg, yield 75.4%).

[0786] LC-MS, M / Z(ESI):376.0[M+H] +

[0787] Step 3: Synthesis of 2-(difluoromethyl)-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (28C)

[0788]

[0789] At room temperature, 8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carbaldehyde (15 mg, 39.96 μmol) was added to dichloromethane (1.50 mL), and then diethylaminosulfur trifluoride (14.17 mg, 87.92 μmol) was added dropwise to the reaction solution under nitrogen protection at 0°C, and then stirred at 25°C for 2 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (25 mL) was added dropwise to the reaction solution, and then extracted with ethyl acetate (25 mL×2). The organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified on a preparative plate (petroleum ether:ethyl acetate = 1:1) to give a yellow oily compound 2-(difluoromethyl)-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (28C) (8.00 mg, 50.4% yield).

[0790] LC-MS, M / Z(ESI):398.0[M+H] +

[0791] Step 4: Synthesis of 5-(2-(difluoromethyl)-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (28)

[0792]

[0793] 2-(Difluoromethyl)-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (8 mg, 20.13 μmol) was added to 1 M aqueous hydrochloric acid solution (0.80 mL) at room temperature, and the mixture was stirred at 50° C. for 12 hours. The product was then separated by reverse-phase high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150×25mm×10μm; solvent: A=water+0.225vol% formic acid (99%), B=acetonitrile; gradient: 18%-48%, 10 minutes) to obtain the target compound 5-(2-(difluoromethyl)-8-((1S,2S)-2-(difluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (28) (4.73 mg, yield 63.1%).

[0794] 1H NMR (400MHz, DMSO-d6): δ8.56(s,1H),8.01(s,1H),7.56(s,1H),7.00-7.30(m,1H),5.80- 6.30(m,1H),2.73-2.76(m,1H),2.42-2.45(m,1H),1.62-1.64(m,1H),1.43-1.47(m,1H).

[0795] LC-MS, M / Z(ESI):370.0[M+H] + .

[0796] Example 29: Preparation of target compound 29

[0797] 5-(7-Chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione (29)

[0798]

[0799] The synthetic route of target compound 29 is as follows:

[0800]

[0801] Step 1: Synthesis of 7-chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrrolo[1,2-b]pyridazine (29A)

[0802]

[0803] At 25°C, 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrrolo[1,2-b]pyridazine (40.0 mg, 115.5 μmol) was added to N,N-dimethylformamide (0.50 mL), followed by the addition of N-chlorosuccinimide (15.4 mg, 115.5 μmol), and the mixture was stirred at 25°C for 2 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (25 mL x 2). The organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by a preparative plate (petroleum ether:ethyl acetate = 2:1) to give a green solid compound 7-chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrrolo[1,2-b]pyridazine (29A) (38.5 mg, yield 87.5%).

[0804] LC-MS, M / Z(ESI):381.0[M+H] +

[0805] Step 2: Synthesis of 5-(7-chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione (29)

[0806]

[0807] 7-Chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-2-(2,4-dimethoxypyrimidin-5-yl)pyrrolo[1,2-b]pyridazine (38.5 mg, 101.1 μmol) was added to a 1 M aqueous hydrochloric acid solution (1.01 mL) at 25°C and stirred at 50°C for 12 hours. After completion of the reaction, the reaction solution was directly concentrated to obtain the crude product, which was then separated by reverse-phase high-performance liquid chromatography (column: Phenomenex Synergi C18 150×25mm×10μm; mobile phase: A=water+0.225% by volume formic acid, B=acetonitrile; gradient: 22%-55% over 11 minutes), followed by chiral separation (column: Phenomenex-Cellulose-2 The target compound 5-(7-chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione (29) (2.29 mg, 6.41% yield) was separated using a 4% column chromatography-mass spectrometer (250 mm×30 mm, 10 μm; solvent: A = water + 0.1% volume ammonia water (30%), B = methanol; gradient: 45%-45%, 35 min).

[0808] 1 H NMR (400MHz, DMSO-d6): δ10.62-11.83(m,2H),7.95(s,1H),6.98(d,1H),6.94 (s,1H),6.83(d,1H),5.84-6.14(m,1H),1.89-1.99(m,2H),1.31-1.40(m,2H).

[0809] LC-MS, M / Z(ESI):353.0[M+H] + .

[0810] Test Example 1: In vitro inhibitory activity of compounds on recombinant human CD73 enzyme

[0811] The experiment was performed 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) was prepared into a 3× stock solution with Tris-MgCl2 buffer and added to a 96-well white plate at a rate of 20 μL / well to a final concentration of 0.1 μg / mL. The compound was diluted to a 3× stock solution with a suitable concentration gradient using Tris-MgCl2 buffer and added to the above 96-well test white plate at a rate of 20 μL / well. After mixing, the compound was incubated at room temperature for 30 min. A positive control group (no compound) and a negative control group (no CD73) were also set up. AMP (Sigma; A1752-5G) was prepared into a 3× stock solution with Tris-MgCl2 buffer and added to the above 96-well white plate at a rate of 20 μL / well to a final concentration of 100 μM. After mixing, the compound was incubated at 37°C for 60 min. ATP was diluted with Tris-MgCl2 buffer. ATP (Sigma; A7699-1G) was prepared into a 7× stock solution in buffer and added to the above 96-well white plate at a final concentration of 100 μM at 10 μL / well. The mixture was mixed and incubated for 5 min. The ATP was detected using an ATP-GLO kit (Promega; G7573).

[0812] The inhibition rate of compounds at different concentrations on Human-CD73 was calculated according to the following formula. Then, the compound concentration was used as the X-axis and the inhibition rate was used as the Y-axis. The IC value of the compound on Human-CD73 inhibition was calculated using Prism software. 50 value:

[0813]

[0814] Table 1 In vitro inhibitory activity of test compounds on CD73 enzyme

[0815] Test compound <![CDATA[IC 50 (nM)]]> 1 91.05 2 9.989 3 12.08 4 561 5 56.27 6 47.09 7 450 8 38.91 9 80.19 10 16.84 11 14.92 12 36.61 13 802.6 14 38.91 15 46.65 16 71.38 17 12.77 18 39.74 19 40.81 20 18.69 21 18.52 22 21.05 23 38.60 24 13.88 25 17.81 26 277.6 27 86.31 28 44.06 29 130.4

[0816] The experimental results show that the compound of the present invention has a good inhibitory effect on CD73 enzyme.

[0817] Test Example 2: Pharmacokinetic Test

[0818] Mouse pharmacokinetic studies were conducted using male ICR mice weighing 20-25 g and fasted overnight. Three mice were orally gavaged and administered 10 mg / kg. Blood was collected before dosing, and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing. Three additional mice were administered intravenously (3 mg / kg), and blood was collected before dosing, and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing. Blood samples were centrifuged at 6800 g for 6 minutes at 2-8°C, and plasma was collected and stored at -80°C. Plasma was collected at each time point and mixed with 3-5 times the volume of acetonitrile containing the internal standard. The mixture was vortexed for 1 minute and centrifuged at 13,000 rpm at 4°C for 10 minutes. The supernatant was mixed with 3 times the volume of water, and the appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin 7.0 software.

[0819] Table 2 Results of mouse pharmacokinetic tests

[0820]

[0821] The results of mouse experiments show that the compound of the present invention exhibits excellent pharmacokinetic properties and good drugability.

[0822] Test Example 3: In vivo efficacy test of CT-26 colorectal cancer

[0823] After the mice were adapted for feeding for one week, CT-26 cells in the logarithmic phase were resuspended in PBS and 5x10 5 CT-26 cells were inoculated subcutaneously on the right posterior side of the mouse, and the tumor growth was observed regularly. When the tumor grew to an average volume of 80-100 mm 3 The mice were randomly divided into a model group and a treatment group (single-drug, combined with PD-1 antibody) according to the tumor size and weight. The tumor size and animal weight were measured and recorded before and during the treatment. After the treatment, the difference in tumor size between the model group and the treatment group was compared to determine the drug efficacy.

[0824] The experimental results show that the compound of the present invention has a significant inhibitory effect on the growth of CT-26 colorectal cancer when used alone or in combination with PD-1 antibody. Test Example 4: In vivo efficacy test on E.G7-OVA T cell lymphoma

[0825] After one week of adaptive feeding of mice, E.G7-OVA cells in the logarithmic phase were resuspended in PBS and an appropriate number of E.G7-OVA cells were inoculated subcutaneously at the right posterior part of the mouse at a rate of 100 μL / mouse. The tumor growth was observed regularly. When the tumor grew to an average volume of 80-100 mm 3The mice were randomly divided into a model group and a treatment group (single drug, combined with PD-1 antibody) according to the tumor size and weight. The tumor size and animal weight were measured and recorded before and during the treatment. After the treatment, the difference in tumor size between the model group and the treatment group was compared to determine the drug efficacy.

[0826] The experimental results show that the compound of the present invention, when used alone or in combination with PD-1 antibody, has a significant effect of inhibiting the growth of E.G7-OVAT cell lymphoma.

Claims

1. The compound represented by formula I, and its pharmaceutically acceptable salt: in, m is 0, 1, or 2; Middle R 1 are independently selected from hydrogen, halogen, unsubstituted or replaced by R a Substituted C1-C6 alkyl; the R a In the substituted C1-C6 alkyl group, the substitutions are independently one or more of the following substituents: halogen, C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different; n is 0; X is selected from N or C; Z 1 , Z 2 are each independently selected from N or C; Middle Y 1 , Y 2 , Y 3 are independently selected from N, C; said Y 1 , Y 2 , Y 3 Each independently represented by one or more R 2 replace; R 2 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R b The substituted group, the R b The substitution may be one or more substitutions, and the R b Each is independently a substituent of the following: halogen, C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different, The unsubstituted or R b In the substituted groups, the groups are each independently selected from C1-C6 alkyl, Wherein, the compound represented by formula I is not the following structural formula:

2. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: described for 3. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: when When it is a 5-membered heteroaryl group, the heteroatom of the heteroaryl group is N.

4. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: when When it is a 5-membered heteroaryl group, the heteroatom of the heteroaryl group is N, and the number of heteroatoms of the heteroaryl group is 1-3.

5. The compound of formula I according to claim 4 or a pharmaceutically acceptable salt thereof, characterized in that: The heteroaryl group has 1 or 2 heteroatoms.

6. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: In the case of R 1 When it is a halogen, the halogen is F, Cl, Br or I.

7. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: In the case of R 1 When it is halogen, m is 1 or 2.

8. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: middle, When R 1 is unsubstituted or replaced by R a In the case of a substituted C1-C6 alkyl group, m is 1 or 2.

9. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: middle, When R 1 To be R a In the case of substituted C1-C6 alkyl, the number of substitutions is independently 1-3.

10. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: In, R 1 are independently selected from unsubstituted or substituted by R a Substituted C1-C4 alkyl, said R a Substitution is one or more substitutions, the R a Each is independently selected from the following substituents: halogen, C1-C6 alkyl.

11. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: In, R 1 are independently selected from unsubstituted or substituted by R a Substituted C1-C3 alkyl, said R a Substitution is one or more substitutions, the R a Each is independently selected from the following substituents: halogen, C1-C6 alkyl.

12. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: In, R 1 are independently selected from unsubstituted or substituted by R a substituted methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, said R a Substitution is one or more substitutions, the R a Each is independently selected from the following substituents: halogen, C1-C6 alkyl.

13. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: In, R 1 are independently selected from unsubstituted or substituted by R a Substituted methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, when R a When it is a halogen, the halogen is F, Cl, Br or I.

14. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: In, R 1 are independently selected from unsubstituted or substituted by R a Substituted C1-C4 alkyl, said R a Substitution is one or more substitutions, the R a Each is independently selected from the following substituents: halogen, C1-C6 alkyl; wherein m is 1 or 2, and n is 0.

15. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: In, when Y 1 、Y 2 、Y 3 Each independently represented by one or more R 2 When substituted, the R 2 The total number is 1 to 3.

16. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 2 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R b Substituted C1-C6 alkyl, said R b Substitution is one or more substitutions, the R b Each is independently a substituent: halogen, C1-C6 alkyl.

17. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: When R 2 When it is a halogen, the halogen is F, Cl, Br, or I.

18. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 2 are independently selected from unsubstituted or substituted by R b Substituted C1-C6 alkyl, said R b Substitution is one or more substitutions, the R b Each is independently selected from the following substituents: halogen, C1-C6 alkyl.

19. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 2 are independently selected from unsubstituted or substituted by R b Substituted C1-C4 alkyl, said R b Substitution is one or more substitutions, the R b Each is independently selected from the following substituents: halogen, C1-C6 alkyl.

20. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 2 are independently selected from unsubstituted or substituted by R b substituted methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, said R b Substitution is one or more substitutions, the R b Each is independently selected from the following substituents: halogen, C1-C6 alkyl.

21. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: When R 2 When it is a substituted C1-C6 alkyl, the number of substitutions is 3.

22. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: When R 2 is a substituted C1-C6 alkyl, and when the substituents are each independently halogen, the halogen is F, Cl, Br or I.

23. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: When R 2 is a substituted C1-C6 alkyl group, wherein the substitution is one or more substitutions, and the substitutions are each independently selected from C1-C4 alkyl groups.

24. The compound of formula I according to claim 23, or a pharmaceutically acceptable salt thereof, wherein: R 2 is a substituted methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl group.

25. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: In, Z 1 , Z 2 are each independently selected from N or C; When R 2 To be R b In the case of a substituted C1-C6 alkyl group, the number of substitutions is 2 or 3.

26. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: In, Z 1 , Z 2 are each independently selected from N or C; When Y 1 、Y 2 、Y 3 Each independently represented by one or more R 2 When substituted, the R 2 The total number is 1 to 3, R 2 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R b Substituted C1-C6 alkyl, said R b Substitution is one or more substitutions, the R b Each is independently selected from the following substituents: halogen, C1-C6 alkyl.

27. The compound of formula I according to claim 26, or a pharmaceutically acceptable salt thereof, wherein: When R 2 When it is a halogen, the halogen is F, Cl, Br, or I.

28. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 2 is selected from hydrogen, -F, -Cl, -Br, amino, cyano, -CH3, -CF3, -CHF2 or -CH2CH3.

29. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Its X is selected from C or N; The Z 1 , Z 2 、Y 1 、Y 2 、Y 3 As defined in claim 1.

30. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: when for When R 2 In the Y 1 、Y 2 、Y 3 The replacement of 31. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: when for When R 2 In the Y 1 、Y 2 、Y 3 The replacement of 32. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: when for When R 2 In the Y 1 、Y 2 、Y 3 The replacement of 33. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: when for When R 2 In the Y 1 、Y 2 、Y 3 The replacement of 34. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: when for When R 2 In the Y 1 、Y 2 、Y 3 The replacement of 35. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: when for When for 36. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: described for 37. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Selected from 38. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: described for 39. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Selected from 40. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: The compound structural formula is m is 0, 1, or 2; Middle R 1 are independently selected from hydrogen, halogen, unsubstituted or replaced by R a Substituted C1-C6 alkyl; the R a In the substituted C1-C6 alkyl group, the R a Substitution is one or more substitutions, the R a Each is independently selected from the following substituents: halogen, C1-C6 alkyl; n is 0; X is selected from N or C; Middle Y 1 、Y 2 are independently selected from N, C; said Y 1 、Y 2 Each independently represented by one or more R 2 replace; R 2 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R b The substituted group, the R b Substitution is one or more substitutions, the R b Each independently selected from the following substituents: halogen, C1-C6 alkyl; the unsubstituted or R b In the substituted groups, the groups are each independently selected from C1-C6 alkyl groups.

41. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: The compound structural formula is m is 0, 1, or 2; Middle R 1 are independently selected from hydrogen, halogen, unsubstituted or replaced by R a Substituted C1-C6 alkyl; the R a In the substituted C1-C6 alkyl group, the R a Substitution is one or more substitutions, the R a Each is independently selected from the following substituents: halogen, C1-C6 alkyl; n is 0; X is selected from N or C; Middle Y 1 、Y 3 are independently selected from N, C; said Y 1 、Y 3 Each independently represented by one or more R 2 replace; R 2 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R b The substituted group, the R b Substitution is one or more substitutions, the R b Each independently selected from the following substituents: halogen, C1-C6 alkyl; the unsubstituted or R b In the substituted groups, the groups are each independently selected from C1-C6 alkyl groups.

42. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: The compound structural formula is m is 0, 1, or 2; Middle R 1 are independently selected from hydrogen, halogen, unsubstituted or replaced by R a Substituted C1-C6 alkyl; the R a In the substituted C1-C6 alkyl group, the R a Substitution is one or more substitutions, the R a Each is independently selected from the following substituents: halogen, C1-C6 alkyl; n is 0; X is selected from N or C; Middle Y 1 、Y 2 、Y 3 are independently selected from N, C; said Y 1 、Y 2 、Y 3 Each independently represented by one or more R 2 replace; R 2 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R b The substituted group, the R b Substitution is one or more substitutions, the R b Each independently selected from the following substituents: halogen, C1-C6 alkyl; the unsubstituted or R b In the substituted groups, the groups are each independently selected from C1-C6 alkyl groups.

43. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: The compound structural formula is m is 0, 1, or 2; Middle R 1 are independently selected from hydrogen, halogen, unsubstituted or replaced by R a Substituted C1-C6 alkyl; the R a In the substituted C1-C6 alkyl group, the R a Substitution is one or more substitutions, the R a Each is independently selected from the following substituents: halogen, C1-C6 alkyl; n is 0; X is selected from N or C; Z 2 Independently selected from N or C; Middle Y 1 、Y 2 、Y 3 are independently selected from N, C; said Y 1 、Y 2 、Y 3 Each independently represented by one or more R 2 replace; R 2 are independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or replaced by R b The substituted group, the R b Substitution is one or more substitutions, the R b Each independently selected from the following substituents: halogen, C1-C6 alkyl; the unsubstituted or R b In the substituted groups, the groups are each independently selected from C1-C6 alkyl groups.

44. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: The compound represented by formula I is selected from any one of the following compounds:

45. A pharmaceutical composition, characterized in that It comprises a compound represented by formula I as described in any one of claims 1 to 44, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

46. ​​Use of a compound of formula I according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, in combination with a PD-1 / PD-L1 / CTLA-4 antibody or a PD-1 / PD-L1 / CTLA-4 inhibitor in the preparation of a medicament for treating CD73-related diseases.

47. Use of a compound of formula I according to any one of claims 1 to 44, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 45 in the preparation of a medicament for treating a disease associated with CD73.

48. The use according to claim 46 or claim 47, characterized in that The CD73-related disease is cancer.

49. The use according to claim 48, characterized in that The cancer is selected from bladder cancer, breast cancer, bile duct cancer, rectal cancer, colon cancer, stomach cancer, gallbladder cancer, glioblastoma, head and neck cancer, liver cancer, lung cancer, lymphoma, medulloblastoma, melanoma, gastrointestinal stromal tumor, ovarian cancer, pancreatic cancer, prostate cancer or kidney cancer.

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