Class of CD73 inhibitors with oxoaromatic heterocyclic structure, preparation methods therefor, pharmaceutical compositions thereof, and use thereof

Abstract

The present invention pertains to the technical field of medicines. Disclosed are a class of oxoaromatic heterocyclic derivatives, preparation methods therefor, pharmaceutical compositions thereof, and use thereof. Specifically, the present invention relates to a class of oxoaromatic heterocyclic derivatives represented by general formula I, pharmaceutically acceptable salts thereof, stereoisomers thereof, preparation methods therefor, compositions comprising one or more of the compounds, and use of the compounds in the treatment of CD73-related diseases, such as tumors, cancer, inflammation-related diseases, immune diseases, diseases of the nervous system, neurodegenerative diseases, diseases of the central nervous system, depression, Parkinson's disease, sleep disorders, fibrosis, and cerebral and cardiac ischemic diseases.

Description

A class of CD73 inhibitors with oxyaromatic heterocyclic structures, their preparation methods, pharmaceutical compositions and uses Technical Field

[0001] This invention discloses a class of oxoaromatic heterocyclic derivatives, their preparation methods, pharmaceutical compositions, and uses. Specifically, it relates to a class of oxoaromatic heterocyclic derivatives of general formula I, their pharmaceutically acceptable salts, their stereoisomers and methods for their preparation, compositions containing one or more of these compounds, and the uses of these compounds in treating CD73-related diseases such as tumors, cancers, inflammation-related diseases, immune-related diseases, nervous system diseases, neurodegenerative diseases, central nervous system diseases, depression, Parkinson's disease, sleep disorders and fibrosis, and ischemic diseases of the brain and heart. This invention belongs to the field of pharmaceutical technology. Background Technology

[0002] CD73, also known as extracellular 5'-nucleotidase, is responsible for the further dephosphorylation of AMP to ADO after ATP is catalyzed by CD39 to produce adenosine monophosphate (AMP). Human CD73 is a multifunctional transmembrane glycoprotein composed of 523 amino acids encoded by the NT5E gene (located at 6q14-21), with a relative molecular mass of 70,000. It is anchored to the cell membrane via glycosylphosphatidylinositol (GPI). The CD73 protein consists of three domains: the N-terminal domain (27-317AA) contains two zinc ion binding sites and at least one N-glycosylation site at aspartic acid position 311; the C-terminal domain (337-549AA) contains a substrate binding site and is non-covalently bound to the plasma membrane via the GPI anchor; the N-terminal and C-terminal domains are connected by a short helix (318-336AA), which controls enzyme motility. Therefore, CD73 exists in two conformations: "open" and "closed". Catalytic reactions require CD73 to change from the open conformation to the closed conformation, which exposes the active binding site and allows the substrate to bind.

[0003] CD73 is a novel immune checkpoint associated with adenosine metabolism, which promotes tumor progression by inhibiting immune responses and inducing angiogenesis. Studies have found that CD73 is widely expressed on the surface of various human tissue cells, including lymphocytes, endothelial cells, and epithelial cells, controlling a variety of physiological functions, such as epithelial ion exchange, fluid transport, platelet function, tissue hypoxia, and vascular leakage. It mainly participates in the following physiological functions: (1) Affecting the salvage synthesis of purine nucleotides. Adenosine produced by CD73 controls the production of purine nucleotides through CD39 and CD73, thereby regulating nucleotide signal transduction; adenosine can induce immunosuppression and angiogenesis. (2) Catalyzing 5'-AMP, the generated adenosine binds to A1, A2A, A2B, and A3 adenosine receptors, producing different physiological effects through biological signal transduction. (3) Participating in T cell activation. Adenosine produced by CD73 hydrolysis can activate immune cells, affect immune cell proliferation, and regulate CD4+CD25+Treg cells, reducing the immune function of T cells. CD73 is a cell surface enzyme that converts ATP, which has immune-activating functions, into adenosine, which has immunosuppressive effects. Adenosine, by binding to the downstream adenosine receptor (A2AR), downregulates the activity of various immune cells, including CD4+ T cells and NK cells. In the tumor microenvironment, hypoxia induces overexpression of CD73 on the surface of cancer cells, which then dephosphorylates AMP to adenosine, creating an immunosuppressive tumor microenvironment that promotes tumor growth. Therefore, inhibiting CD73 may reduce adenosine levels and activate T cell function, becoming an important strategy for the development of anti-tumor drugs.

[0004] While immune checkpoint inhibitors, such as PD-1 and CTLA-4, have demonstrated a "long-tail" advantage in overall survival across various cancer types and are gradually expanding from advanced tumor treatment to early adjuvant / neoadjuvant therapy, low response rates remain a major obstacle to clinical application. Besides tumor-specific factors like the number of neoantigens, host factors, particularly the state of the tumor's local immune microenvironment, are closely related to the efficacy of immunotherapy. Overcoming immunotherapy resistance may be a key strategy by relieving the inhibitory effect of the tumor microenvironment on immune cells, thus improving the treatment response rate. Developing a combination of CD73 inhibitors and PD-L1 inhibitors may be a promising approach. Currently, although several monoclonal antibodies and small molecule CD73 inhibitors have entered clinical trials, various issues remain. Further research is needed on CD73 inhibitors with novel structures to identify highly active, selective, and low-toxicity candidate drugs. Summary of the Invention

[0005] The technical problem solved by the present invention is to provide a class of oxoaromatic heterocyclic derivatives of general formula I with CD73 inhibitory activity, as well as its stereoisomers and pharmaceutically acceptable salts, its preparation method, pharmaceutical composition and its use in the preparation of drugs for the prevention or treatment of CD73-related diseases.

[0006] To solve the technical problem of this invention, the present invention provides the following technical solution:

[0007] The first aspect of the technical solution of the present invention is to provide a class of oxoaromatic heterocyclic derivatives as shown in general formula I and their pharmaceutically acceptable salts;

[0008] In the formula:

[0009] R1 is selected from hydrogen or methyl.

[0010] R2 is selected from

[0011] X and Y are arbitrarily selected from CH, N, and CF, respectively;

[0012] R3 is selected from

[0013] Wherein: R4 is selected from hydrogen,

[0014] Wherein R is selected from hydrogen, halogen, cyano, hydroxy, trifluoromethyl, hydroxymethyl, acetyl, trifluoroacetyl, ethynyl, vinyl, hydroxyethyl, amino, acetamido, hydroxyformyl, C1-C6 alkoxyformyl, nitro, methanesulfonyl, aminosulfonyl, carbamoyl, C1-C6 alkylaminoformyl, substituted C1-C6 alkyl, substituted C3-C10 cycloalkyl, substituted C1-C6 alicyclic, substituted C5-C10 aryl, substituted C1-C6 aromatic heterocyclic, substituted C1-C6 alkoxy, substituted C1-C6 alkylamino. The substituted C3-C10 cycloalkoxy group, substituted C3-C10 cycloalkylamino group, substituted C1-C6 aromatic heterocyclic oxy group, substituted C1-C6 aromatic heterocyclic amino group, substituted C1-C6 aliphatic heterocyclic oxy group, substituted C1-C6 aliphatic heterocyclic amino group, substituted C1-C6 alkoxycarbamoyl group, substituted C1-C6 alkylcarbamoyl group, wherein the substituents include hydrogen, halogen, cyano, hydroxyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, amino, acetamido, hydroxycarbamoyl, oxo, methanesulfonyl, aminosulfonyl, carbamoyl, and when there are multiple substitutions, R can be the same or different;

[0015] n is selected from 1, 2, 3, 4, and 5.

[0016] A preferred class of oxoaromatic heterocyclic derivatives and their pharmaceutically usable salts are characterized in that the "C1-C6 alkyl" includes methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, neopentyl, and hexyl; the "C1-C6 alkoxy" includes methoxy, ethoxy, isopropoxy, propoxy, tert-butoxy, butoxy, isopentoxy, and pentoyloxy; the "C1-C6 alkylamino" includes methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, tert-butylamino, pentoamino, and neopentylamino; the halogen includes fluorine, chlorine, and bromine; the "cycloalkanes" also include fused and spirocyclic polycyclics, such as adamantane, bicyclo[2,2,2]octane, and bicyclo[1,1,1]pentane; the "aliphatic heterocycles" also include fused and spirocyclic heterocycles; aliphatic or aromatic heterocycles refer to a ring containing at least one heteroatom of nitrogen, oxygen, or sulfur.

[0017] A preferred class of oxoaromatic heterocyclic derivatives and their pharmaceutically acceptable salts, characterized in that R2 is selected from... General Formula II is obtained

[0018] In the formula, the definitions of R1, R3, R4, R, X, Y, and n are the same as those in claim 1.

[0019] The most preferred class of oxoaromatic heterocyclic derivatives and their stereoisomers and their pharmaceutically acceptable salts, including but not limited to the following compounds:

[0020] 4-(3-(2-fluoro-4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0021] (S)-4-(3-(4-cyanobenzyloxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0022] 4-(3-(2,5-difluoro-4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0023] 4-(3-(3-fluoro-4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0024] 4-(3-(3-chloro-4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0025] 4-(3-(4-cyanophenyl-difluoromethoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0026] 4-(3-(4-trifluoromethylbenzyloxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0027] 4-(3-(3-fluoro-4-trifluoromethylbenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0028] 4-(3-(3-chloro-4-trifluoromethylbenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0029] 4-(3-(2-fluoro-4-trifluoromethylbenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0030] 4-(3-(4-trifluoromethylphenyl-difluoromethoxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0031] 4-(3-(3-fluoro-4-difluoromethylbenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0032] 4-(3-(3-chloro-4-difluoromethylbenzyloxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0033] 4-(3-(4-difluoromethylbenzyloxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0034] 4-(3-(4-difluoromethylphenyl-difluoromethoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0035] 4-(3-(4-difluorochloromethylphenyl-difluoromethoxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0036] 4-(3-(2-difluoromethylpyridin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0037] 4-(3-(5-trifluoromethylpyridin-2-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0038] 4-(3-(3-fluoro-5-trifluoromethylpyridin-2-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0039] 4-(3-(2-trifluoromethylpyridin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0040] 4-(3-(2-fluoro-6-trifluoromethylpyridin-3-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0041] 4-(3-(2-chloro-6-trifluoromethylpyridin-3-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0042] 4-(3-(2-amino-6-trifluoromethylpyridin-3-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0043] 4-(3-(2-hydroxy-6-trifluoromethylpyridin-3-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0044] 4-(3-(2-cyanopyridin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0045] 4-(3-(2-amino-6-cyanopyridin-3-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0046] 4-(3-(2-fluoro-6-cyanopyridin-3-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0047] 4-(3-(2-fluoro-3-cyanopyridin-6-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0048] 4-(3-(2-chloro-3-cyanopyridin-6-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0049] 4-(3-(4-acetylbenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0050] 4-(3-(4-hydroxyformylbenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0051] 4-(3-(4-methoxycarboxybenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0052] 4-(3-(4-carbamoylbenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0053] 4-(3-(5-cyanopyridin-2-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0054] 4-(3-(5-cyanopyrazin-2-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0055] 4-(3-(3-cyanopyridazine-6-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0056] 4-(3-(5-cyanopyrimidine-2-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine

[0057] 4-(3-(2-cyanopyrimidine-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine

[0058] 4-(3-(2-aminopyridin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0059] 4-(3-(2-N,N-dimethylaminopyridin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0060] 4-(3-(3-chloro-5-trifluoromethylpyridin-2-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0061] 4-(3-(2-cyanopyridin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0062] 4-(3-(2-difluoromethylpyridin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0063] 4-(3-(2-trifluoromethyl-4-chloropyridin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0064] 4-(3-(2-trifluoromethyl-4-fluoropyridine-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0065] 4-(3-(2-trifluoromethylpyrimidin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0066] 4-(3-(2-trifluoromethylpyrazine-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0067] 4-(3-(4-trifluoromethylphenoxymethyl)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0068] 4-(3-(4-carboxyphenoxymethyl)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0069] 4-(3-(4-carbamoylphenoxymethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0070] 4-(3-(4-nitrophenoxymethyl)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0071] 4-(3-(4-cyanophenoxymethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0072] 4-(3-(5-cyanopyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0073] 4-(3-(5-cyanopyrimidine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine

[0074] 4-(3-(4-amino-5-cyanopyrimidine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine

[0075] 4-(3-(4-methoxy-5-cyanopyrimidine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine

[0076] 4-(3-(4-methoxy-5-cyanopyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0077] 4-(3-(4-trifluoromethyl-5-cyanopyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0078] 4-(3-(4-methyl-5-cyanopyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0079] 4-(3-(3-fluoro-5-cyanopyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0080] 4-(3-(2-amino-3-cyanopyridin-6-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0081] 4-(3-(2-N,N-dimethylamino-3-cyanopyridin-6-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0082] 4-(3-(2-hydroxy-3-cyanopyridin-6-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0083] 4-(3-(5-trifluoromethylpyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0084] 4-(3-(5-trifluoromethylpyrimidin-2-oxomethyl)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0085] 4-(3-(4-methylamino-5-trifluoromethylpyrimidin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0086] 4-(3-(4-methoxy-5-trifluoromethylpyrimidin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0087] 4-(3-(4-chloro-5-trifluoromethylpyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0088] 4-(3-(4-fluoro-5-trifluoromethylpyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0089] 4-(3-(3-fluoro-5-trifluoromethylpyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0090] 4-(3-(5-difluoromethylpyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0091] 4-(3-(4-boronic acid-5-trifluoromethylpyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0092] 4-(3-(5-trifluoromethylpyrazine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0093] 4-(3-(4-oxo-5-trifluoromethyl-1H-pyrimidin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0094] 4-(3-(5-chloropyrimidin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0095] 4-(3-(5-methylpyrimidin-2-oxomethyl)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0096] 4-(3-(5-hydroxymethylpyrimidin-2-oxomethyl)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0097] 4-(3-(5-cyanopyrazin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0098] 4-(3-(5-cyano-6-methoxypyrazine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0099] 4-(3-(5-cyano-6-aminopyrazine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0100] 4-(3-(5-ethynylpyrazin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0101] 4-(3-(5-acetylpyrazine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0102] 4-(3-(5-carbamoylpyrazine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0103] 4-(3-(5-hydroxyformylpyrazine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0104] 4-(3-(4-trifluoromethylphenoxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0105] 4-(3-(4-cyanophenoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0106] 4-(3-(4-nitrophenoxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0107] 4-(3-(4-acetylphenoxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0108] 4-(3-(4-methanesulfonylphenoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0109] 4-(3-(5-cyanopyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0110] 4-(3-(4-trifluoromethyl-5-cyanopyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0111] 4-(3-(4-methoxy-5-cyanopyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0112] 4-(3-(3-fluoro-5-cyanopyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0113] 4-(3-(5-trifluoromethylpyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0114] 4-(3-(3-fluoro-5-trifluoromethylpyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0115] 4-(3-(4-methoxy-5-trifluoromethylpyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0116] 4-(3-(4-amino-5-trifluoromethylpyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0117] 4-(3-(3-fluoro-5-trifluoromethylpyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0118] 4-(3-(3-fluoro-5-trifluoromethylformylpyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0119] 4-(3-(2-trifluoromethylpyridin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0120] 4-(3-(2-difluoromethyl-4-oxo-1H-pyridin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0121] 4-(3-(2-trifluoromethyl-4-methylpyridin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0122] 4-(3-(2-cyano-3-methylpyridin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0123] 4-(3-(2-cyanopyridin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0124] 4-(3-(2-carboxypyridin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0125] 4-(3-(2-methoxypyridin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0126] 4-(3-(2-acetylpyridin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0127] 4-(3-(2-trifluoromethylpyrazine-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0128] 4-(3-(2-alkynylpyrazin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0129] 4-(3-(2-cyanopyrazin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0130] 4-(3-(2-carbamoylpyrazine-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0131] 4-(3-(2-carboxypyrazin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0132] 4-(3-(2-cyano-3-aminopyrazine-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0133] 4-(3-(2-acetylpyrazin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0134] 4-(3-(5-trifluoromethylpyrimidin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0135] 4-(3-(5-cyanopyrimidin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0136] 4-(3-(4-amino-5-cyanopyrimidine-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine

[0137] 4-(3-(4-methoxy-5-cyanopyrimidine-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine

[0138] 4-(3-(5-carbamoylpyrimidin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0139] 4-(3-(5-carboxypyrimidin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0140] 4-(3-(5-alkynylpyrimidin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0141] 4-(3-(2-cyanopyrimidin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0142] 4-(3-(2-alkynylpyrimidin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0143] 4-(3-(2-trifluoromethylpyrimidin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0144] 4-(3-(2-difluoromethylpyrimidin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0145] 4-(3-(2-methoxypyrimidin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0146] 4-(3-(2-carboxypyrimidin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0147] 4-(3-(pyrimidin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0148] 4-(3-(pyridin-4-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0149] 4-(3-(1-oxopyridin-4-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0150] 4-(3-(3-chloropyridazine-6-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0151] 4-(3-(3-cyanopyridazin-6-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0152] 4-(3-(3-trifluoromethylpyridazine-6-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0153] 4-(3-(3-carboxypyridazine-6-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0154] 4-(3-(4-cyanoanilino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0155] 4-(3-(5-cyanopyridin-2-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0156] 4-(3-(2-cyanopyridin-5-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0157] 4-(3-(2-cyanopyrimidine-5-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine

[0158] 4-(3-(2-cyanopyrazin-5-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0159] 4-(3-(5-cyanopyrimidine-2-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine

[0160] 4-(3-(3-cyanopyridazine-6-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0161] 4-(3-(3-trifluoromethylpyridazine-6-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0162] 4-(3-(4-trifluoromethylphenylamino)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0163] 4-(3-(2-trifluoromethylpyridin-5-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0164] 4-(3-(5-trifluoromethylpyridin-2-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0165] 4-(3-(2-trifluoromethylpyrazine-5-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0166] 4-(3-(2-trifluoromethylpyrimidin-5-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0167] 4-(3-(4-cyanobenzylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0168] 4-(3-(4-trifluoromethylbenzylamino)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0169] 4-(3-(4-alkynylbenzylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0170] 4-(3-(3-fluoro-4-cyanobenzylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0171] 4-(3-(2-fluoro-4-cyanobenzylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0172] 4-(3-(2-cyanopyridin-5-methylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0173] 4-(3-(2-cyano-3-fluoropyridine-5-methylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0174] 4-(3-(2-alkynylpyridin-5-methylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0175] 4-(3-(2-cyanopyrimidine-5-methylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine

[0176] 4-(3-(2-cyanopyrazin-5-methylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0177] 4-(3-(2-cyanopyrazin-5-aminomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0178] 4-(3-(5-cyanopyridin-2-aminomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0179] 4-(3-(4-cyanophenylaminomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0180] 4-(3-(3-cyanopyridazine-6-aminomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0181] 4-(3-(5-cyanopyrimidine-2-aminomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine

[0182] 4-(3-(2-cyanopyrimidine-5-aminomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine

[0183] 4-(3-(2-trifluoromethylpyrazine-5-aminomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0184] 4-(3-(5-trifluoromethylpyridin-2-aminomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0185] 4-(3-(tert-butylaminoformoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0186] 4-(3-(cyclopentanamide)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0187] 4-(3-(cyclohexylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0188] 4-(3-(bicyclo[1,1,1]pentan-1-carbamoyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0189] 4-(3-(adamantaneaminoformoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0190] 4-(3-(bicyclo[2,2,2]oct-1-carbamoyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0191] 4-(3-(cyclopentanamide)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0192] 4-(3-(cyclohexylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0193] 4-(3-(adamantaneamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0194] 4-(3-(tert-butylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0195] 4-(3-(bicyclo[1,1,1]pentan-1-carbamoylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0196] 4-(3-(bicyclo[2,2,2]oct-1-carbamoylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0197] 4-(3-(2-trifluoromethylpyridin-5-carbamoyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0198] 4-(3-(2-trifluoromethylpyrimidin-5-carbamoyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0199] 4-(3-(4-trifluoromethylphenylcarbamoyl)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0200] 4-(3-(4-trifluoromethylbenzoylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0201] 4-(3-(3-fluoro-4-cyanobenzoamide)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0202] 4-(3-(4-cyanoanilinoyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0203] 4-(3-(pyrrolidine-1-formyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0204] 4-(3-(4-cyanobenzamido)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0205] 4-(3-(2-fluoro-4-cyanobenzoamido)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0206] 4-(3-(3-fluoro-4-cyanobenzoamido)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0207] 4-(3-(3-chloro-4-cyanobenzamido)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0208] 4-(3-(5-cyanopyridin-2-carbamate)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0209] 4-(3-(5-cyanopyrazin-2-carbamate)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0210] 4-(3-(2-cyanopyridin-5-carbamate)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0211] 4-(3-(2-cyanopyrimidine-5-carbamate)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine

[0212] 4-(3-(4-cyanoanilinoyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0213] 4-(3-(2-fluoro-4-cyanoanilinecarboxyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0214] 4-(3-(3-fluoro-4-cyanoanilinecarboxyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0215] 4-(3-(3-chloro-4-cyanoanilinecarboxyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0216] 4-(3-(5-cyanopyridin-2-carbamoyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0217] 4-(3-(5-cyanopyrazin-2-carbamoyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0218] 4-(3-(2-cyanopyridin-5-carbamoyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0219] 4-(3-(2-cyanopyrimidin-5-carbamoyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0220] 4-(3-(5-cyanopyrimidine-2-carbamoyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine

[0221] The above-described class of aromatic heterocyclic derivatives and their stereoisomers and their pharmaceutically acceptable salts are characterized in that the pharmaceutically acceptable salts include salts formed by combining with inorganic acids, organic acids, alkali metal ions, alkaline earth metal ions or organic bases that can provide physiologically acceptable cations, as well as ammonium salts.

[0222] Further, the aforementioned class of aromatic heterocyclic derivatives and their stereoisomers, as well as their pharmaceutically acceptable salts, are characterized in that the inorganic acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid, or sulfuric acid; the organic acid is selected from methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, citric acid, maleic acid, tartaric acid, fumaric acid, citric acid, or lactic acid; the alkali metal ion is selected from lithium ion, sodium ion, or potassium ion; the alkaline earth metal ion is selected from calcium ion or magnesium ion; and the organic base that can provide physiologically acceptable cations is selected from methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris(2-hydroxyethyl)amine.

[0223] The second aspect of the present invention is to provide a preparation route for the compound described in the first aspect:

[0224] To prepare the compound of general formula I according to the present invention, the synthetic steps for preparing the compound of general formula I according to the present invention are as follows:

[0225] In step (a), compound 1 is used as a raw material and undergoes a nucleophilic substitution reaction with compound R3H under an alkaline environment to generate compound 2 containing R3 substitution; in step (b), compound 2 undergoes a coupling reaction with R2-based boric acid R2B(OH)2 in a palladium-catalyzed environment to obtain target compound I containing R2 groups.

[0226] To prepare the compound of general formula II according to the present invention, the synthetic steps for preparing the compound of general formula II according to the present invention are as follows:

[0227] In step (a), using compound 1 as a starting material, compound R3H undergoes a nucleophilic substitution reaction with compound 1 under alkaline conditions to generate substituted compound 2; in step (b), under the action of palladium catalyst, compound 2 undergoes a coupling reaction with boric acid compound 3 to generate compound 4; in step (c), under acidic conditions, such as hydrochloric acid or boron tribromide, compound 4 undergoes demethylation and rearrangement to generate target compound II.

[0228] In step (a), compound 1 is used as a starting material and undergoes a nucleophilic substitution reaction with compound 5 under alkaline conditions to generate compound 6; in step (b), compound 6 undergoes a coupling reaction with compound 3 containing boric acid under palladium catalysis to obtain compound 7; in step (c), the hydroxyl group in compound 7 undergoes a nucleophilic substitution reaction with R4Br or R4Cl to generate compound 8; in step (d), the hydroxyl group in compound 6 undergoes a nucleophilic addition reaction with isocyanate R4NCO to generate compound 9; in step (e), under acidic conditions, such as hydrochloric acid or boron tribromide, compounds 8 and 9 are demethylated and rearranged to obtain target compound II;

[0229] In step (a), compound 1 is used as a starting material and undergoes a nucleophilic substitution reaction with compound 10 under alkaline conditions to generate compound 11; in step (b), under palladium catalysis, compound 11 undergoes a coupling reaction with compound 3 containing boric acid, and then loses Boc under acidic conditions to obtain compound 12; in step (c), the amino group in compound 12 undergoes a nucleophilic substitution reaction with R4Br or R4Cl to generate compound 13; in step (d), the amino group in compound 12 undergoes a nucleophilic addition reaction with R4NCO to generate compound 14; in step (e), under acidic conditions, such as hydrochloric acid or boron tribromide, compounds 13 and 14 are demethylated and rearranged to obtain target compound II;

[0230] The definitions of R1, R2, R3, R4, X, and Y are the same as those of any one of claims 1-4.

[0231] Furthermore, the starting materials and intermediates in the above reactions are readily available, and each step of the reaction can be easily synthesized using conventional methods in organic synthesis, based on reported literature or by those skilled in the art. The compounds of Formula I can exist in solvated or non-solvated forms, and different solvates may be obtained by crystallization using different solvents. Pharmaceutically acceptable salts of Formula I include various acid addition salts, such as acid addition salts of the following inorganic or organic acids: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, citric acid, maleic acid, tartaric acid, fumaric acid, citric acid, and lactic acid. Pharmaceutically acceptable salts of Formula I also include various alkali metal salts (lithium, sodium, potassium), alkaline earth metal salts (calcium, magnesium), and ammonium salts, and salts of organic bases that provide physiologically acceptable cations, such as salts of methylamine, dimethylamine, trimethylamine, piperidine, morpholine, and tris(2-hydroxyethyl)amine. All of these salts within the scope of this invention can be prepared using conventional methods. During the preparation of the compound of general formula I, its solvates, and its salts, polycrystalline or eutectic crystals may occur under different crystallization conditions.

[0232] A third aspect of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, a class of aromatic heterocyclic derivatives and their stereoisomers as described in the first aspect of the present invention, as well as pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers or excipients.

[0233] This invention also relates to pharmaceutical compositions in which the compounds of the invention are the active ingredients. These pharmaceutical compositions can be prepared according to methods known in the art. They can be formulated into any dosage form suitable for human or animal use by combining the compounds of the invention with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants. The content of the compounds of the invention in their pharmaceutical compositions is typically 0.1-95% by weight.

[0234] The compounds of this invention or pharmaceutical compositions containing them can be administered in unit dose form via enteral or non-enteric routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

[0235] Dosage forms can be liquid, solid, or semi-solid. Liquid dosage forms can include solutions (including true solutions and colloidal solutions), emulsions (including o / w, w / o, and double emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments, etc.; solid dosage forms can include tablets (including regular tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, pellets, suppositories, films, patches, aerosols, and sprays, etc.; semi-solid dosage forms can include ointments, gels, and pastes, etc.

[0236] The compounds of this invention can be formulated into conventional formulations, as well as sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.

[0237] To formulate the compounds of the present invention into tablets, a wide variety of excipients known in the art can be used, including diluents, binders, wetting agents, disintegrants, lubricants, and flow aids. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, dicalcium phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropanol, etc.; binders can be starch paste, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; lubricants and flow aids can be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0238] Tablets can also be further processed into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets.

[0239] To formulate the drug delivery unit into capsules, the active ingredient, the compound of the present invention, can be mixed with a diluent and a disintegrant, and the mixture can be placed directly into hard or soft capsules. Alternatively, the active ingredient, the compound of the present invention, can be first formed into granules or microspheres with a diluent, binder, and disintegrant, and then placed into hard or soft capsules. The diluents, binders, wetting agents, disintegrants, and disintegrants used to prepare tablets of the compound of the present invention can also be used to prepare capsules of the compound of the present invention.

[0240] To prepare the compounds of this invention into injectable formulations, water, ethanol, isopropanol, propylene glycol, or mixtures thereof can be used as solvents, and appropriate amounts of commonly used solubilizers, co-solvents, pH adjusters, and osmotic pressure regulators can be added. Solubilizers or co-solvents can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; pH adjusters can be phosphates, acetates, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulators can be sodium chloride, mannitol, glucose, phosphates, acetates, etc. If preparing lyophilized powder injections, mannitol, glucose, etc., can also be added as supporting agents.

[0241] In addition, colorants, preservatives, flavorings, tasters or other additives may be added to pharmaceutical preparations if necessary.

[0242] To achieve the purpose of medication and enhance the therapeutic effect, the drug or drug composition of the present invention can be administered using any known method of administration.

[0243] The dosage of the pharmaceutical compositions of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration, and the dosage form. Generally, the suitable daily dose range of the compounds of the present invention is 0.001-150 mg / kg body weight, preferably 0.01-100 mg / kg body weight. The above dosage can be administered as a single dose unit or divided into several dose units, depending on the physician's clinical experience and the dosing regimen, including the use of other treatment methods.

[0244] The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic or symptomatic drugs. When the compounds of the present invention have a synergistic effect with other therapeutic drugs, their dosage should be adjusted according to the actual situation.

[0245] The fourth aspect of the present invention is to provide a class of aromatic heterocyclic derivatives and their stereoisomers, as well as their pharmaceutically acceptable salts, for use in the preparation of medicaments for the prevention and / or treatment of diseases related to CD73.

[0246] The diseases associated with CD73 are selected from tumors, cancer, inflammation-related diseases, immune-related diseases, nervous system diseases, neurodegenerative diseases, central nervous system diseases, depression, Parkinson's disease, sleep disorders and fibrosis, and ischemic diseases of the brain and heart.

[0247] The cancers mentioned are selected from liver cancer, kidney cancer, lung cancer, pancreatic cancer, stomach cancer, gallbladder cancer, colorectal cancer, colon cancer, bladder cancer, breast cancer, bile duct cancer, ovarian cancer, prostate cancer, thyroid cancer, leukemia, lymphoma, squamous cell carcinoma, glioblastoma, head and neck cancer, medulloblastoma, melanoma, glioma, and head and neck cancer.

[0248] Beneficial technical effects:

[0249] The aromatic heterocyclic derivative compounds of this invention are a novel type of CD73 inhibitor, which differs from previously reported CD73 inhibitor structures. They not only exhibit high inhibitory activity against CD73 but also excellent selectivity, potentially exhibiting low toxicity and favorable metabolic properties. They may be developed into highly effective and low-toxic tumor immunotherapy drugs, benefiting a wide range of patients. Detailed Implementation

[0250] The invention will be further described below with reference to embodiments, but this does not limit the scope of the invention.

[0251] Instruments used for measurement: Nuclear magnetic resonance spectroscopy was performed using a Vaariaan Mercury 300 nuclear magnetic resonance spectrometer. Mass spectrometry was performed using a ZAD-2F and a VG300 mass spectrometer.

[0252] Example 1: 4-(3-(4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0253] Synthesis of 4-bromo-6-chloro-2-methylpyridazine-3(2H)-one

[0254] 4-Bromo-6-chloropyridazine-3(2H)-one (2.1 g, 10.0 mmol) was added to 30 mL of DMF and stirred at room temperature (25 °C) to dissolve. Cesium carbonate (3.4 g, 10.5 mmol) was added, followed by slow dropwise addition of iodomethane (1.9 mL, 30.0 mmol). After the addition was complete, the mixture was stirred at room temperature (25 °C) for 1–2 h. Once the reaction was complete, the mixture was quenched with saturated ammonium chloride. 30 mL of pure water was added, and the mixture was extracted twice with 50 mL of EA. The organic phases were combined and washed once with 40 mL of pure water and once with 40 mL of saturated brine. The mixture was dried over 10 g of anhydrous sodium sulfate for 2 h, filtered, and the filtrate was evaporated under reduced pressure to dryness, yielding 2.05 g of a pale yellow solid with a yield of 92%, which could be used directly in the next step. 1 H NMR (400MHz, DMSO-d6) δ8.23 (s, 1H), 3.66 (s, 3H).

[0255] Synthesis of tert-butyl 3-(4-cyanobenzoxy)-4,4-difluoropyrrolidine-1-carboxylic acid

[0256] 1-Boc-3-hydroxy-4,4-difluoropyrrolidine (446 mg, 2 mmol) was added to 10 mL of ultra-dry THF and dissolved by stirring at room temperature (20 °C). NaH (60% dispersed in mineral oil, 120 mg, 3.0 mmol) was slowly and added in portions. The reaction was carried out at room temperature (20 °C) for 15 min. 4-cyanobenzyl bromide (431 mg, 2.2 mmol) was added, and the reaction was carried out for 12 h. The reaction was quenched with 15 mL of pure water and extracted twice with 20 mL of EA. The organic phases were combined and washed once with 20 mL of pure water and once with 20 mL of saturated brine. The mixture was dried over 5 g of anhydrous sodium sulfate for 2 h, filtered, and the filtrate was evaporated to dryness under reduced pressure. The filtrate was separated by column chromatography to obtain a colorless oily substance with a yield of 58%. 1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.83(s,1H),7.55(s,1H),7.54(s,1H),4.7 8(s,2H),4.37-4.33(m,1H),3.74-3.59(m,3H),3.41-3.37(m,1H),1.41(s,9H).

[0257] Synthesis of 3-(4-cyanobenzyloxy)-4,4-difluoropyrrolidine

[0258] The 3-(4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (392 mg, 1.16 mmol) obtained in the previous step was added to 10 mL of dichloromethane and stirred to dissolve. Then, 1 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature (20 °C) for 1–2 h. After the reaction was complete, the solution was evaporated to dryness under reduced pressure, then evaporated once with 20 mL of dichloromethane, and then once with 20 mL of toluene, yielding a deep red liquid. The yield was 100%, and this liquid was used directly in the next step. MS(ESI) m / e: [M+H]+=239.10

[0259] Synthesis of 4-(3-(4-cyanobenzyloxy)-4,4-difluoropyrrolidone-1-yl)-6-chloropyridazine-3(2H)-one

[0260] 4-Bromo-6-chloropyridazine-3(2H)-one (209 mg, 1 mmol) was added to 10 mL of DMF and dissolved by stirring at room temperature (25 °C). DIPEA (1.3 g, 10 mmol) and 3-(4-cyanobenzyloxy)-4,4-difluoropyrrolidine (obtained in the previous step) were added sequentially. The mixture was gradually heated to 100 °C with stirring and reacted for 2–3 h. The reaction was stopped by TLC (PE:EA = 2:1). 15 mL of pure water was added, and the mixture was extracted twice with 30 mL of EA. The organic layers were combined, dried over anhydrous Na₂SO₄, filtered, mixed, and purified by silica gel column chromatography (40% EtOAc / PE) to obtain 178 mg of a gray solid, with a yield of 48.7%. HRMS(ESI)calcd for C 16 H 13 ClF2N4O2[M+H] + :367.0695,found 367.0772.

[0261] Synthesis of 4-(3-(4-cyanobenzyloxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one

[0262] 4-(3-(4-cyanobenzyloxy)-4,4-difluoropyrrolidone-1-yl)-6-chloropyridazine-3(2H)-one (114 mg, 0.31 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (68 mg, 0.37 mmol), and K₂CO₃ (128 mg, 0.93 mmol) were weighed sequentially and added to a microwave-safe tube. 3 mL of a pre-prepared dioxane / water mixture (5:1, v / v) was added, and the mixture was bubbled with argon gas. Then, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (36 mg, 0.05 mmol) was added. The mixture was microwave-safe at 120 °C for 1 h 20 min under argon protection. After the reaction was complete, the sample was mixed and purified under medium pressure (80% EtOAc / PE) to obtain a gray solid with a yield of 54.6%. HRMS(ESI)calcd for C 22 H 20 F2N6O4[M+H] + :471.1514,found 471.1594.

[0263] Synthesis of 4-(3-(4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0264] Weigh 66 mg (0.14 mmol) of 4-(3-(4-cyanobenzyloxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one and dissolve it in 3 mL of methanol. Add 1 mL of 4N HCl and gradually heat to 80 °C. Continue the reaction for 6–8 h, during which solid gradually precipitates. Stop heating and allow to cool naturally to room temperature. Filter, collect the filter cake, and recrystallize from methanol to give 41 mg of white solid, yield 66.1%. 1 H NMR (400MHz, DMSO-d6) δ12.61(s,1H),11.33(s,1H),11.22(d,J=6.0Hz,1H),7.85(d,J=1.8Hz,1H),7.83(d,J=1.9Hz,1H),7.70(d,J=6.1Hz,1H),7.57 (d,J=1.8Hz,1H),7.55(s,1H),6.61(s,1H),4.83(s,2H),4.44-4.40(m,1H) ,4.27–4.05(m,2H),3.94-3.89(m,1H),3.72-3.68(m,1H).HRMS(ESI)calcd for C 20 H 16 F2N6O4[M+H]+ :443.1201,found 443.1270.

[0265] Example 2: (R)-4-(3-(4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0266] Replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (R)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine, the synthesis method and experimental procedures were as described in Example 1, yielding (R)-4-(3-(4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 34.8%. 1 H NMR (400MHz, DMSO-d6) δ12.61(s,1H),11.34(s,1H),11.22(s,1H),7.85(s,1H),7.83(s,1H),7.70(d,J=6.0Hz,1H),7.57(s,1H),7 .55(s,1H),6.61(s,1H),4.83(s,2H),4.44-4.39(m,1H),4.25–4.08(m,2H),3.94-3.88(m,1H),3.72-3.67(m,1H).HRMS(ESI)calcd for C 20 H 16 F2N6O4[M+H]+:443.1201, found 443.1291.

[0267] Example 3: (S)-4-(3-(4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0268] Replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine, the synthesis method and experimental procedures were as described in Example 1, yielding (S)-4-(3-(4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 36.1%. 1H NMR (400MHz, DMSO-d6) δ12.61(s,1H),11.34(s,1H),11.22(s,1H),7.85(s,1H),7.83(s,2H),7.70(d,J=3.9Hz,1H),7.57(s,1H),7 .55(s,1H),6.61(s,1H),4.83(s,2H),4.45-4.39(m,1H),4.26–4.08(m,2H),3.95-3.89(m,1H),3.73-3.68(m,1H).HRMS(ESI)calcd for C 20 H 16 F2N6O4[M+H]+:443.1201, found 443.1289.[α]25℃D=–134.238°[c 2mg / mL, Methanol(10%TEA)].

[0269] Example 4: (S)-4-(3-(2-fluoro-4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0270] The synthesis method and experimental procedures were the same as in Example 1, replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 2-fluoro-4-cyanobenzyl bromide, to obtain a white solid (S)-4-(3-(2-fluoro-4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine in white solid, with a yield of 39.5%. MS(ESI) m / e: [M+H]+=461.11.

[0271] Example 5: 4-(3-(4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydropyridazine

[0272] Replacing 4-bromo-6-chloro-3-oxo-2,3-dihydropyridazine with 4-bromo-6-chloro-3-oxo-2,3-dihydropyridazine, the synthesis method and experimental procedures were as described in Example 1, yielding 4-(3-(4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydropyridazine, a white solid, in yield of 46.0%. 1 HNMR (400MHz, DMSO-d6) δ11.35(s,1H),11.27(s,1H),7.84(d,J=1.8Hz,1H),7.83(d,J=1.9Hz,1H),7.73(d,J=4.6Hz,1H),7.57(d,J=1.8Hz,1H), 7.55(s,1H),6.65(s,1H),4.83(s,2H),4.45-4.41(m,1H),4.25–4.07(m, 2H),3.93-3.89(m,1H),3.73-3.69(m,1H),3.60(s,3H).HRMS(ESI)calcd for C 21 H 18 F2N6O4[M+H] + :457.1358,found 457.1443

[0273] Example 6: (S)-4-(3-(3-fluoro-4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0274] Replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 3-fluoro-4-cyanobenzyl bromide, and following the synthetic method and experimental procedures as described in Example 1, yielded a white solid (S)-4-(3-(3-fluoro-4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine in yield of 42.5%. MS(ESI) m / e: [M+H]+ = 461.11.

[0275] Example 7: 4-(3-(4-cyanobenzyloxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0276] Replacing 1-Boc-3-hydroxypyrrolidine with 1-Boc-3-hydroxy-4,4-difluoropyrrolidine, the synthesis method and experimental procedures were as described in Example 1, yielding a white solid of 4-(3-(4-cyanobenzyloxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine, with a yield of 49.7%. 1 H NMR (400MHz, DMSO-d6) δ12.41(s,1H),11.32(s,1H),11.22(s,1H),7.80(d,J=8.3Hz,2H),7.71(s,1H),7.52(d,J=8.3Hz,2 H),6.54(s,1H),4.72–4.46(m,2H),4.25(s,1H),3.88-3.78(m,2H),3.65-3.56(m,2H),2.16–1.91(m,2H).HRMS(ESI)calcd for C 20 H 18 N6O4[M+H] + :407.1390,found 407.1445.

[0277] Example 8: (S)-4-(3-(3-chloro-4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0278] The synthesis method and experimental procedures were the same as in Example 1, replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 3-chloro-4-cyanobenzyl bromide, to obtain a white solid (S)-4-(3-(3-chloro-4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine in white solid with a yield of 40.8%. MS (ESI) m / e: [M+H]+=477.08.

[0279] Example 9: 4-(3-(4-methanesulfonylbenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0280] 4-Methanesulfonylbenzyl bromide was used instead of 4-cyanobenzyl bromide. The synthesis method and experimental procedures were the same as in Example 1, yielding a white solid of 4-(3-(4-methanesulfonylbenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine in 33.0% yield. 1 H NMR (400MHz, DMSO-d6) δ12.63(s,1H),11.35(s,1H),11.27(s,1H),7.93(s,1H),7.91(s,1H),7.71(d,J=6.1Hz,1H),7.64(s,1H),7.62(s,1H),6 .63(s,1H),4.85(s,2H),4.46-4.40(m,1H),4.28–4.02(m,2H),3.95-3. 90(m,1H),3.74-3.69(m,1H),3.20(s,3H).MS(ESI)m / e:[M+H]+=496.11.

[0281] Example 10: (S)-4-(3-(2-cyanopyridin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0282] The synthesis method and experimental procedures were the same as in Example 1, replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 2-cyano-5-bromomethylpyridine, to obtain (S)-4-(3-(2-cyanopyridin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 39.8%. MS (ESI) m / e: [M+H]+=477.08.

[0283] Example 11: 4-(3-(3-chloro-4-cyanobenzyloxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydropyridazine

[0284] The synthesis method and experimental procedures were the same as in Example 1, with 1-Boc-3-hydroxypyrrolidine replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine, 3-chloro-4-cyanobenzyl bromide replacing 4-cyanobenzyl bromide, and 4-bromo-6-chloro-2-methyl-3-oxo-2,3-dihydropyridazine replacing 4-bromo-6-chloro-3-oxo-2,3-dihydropyridazine. A white solid was obtained with a yield of 33.8%. 1 H NMR (400MHz, DMSO-d6) δ11.31(s,1H),11.23(d,J=6.2Hz,1H),8.04(d,J=1.6Hz, 1H),7.82(d,J=7.1Hz,1H),7.71(d,J=6.1Hz,1H),7.66(d,J=8.0Hz,1H),6.56(s, 1H),4.70–4.61(m,2H),4.32(s,1H),3.95-3.91(m,1H),3.79-3.75(m,1H),3.65- 3.55(m,2H),3.58(s,3H),2.17-2.13(m,1H),2.03-1.98(m,1H).HRMS(ESI)calcd for C 21 H 19 ClN6O4[M+H] + :455.1156,found 455.1226

[0285] Example 12, (S)-4-(3-(3-trifluoromethyl-4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0286] The synthesis method and experimental procedures were the same as in Example 1, replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 3-trifluoromethyl-4-cyanobenzyl bromide, to obtain a white solid (S)-4-(3-(3-trifluoromethyl-4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine in a yield of 40.8%. MS (ESI) m / e: [M+H]+=511.11.

[0287] Example 13: 4-(3-(5-cyanopyridin-2-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0288] Replacing 4-cyanobenzyl bromide with 2-bromomethyl-5-cyanopyridine, the synthesis method and experimental procedures were as described in Example 1, yielding a white solid of 4-(3-(5-cyanopyridine-2-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine in yield of 54.3%. 1 H NMR (400MHz, DMSO-d6) δ12.61(s,1H),11.34(s,1H),11.22(s,1H),8.99(dd,J=4 .5,2.1Hz,1H),8.34(dd,J=8.2,2.2Hz,0.5H),8.24(dd,J=8.1,2.3Hz,0.5H),7. 70(s,1H),7.59–7.53(m,1H),6.62(s,1H),4.88(d,J=18.7Hz,2H),4.53-4.48(m ,1H),4.24-4.10(m,2H),3.95-3.90(m,1H),3.77-3.72(m,1H).HRMS(ESI)calcd for C 19 H 15 F2N7O4[M+H] + :444.1154,found 444.1258.

[0289] Example 14: (S)-4-(3-(2-chloro-3-cyanopyridin-6-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0290] Replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 2-chloro-3-cyano-6-bromomethylpyridine, the synthetic method and experimental procedures were as described in Example 1, yielding (S)-4-(3-(2-chloro-3-cyanopyridin-6-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 39.8%. MS (ESI) m / e: [M+H]+ = 477.08.

[0291] Example 15: 4-(3-(5-cyanopyridin-2-methoxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydropyridazine

[0292] The synthesis method and experimental procedures were as described in Example 1, yielding 4-(3-(5-cyanopyridin-2-methoxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 39.6%. The method was modified by replacing 1-Boc-3-hydroxypyrrolidine with 1-Boc-3-hydroxy-4,4-difluoropyrrolidine, 5-cyano-2-bromomethylpyridine with 4-cyanobenzidine with 4-bromo-6-chloro-3-oxo-2,3-dihydropyridazine. 1 H NMR (400MHz, DMSO-d6) δ11.31(s,1H),11.23(d,J=6.2Hz,1H),8.96(d,J=2.2Hz,1H ),8.28(dd,J=8.2,2.2Hz,1H),7.71(d,J=6.1Hz,1H),7.60(d,J=8.2Hz,1H),6.56( s,1H),4.76–4.64(m,2H),4.32(s,1H),3.93-3.88(m,1H),3.80-3.75(m,1H),3.65 -3.55(m,2H),3.58(s,3H),2.17-2.12(m,1H),2.04–1.99(m,1H).HRMS(ESI)calcd for C 20 H 19 N7O4[M+H] + :422.1499,found 422.1567

[0293] Example 16: (S)-4-(3-((4-cyanophenyl)difluoromethoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0294] The synthesis method and experimental procedures were the same as in Example 1, replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-chlorodifluoromethylbenzonitrile with 4-cyanobenzyl bromide, to obtain a white solid (S)-4-(3-((4-cyanophenyl)difluoromethoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine in white solid, with a yield of 29.8%. MS (ESI) m / e: [M+H]+=479.10.

[0295] Example 17: 4-(3-(2-cyanopyridin-5-methoxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydropyridazine

[0296] The synthesis method and experimental procedures were the same as in Example 1, yielding 4-(3-(2-cyanopyridin-5-methoxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydropyridazine as a white solid with a yield of 45.2%. The method was substituted with 1-Boc-3-hydroxypyrrolidine, 2-cyano-5-bromomethylpyridine instead of 4-cyanobenzyl bromide, and 4-bromo-6-chloro-3-oxo-2,3-dihydropyridazine instead of 4-bromo-6-chloro-3-oxo-2,3-dihydropyridazine. 1 HNMR (400MHz, DMSO-d6) δ11.31(s,1H),11.24(d,J=6.2Hz,1H),7.78(d,J=2.0Hz,1H),7. 76(d,J=2.1Hz,1H),7.71(d,J=6.1Hz,1H),7.15(d,J=2.0Hz,1H),7.13(d,J=2.1Hz,1H), 6.57(s,1H),4.16–4.05(m,2H),3.88-3.83(m,1H),3.75-3.70(m,1H),3.61-3.50(m,2H) ,3.58(s,3H),2.74-2.66(m,1H),2.13-2.06(m,1H),1.83–1.73(m,1H).HRMS(ESI)calcd for C 20 H 19 N7O4[M+H] + :422.1499,found 422.1560

[0297] Example 18: (S)-4-(3-(5-cyanopyrazin-2-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0298] The synthesis method and experimental procedures were the same as in Example 1, replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 5-cyano-2-bromomethylpyrazine, to obtain a white solid (S)-4-(3-(5-cyanopyrazin-2-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine in white solid, with a yield of 39.8%. MS (ESI) m / e: [M+H]+=477.08.

[0299] Example 19: 4-(3-(4-cyanobenzyloxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydropyridazine

[0300] The synthesis method and experimental procedures were the same as in Example 1, using 1-Boc-3-hydroxypyrrolidine instead of 1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-bromo-6-chloro-2-methyl-3-oxo-2,3-dihydropyridine instead of 4-bromo-6-chloro-3-oxo-2,3-dihydropyridine, to obtain a white solid with a yield of 47.8%. 1 H NMR (400MHz, DMSO-d6) δ11.31(d,J=2.0Hz,1H),11.23(d,J=6.1Hz,1H),7.81(s,1H),7.79(s,1H),7.71(d,J=6.1Hz,1H),7.52(s,1H),7.50( s,1H),6.55(s,1H),4.71–4.55(m,2H),4.25(s,1H),3.88-3.75(m,2H),3.62-3.54(m,2H),3.58(s,3H),2.18–1.95(m,2H).HRMS(ESI)calcd for C 21 H 20 N6O4[M+H] + :421.1546,found 421.1613

[0301] Example 20: (S)-4-(3-(3-cyanopyridazine-6-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0302] Replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 3-cyano-6-bromomethylpyridazine, the synthetic method and experimental procedures were as described in Example 1, yielding (S)-4-(3-(3-cyanopyridazine-6-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 39.8%. MS (ESI) m / e: [M+H]+ = 477.08.

[0303] Example 21: 4-(3-(2-fluoro-4-cyanobenzyloxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0304] Replacing 1-Boc-3-hydroxypyrrolidine with 1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 2-fluoro-4-cyanobenzyl bromide, and following the synthetic method and experimental procedures as described in Example 1, yielded a white solid of 4-(3-(2-fluoro-4-cyanobenzyloxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine in 38.8% yield. 1 H NMR (400MHz, DMSO-d6) δ12.37 (s, 1H), 11.29 (s, 1H), 11.17 (d, J = 5.1Hz, 1H), 7.84(dd,J=10.0,1.5Hz,1H),7.71–7.62(m,3H),6.51(s,1H),4.69–4.62(m,2 H),4.28-4.26(m,1H),3.90-3.85(m,1H),3.78-3.73(m,1H),3.65-3.60(m,1 H),3.55-3.50(m,1H),2.14-2.09(m,1H),2.05–1.94(m,1H).HRMS(ESI)calcd for C 20 H 17 FN6O4[M+H] + :425.1295,found 425.1352.

[0305] Example 22: (S)-4-(3-(5-cyanopyrimidine-2-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine

[0306] The synthesis method and experimental procedures were the same as in Example 1, replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxypyrrolidine and 4-cyanobenzyl bromide with 5-cyano-2-bromomethylpyrimidine, to obtain (S)-4-(3-(5-cyanopyrimidine-2-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 39.8%. MS (ESI) m / e: [M+H]+=445.11.

[0307] Example 23: 4-(3-(3-fluoro-4-cyanobenzyloxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydropyridazine

[0308] The synthesis method and experimental procedures were the same as in Example 1, using 1-Boc-3-hydroxypyrrolidine instead of 1-Boc-3-hydroxy-4,4-difluoropyrrolidine, 3-fluoro-4-cyanobenzyl bromide instead of 4-cyanobenzyl bromide, and 4-bromo-6-chloro-2-methyl-3-oxo-2,3-dihydropyridazine instead of 4-bromo-6-chloro-3-oxo-2,3-dihydropyridazine. A white solid was obtained with a yield of 39.5%. 1 H NMR (400MHz, DMSO-d6) δ11.31(s,1H),11.23(d,J=6.1Hz,1H),7.88(dd,J=8.0,6.8Hz,1 H),7.71(dd,J=6.1,2.6Hz,1H),7.44(d,J=10.4Hz,1H),7.36(dd,J=8.0,1.4Hz,1H),6.5 5(s,1H),4.71–4.57(m,2H),4.26(d,J=4.2Hz,1H),3.90-3.86(m,1H),3.78-3.74(m,1H) ,3.66-3.55(m,2H),3.58(s,3H),2.14-2.09(m,1H),2.07–1.94(m,1H).HRMS(ESI)calcd for C 21 H 19 FN6O4[M+H] +:439.1452,found 439.1547

[0309] Example 24: (S)-4-(3-(2-cyanopyrimidine-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine

[0310] The synthesis method and experimental procedures were the same as in Example 1, replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxypyrrolidine and 4-cyanobenzyl bromide with 2-cyano-5-bromomethylpyrimidine, to obtain (S)-4-(3-(2-cyanopyrimidine-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 40.7%. MS (ESI) m / e: [M+H]+=445.11.

[0311] Example 25: (S)-4-(3-(4-ethynylbenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0312] The synthesis method and experimental procedures were the same as in Example 1, replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxypyrrolidine and 4-cyanobenzyl chloride with 4-ethynylbenzyl chloride, yielding a white solid (S)-4-(3-(4-ethynylbenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine in white solid, with a yield of 31.1%. MS (ESI) m / e: [M+H]+ = 442.13.

[0313] Example 26: 4-(3-(4-cyanophenoxymethyl)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydropyridazine

[0314] The synthesis method and experimental procedures were the same as in Example 1, with 1-Boc-3-hydroxymethylpyrrolidine replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine, 4-cyanobromobenzene replacing 4-cyanobenzyl bromide, and 4-bromo-6-chloro-2-methyl-3-oxo-2,3-dihydropyridazine replacing 4-bromo-6-chloro-3-oxo-2,3-dihydropyridazine. A white solid was obtained with a yield of 42.3%.1 H NMR (400MHz, DMSO-d6) δ11.31(s,1H),11.25(d,J=5.8Hz,1H),7.78(s,1H),7.76(s,1H),7.71(d,J=6.0 Hz,1H),7.15(s,1H),7.13(s,1H),6.57(s,1H),4.10(t,J=7.2Hz,2H),3.88-3.81(m,1H),3.75-3.69(m 1H),3.58(s,3H),3.56-3.50(m,2H),2.73-2.67(m,1H),2.13-2.05(m,1H),1.82-1.75(m,1H).HRMS(ESI)calcd for C 21 H 20 N6O4[M+H] + :421.1546found 421.1617.

[0315] Example 27: 4-(3-(4-cyanophenoxymethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0316] The synthesis method and experimental procedures were the same as in Example 1, using 1-Boc-3-hydroxymethyl-4,4-difluoropyrrolidine instead of 1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobromobenzene instead of 4-cyanobenzyl bromide, to obtain a white solid with a yield of 13.4%. 1 H NMR (400MHz, DMSO-d6) δ12.63 (s, 1H), 11.34 (s, 1H), 11.26 (d, J = 6.2Hz, 1H), 7. 80(s,1H),7.77(s,1H),7.72(d,J=6.1Hz,1H),7.17(s,1H),7.15(s,1H),6.65( s,1H),4.37(dd,J=10.2,6.9Hz,1H),4.32–4.20(m,3H),4.01(dd,J=12.1,8.5H z,1H),3.57(t,J=9.4Hz,1H),3.31–3.17(m,1H).MS(ESI)m / e:[M+H]+=443.12.

[0317] Example 28: (R)-4-(3-(2-fluoro-4-cyanophenoxymethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0318] Replacing 1-Boc-3-hydroxymethyl-4,4-difluoropyrrolidine with (R)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 2-fluoro-4-cyanobromobenzene, the synthesis method and experimental procedures were as described in Example 1, yielding (R)-4-(3-(2-fluoro-4-cyanophenoxymethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 34.7%. MS (ESI) m / e: [M+H]+ = 461.11.

[0319] Example 29: (R)-4-(3-(3-fluoro-4-cyanophenoxymethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0320] Replacing 1-Boc-3-hydroxymethyl-4,4-difluoropyrrolidine with (R)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 3-fluoro-4-cyanobromobenzene, the synthesis method and experimental procedures were as described in Example 1, yielding (R)-4-(3-(3-fluoro-4-cyanophenoxymethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 34.8%. MS (ESI) m / e: [M+H]+ = 461.11.

[0321] Example 30: (R)-4-(3-(3-chloro-4-cyanophenoxymethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0322] The synthesis method and experimental procedures were the same as in Example 1, replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (R)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 3-chloro-4-cyanobromobenzene, yielding (R)-4-(3-(3-chloro-4-cyanophenoxymethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 38.8%. MS (ESI) m / e: [M+H]+=477.08.

[0323] Example 31: 4-(3-(5-cyanopyridin-2-oxomethyl)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0324] The synthesis method and experimental procedures were the same as in Example 1, using 1-Boc-3-hydroxymethylpyrrolidine instead of 1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 2-chloro-5-cyanopyridine instead of 4-cyanobenzyl bromide, to obtain a white solid with a yield of 33.6%. 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),8.69(d,J=2.3Hz,1H),8.16(dd,J=8.7,2 .4Hz,1H),7.75(s,1H),7.05(d,J=8.7Hz,1H),6.57(s,1H),4.43(dd,J=10.8,6 .3Hz,2H),3.8991-3.82(m,1H),3.78-3.69(m,1H),3.61-3.48(s,1H),2.76-2. 67(m,1H),2.11-2.06(m,1H),1.80-1.74(m,1H).MS(ESI)m / e:[M+H]+=408.14.

[0325] Example 32, (R)-4-(3-(5-cyanopyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0326] Replacing 1-Boc-3-hydroxymethyl-4,4-difluoropyrrolidine with (R)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 2-chloro-5-cyanopyridine, the synthesis method and experimental procedures were as described in Example 1, yielding (R)-4-(3-(5-cyanopyridine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 38.1%. MS (ESI) m / e: [M+H]+ = 444.12.

[0327] Example 33: (R)-4-(3-(5-cyanopyrazin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0328] Replacing 1-Boc-3-hydroxymethyl-4,4-difluoropyrrolidine with (R)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 2-chloro-5-cyanopyrazine, the synthesis method and experimental procedures were as described in Example 1, yielding (R)-4-(3-(5-cyanopyrazine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 42.1%. MS (ESI) m / e: [M+H]+ = 445.11.

[0329] Example 34: 4-(3-(5-cyanopyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0330] The synthesis method and experimental procedures were the same as in Example 1, using 1-Boc-3-hydroxymethyl-4,4-difluoropyrrolidine instead of 1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 2-chloro-5-cyanopyridine instead of 4-cyanobenzyl bromide, to obtain a white solid with a yield of 14.7%. 1 H NMR (400MHz, DMSO-d6) δ12.64(s,1H),11.35(s,1H),11.30(s,1H),8.72(d,J=2.3Hz,1H), 8.18(dd,J=8.7,2.3Hz,1H),7.73(d,J=6.0Hz,1H),7.06(d,J=8.7Hz,1H),6.65(s,1H),4.6 6(dd,J=11.2,6.7Hz,1H),4.52(dd,J=11.2,6.5Hz,1H),4.25(dd,J=16.9,10.1Hz,2H),3. 99(t,J=10.1Hz,1H),3.58(t,J=9.6Hz,1H),3.27(dq,J=14.1,7.3Hz,1H).HRMS(ESI)calcd for C 19 H 15 F2N7O4[M+H] + :444.1154,found 444.1230.

[0331] Example 35: (R)-4-(3-(2-cyanopyridin-5-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0332] The synthesis method and experimental procedures were the same as in Example 1, replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (R)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide, to obtain (R)-4-(3-(2-cyanopyridin-5-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine as a white solid with a yield of 23.4%. MS (ESI) m / e: [M+H]+ = 444.12.

[0333] Example 36: (R)-4-(3-(5-cyanopyrimidine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine

[0334] Replacing 1-Boc-3-hydroxymethyl-4,4-difluoropyrrolidine with (R)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 2-chloro-5-cyanopyrimidine, the synthesis method and experimental procedures were as described in Example 1, yielding (R)-4-(3-(5-cyanopyrimidine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 39.4%. MS (ESI) m / e: [M+H]+ = 445.11.

[0335] Example 37: 4-(3-(4-cyanophenoxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0336] The synthesis method and experimental procedures were the same as in Example 1, using 1-Boc-3-hydroxypyrrolidine instead of 1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobromobenzene instead of 4-cyanobenzyl bromide, to obtain a white solid with a yield of 55.8%. 1H NMR (400MHz, DMSO-d6) δ12.50(s,1H),11.34(s,1H),7.79(d,J=2.0Hz,1H),7.77(d,J=2.1Hz,1H),7.16(d,J=2.1Hz,1H ),7.15(d,J=2.1Hz,1H),6.59(s,1H),5.25(s,1H),4.00(s,2H),3.70-3.61(m,2H),2.29–2.12(m,2H).HRMS(ESI)calcd for C 19 H 16 N6O4[M+H] + :393.1223,found 393.1298

[0337] Example 38: (S)-4-(3-(4-cyanophenoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0338] Replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobromene with 4-cyanobenzyl bromide, the synthesis method and experimental procedures were as described in Example 1, yielding (S)-4-(3-(4-cyanophenoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 54.6%. The yield was 39.4%. MS (ESI) m / e: [M+H]+ = 429.11.

[0339] Example 39: (S)-4-(3-(3-fluoro-4-cyanophenoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0340] The synthesis method and experimental procedures were the same as in Example 1, replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 3-fluoro-4-cyanobromobenzene, yielding a white solid (S)-4-(3-(3-fluoro-4-cyanophenoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine in white solid, with a yield of 49.5%. MS (ESI) m / e: [M+H]+ = 447.10.

[0341] Example 40: 4-(3-(4-trifluoromethylphenoxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0342] The synthesis method and experimental procedures were the same as in Example 1, using 1-Boc-3-hydroxypyrrolidine instead of 1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-trifluoromethylbromobenzene instead of 4-cyanobenzyl bromide, to obtain a white solid with a yield of 40.8%. 1 H NMR(400MHz,DMSO-d6)δ12.45(s,1H),11.32(s,1H),11.22(s,1H),7.71(s,1H),7.67(s,1H),7.65(s,1H),7.17(s,1 H),7.15(s,1H),6.57(s,1H),5.22(s,1H),4.01-3.94(m,2H),3.70-3.60(m,2H),2.29–2.12(m,2H).HRMS(ESI)calcd for C 19 H 16 F3N5O4[M+H] + :436.1154,found 436.1224.

[0343] Example 41: (S)-4-(3-(4-trifluoromethylphenoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0344] Replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 4-trifluoromethylbromobenzene, the synthetic method and experimental procedures were as described in Example 1, yielding (S)-4-(3-(4-trifluoromethylphenoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 34.6%. MS (ESI) m / e: [M+H]+ = 472.10.

[0345] Example 42, (S)-4-(3-(3-fluoro-4-trifluoromethylphenoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0346] Replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 3-fluoro-4-trifluoromethylbromobenzene, the synthesis method and experimental procedures were as described in Example 1, yielding (S)-4-(3-(3-fluoro-4-trifluoromethylphenoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 34.6%. MS (ESI) m / e: [M+H]+ = 490.09.

[0347] Example 43: 4-(3-(5-trifluoromethylpyridin-2-oxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydropyridazine

[0348] The synthesis method and experimental procedures were the same as in Example 1, using 1-Boc-3-hydroxypyrrolidine instead of 1-Boc-3-hydroxy-4,4-difluoropyrrolidine, 2-chloro-5-trifluoromethylpyridine instead of 4-cyanobenzyl bromide, and 4-bromo-6-chloro-2-methyl-3-oxo-2,3-dihydropyridazine instead of 4-bromo-6-chloro-3-oxo-2,3-dihydropyridazine. A white solid was obtained with a yield of 38.9%. 1 H NMR (400MHz, DMSO-d6) δ11.27(s,1H),11.19(d,J=6.2Hz,1H),8.58(dt,J=2.7,1.0Hz,1H),8.03(dd,J=8.8,2.6Hz,1H),7.67(d,J=6.1Hz,1H) ,6.99(d,J=8.8Hz,1H),6.55(s,1H),5.62(d,J=4.5Hz,1H),3.98(s,2H),3.67-3.56(m,2H),3.54(s,3H),2.30–2.07(m,2H).HRMS(ESI)calcd for C 19 H 17 F3N6O4[M+H] + :451.1263,found 451.1333.

[0349] Example 44: (S)-4-(3-(5-cyanopyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0350] Replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 2-chloro-5-cyanopyridine, the synthesis method and experimental procedures were as described in Example 1, yielding (S)-4-(3-(5-cyanopyridine-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 54.6%. The yield was 58.8%. MS (ESI) m / e: [M+H]+ = 430.10.

[0351] Example 45: (S)-4-(3-(5-cyanopyrazin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0352] Replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 2-chloro-5-cyanopyrazine, the synthesis method and experimental procedures were as described in Example 1, yielding (S)-4-(3-(5-cyanopyrazin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 56.8%. MS (ESI) m / e: [M+H]+ = 431.10.

[0353] Example 46: 4-(3-(5-trifluoromethylpyridin-2-oxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0354] The synthesis method and experimental procedures were the same as in Example 1, using 1-Boc-3-hydroxypyrrolidine instead of 1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 2-bromo-5-trifluoromethylpyridine instead of 4-cyanobenzyl bromide, to obtain a white solid with a yield of 50.3%. 1H NMR (400MHz, DMSO-d6) δ12.42(s,1H),11.30(d,J=2.0Hz,1H),11.17(d,J=6.1Hz,1H),8.62(d,J=2.5Hz,1H),8.08(dd,J=8.8,2.6Hz,1H),7.68( d,J=6.1Hz,1H),7.03(d,J=8.7Hz,1H),6.55(s,1H),5.66(d,J=5.0Hz,1H),4.00(s,2H),3.72-3.62(m,2H),2.28-2.18(m,2H).HRMS(ESI)calcd for C 18 H 15 F3N6O4[M+H] + :437.1107,found 437.1773

[0355] Example 47: (S)-4-(3-(5-cyanopyrimidine-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine

[0356] Replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 2-chloro-5-cyanopyrimidine, the synthetic method and experimental procedures were as described in Example 1, yielding (S)-4-(3-(5-cyanopyrimidine-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 60.8%. MS (ESI) m / e: [M+H]+ = 431.10.

[0357] Example 48: 4-(3-(5-trifluoromethylpyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0358] The synthesis method and experimental procedures were the same as in Example 1, using 2-chloro-5-trifluoromethylpyridine instead of 4-cyanobenzyl bromide, to obtain a white solid with a yield of 60.8%. 1H NMR (400MHz, DMSO-d6) δ11.35(s,1H),11.28(d,J=5.2Hz,1H),8.66(d,J=2.0Hz,1H),8.18(dd,J=8.8,2.6Hz,1H),7.73(d,J=6.1Hz,1H),7.19(d,J=8 .7Hz,1H),6.70(s,1H),5.90(d,J=8.6Hz,1H),4.36–4.22(m,2H),4.19(dd,J=12.7,6.4Hz,1H),3.86(d,J=12.7Hz,1H),3.61(s,3H).HRMS(ESI)calcd for C 19 H 15 F5N6O4[M+H] + :487.1075,found487.1142

[0359] Example 49: (S)-4-(3-(5-trifluoromethylpyrimidin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0360] Replacing 1-Boc-3-hydroxy-4,4-difluoropyrrolidine with (S)-1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 2-chloro-5-trifluoromethylpyrimidine, the synthetic method and experimental procedures were as described in Example 1, yielding (S)-4-(3-(5-trifluoromethylpyrimidine-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 61.2%. MS (ESI) m / e: [M+H]+ = 474.09.

[0361] Example 50: 4-(3-(isopropylcarbamoyloxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydropyridazine

[0362] Synthesis of intermediates:

[0363] Synthesis of 4-bromo-6-chloro-2-methylpyridazine-3(2H)-one

[0364] 4-Bromo-6-chloropyridazine-3(2H)-one (2.1 g, 10.0 mmol) was added to 30 mL of DMF and stirred at room temperature (25 °C) to dissolve. Cesium carbonate (3.4 g, 10.5 mmol) was added, followed by slow dropwise addition of iodomethane (1.9 mL, 30.0 mmol). After the addition was complete, the mixture was stirred at room temperature (25 °C) for 1–2 h. Once the reaction was complete, the mixture was quenched with saturated ammonium chloride. 30 mL of pure water was added, and the mixture was extracted twice with 50 mL of EA. The organic phases were combined and washed once with 40 mL of pure water and once with 40 mL of saturated brine. The mixture was dried over 10 g of anhydrous sodium sulfate for 2 h, filtered, and the filtrate was evaporated under reduced pressure to dryness, yielding 2.05 g of a pale yellow solid with a yield of 92%, which could be used directly in the next step. 1 H NMR (400MHz, DMSO-d6) δ8.23 (s, 1H), 3.66 (s, 3H).

[0365] Synthesis of 6-chloro-4-(3-hydroxypyrrolidone-1-yl)-2-methylpyridazin-3(2H)-one

[0366] 4-Bromo-6-chloro-2-methylpyridazine-3(2H)-one (1.11 g, 5 mmol) was added to 10 mL of DMF and dissolved by stirring at room temperature (25 °C). DIPEA (1.3 g, 10.0 mmol) and 3-hydroxypyrrolidine (528 mg, 6 mmol) were added sequentially. The temperature was gradually raised to 100 °C and the reaction was continued for 2–3 h. After the reaction was completed, 15 mL of pure water was added, and the mixture was extracted twice with 30 mL of EA. The organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (80% EtOAc / PE) to give 850 mg of a pale yellow solid, with a yield of 50%. 1 H NMR (400MHz, DMSO–d6) δ6.00(s,1H),4.99(s,1H),4.33(s,1H),3.83–3.57(m,4H),3.52(s,3H),2.02–1.74(m,2H).

[0367] Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-4-(3-hydroxypyrrolidone-1-yl)-2-methylpyridazin-3(2H)-one

[0368] Accurately weigh 990 mg (3.0 mmol) of 6-chloro-4-(3-hydroxypyrrolidin-1-yl)-2-methylpyridazin-3(2H)-one, 700 mg (3.6 mmol) of (2,6-dimethoxypyrimidin-4-yl)boronic acid, and 1240 mg (9 mmol) of K₂CO₃ into a microwave tube. Add 24 mL of a pre-prepared dioxane / water mixture (5:1, v / v). Bubble under argon gas, add 220 mg (0.3 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. Under argon protection, microwave reaction at 120 °C for 1 h 20 min. After the reaction is complete, mix the sample and separate under medium pressure (PE / EA = 80%) to obtain 600 mg of an off-white solid, yield 60.1%. HRMS(ESI)calcd for C 15 H 19 N5O4[M+H] + :334.1437,found 334.1535.

[0369] Synthesis of 6-chloro-4-(3-hydroxypyrrolidone-1-yl)pyridazin-3(2H)-one

[0370] 4-Bromo-6-chloropyridazine-3(2H)-one (1.04 g, 5 mmol) was added to 10 mL of acetonitrile and dissolved by stirring at room temperature (25 °C). DIPEA (970 mg, 7.5 mmol) and 3-hydroxypyrrolidine (528 mg, 6 mmol) were added sequentially, and the temperature was gradually raised to 85 °C. The reaction was continued for 3–4 h. After the reaction was completed, the mixture was cooled to room temperature, and a solid gradually precipitated. The mixture was stirred at room temperature for 2 h, filtered, and a pale yellow solid was obtained. The filter cake was washed with an appropriate amount of acetonitrile and dried under reduced pressure. The yield was 61%. 1 H NMR (400MHz, DMSO–d6) δ12.37(s,1H),5.92(s,1H),4.96(s,1H),4.30(s,1H),3.85–3.42(m,4H),1.98–1.69(m,2H).

[0371] Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-4-(3-hydroxypyrrolidone-1-yl)pyridazin-3(2H)-one

[0372] Replacing 6-chloro-4-(3-hydroxypyrrolidone-1-yl)pyridazin-3(2H)-one with 6-chloro-4-(3-hydroxypyrrolidone-1-yl)-2-methylpyridazin-3(2H)-one, the synthesis was performed according to the method described for 6-(2,4-dimethoxypyrimidin-5-yl)-4-(3-hydroxypyrrolidone-1-yl)-2-methylpyridazin-3(2H)-one, yielding a gray solid in 44.6% yield.1 H NMR(400MHz,DMSO–d6)δ12.46(s,1H),8.43(s,1H),6.21(s,1H),4.94(d,J=3.5Hz,1H),4.31 (s,1H),3.96(s,3H),3.94(s,3H),3.75–2.66(m,2H),3.65–3.50(m,2H),2.01–1.70(m,2H).

[0373] Synthesis of 6-chloro-4-(3-hydroxy-4,4-difluoropyrrolidone-1-yl)pyridazin-3(2H)-one

[0374] The 3-hydroxypyrrolidine was replaced with 3-hydroxy-4,4-difluoropyrrolidine, and the synthesis method was the same as that for the synthesis of 6-chloro-4-(3-hydroxypyrrolidin-1-yl)pyridazin-3(2H)-one. The feed amounts were: 4,4-difluoropyrrolidin-3-ol (1.23 g, 10 mmol), 4-bromo-6-chloropyridazin-3(2H)-one (2.08 g, 10 mmol), yielding 1.33 g of a deep red solid in 53% yield. HRMS(ESI)calcd for C8H8ClF2N3O2[M+H] + :252.0273,found 252.0347.

[0375] Synthesis of 4-(4,4-difluoro-3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one

[0376] Replacing 6-chloro-4-(3-hydroxy-4,4-difluoropyrrolidone-1-yl)pyridazin-3(2H)-one with 6-chloro-4-(3-hydroxypyrrolidone-1-yl)-2-methylpyridazin-3(2H)-one, the synthesis was performed according to the method described for 6-(2,4-dimethoxypyrimidin-5-yl)-4-(3-hydroxypyrrolidone-1-yl)-2-methylpyridazin-3(2H)-one, yielding a deep red solid in 59.8% yield. 1 H NMR (400MHz, DMSO-) d6 )δ12.70(s,1H),8.44(s,1H),6.36(s,1H),6.14(d,J=5.2Hz,1H),4.29(s,1H),4.16-4.04 (m,2H),4.10-4.00(m,1H),3.97(s,3H),3.94(s,3H),3.59-3.53(m,1H).HRMS(ESI)calcd for C 14 H 15 F2N5O4[M+H]+ :356.1092,found 356.1159.

[0377] Synthesis of (S)-6-chloro-4-(3-hydroxy-4,4-difluoropyrrolidone-1-yl)pyridazine-3(2H)-one

[0378] The 3-hydroxypyrrolidine was replaced with (S)-3-hydroxy-4,4-difluoropyrrolidine, and the synthesis method was the same as that for 6-chloro-4-(3-hydroxypyrrolidin-1-yl)pyridazin-3(2H)-one. The feed amounts were: 4,4-difluoropyrrolidin-3-ol (1.23 g, 10 mmol), 4-bromo-6-chloropyridazin-3(2H)-one (2.08 g, 10 mmol), yielding 1.33 g of a deep red solid in 53% yield. HRMS(ESI)calcd for C8H8ClF2N3O2[M+H] + :252.0273,found 252.0321.

[0379] Synthesis of (S)-4-(4,4-difluoro-3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one

[0380] The 6-chloro-4-(3-hydroxy-4,4-difluoropyrrolidone-1-yl)pyridazin-3(2H)-one was replaced with (S)-6-chloro-4-(3-hydroxypyrrolidone-1-yl)-2-methylpyridazin-3(2H)-one, synthesized according to the method described for 6-(2,4-dimethoxypyrimidin-5-yl)-4-(3-hydroxypyrrolidone-1-yl)-2-methylpyridazin-3(2H)-one, yielding a deep red solid in 59.8% yield. HRMS(ESI)calcd for C 14 H 15 F2N5O4[M+H] + :356.1092,found 356.1133.

[0381] Synthesis of (S)-4-(4,4-difluoro-3-aminopyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one

[0382] (S)-3-hydroxy-4,4-difluoropyrrolidine was used instead of (S)-3-tert-butyloxycarboxamide-4,4-difluoropyrrolidine. The synthesis was performed following the method described for (S)-4-(4,4-difluoro-3-hydroxypyrrolidine-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one. After deprotection and neutralization, a red solid was given in 46.7% yield. MS (ESI) m / e: [M+H]+ = 355.13

[0383] Synthesis of 4-(3-(isopropylcarbamoyloxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydropyridazine

[0384] 6-(2,4-Dimethoxypyrimidin-5-yl)-4-(3-hydroxypyrrolidone-1-yl)-2-methylpyridazin-3(2H)-one (100 mg, 0.31 mmol), isopropyl isocyanate (132 mg, 1.55 mmol), and triethylamine (160 mg, 1.55 mmol) were added to 10 ml of toluene. The mixture was gradually heated to 90 °C and reacted for 4–5 h. After the reaction was completed, the mixture was directly stirred and separated under medium pressure (5% DCM / MeOH) to give a white solid with a yield of 50.6%. 1 H NMR (400MHz, DMSO-d6) δ11.32(s,1H),11.23(d,J=6.0Hz,1H),7.71(d,J=6.0Hz,1H),7.12(d,J=7.7Hz,1H),6.55(s,1H),5.15(s,1 H),3.84(s,2H),3.62-3.52(m,2H),3.58(s,3H),2.16–1.95(m,2H),1.03(d,J=2.8Hz,3H),1.02(d,J=3.4Hz,3H).HRMS(ESI)calcd for C 17 H 22 N6O5[M+H] + :391.1652,found 391.1729.

[0385] Example 51: 4-(3-(1-trifluoromethylcyclopropylcarbamoyloxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydropyridazine

[0386] Using 1-trifluoromethylcyclopropyl isocyanate instead of isopropyl isocyanate, the synthesis method and experimental procedures were the same as in Example 50, yielding a white solid with a yield of 65.9%.1 H NMR (400MHz, DMSO-d6) δ11.32(s,1H),11.23(d,J=5.4Hz,1H),8.22(s,1H),7.71(d,J=5.3Hz,1H),6.56(s,1H),5.19( s,1H),3.85(s,2H),3.58(s,3H),2.11(dd,J=9.4,4.6Hz,0H),2.03(s,1H),1.18(s,2H),1.04(s,2H).HRMS(ESI)calcd for C 18 H 19 F3N6O5[M+H] + :457.1369,found 457.1452.

[0387] Example 52: 4-(3-(cyclopropylcarbamoyloxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydropyridazine

[0388] Cyclopropyl isocyanate was used instead of isopropyl isocyanate. The synthesis method and experimental procedures were the same as in Example 50, and a white solid was obtained with a yield of 51.1%. 1 H NMR (400MHz, DMSO-d6) δ11.31(s,1H),11.23(d,J=5.9Hz,1H),7.71(d,J=6.0Hz,1H),7.38(s,1H),6.55(s,1H),5.16(s,1H),3.84(s ,2H),3.63–3.54(m,2H),3.58(s,3H),2.47–2.39(m,2H),2.17–1.98(m,2H),0.57–0.49(m,2H),0.37–0.35(m,2H).HRMS(ESI)calcd for C 17 H 20 N6O5[M+H] + :389.1495,found 389.1562.

[0389] Example 53: 4-(3-(cyclopentanamide)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydropyridazine

[0390] Cyclopentyl isocyanate was used instead of isopropyl isocyanate. The synthesis method and experimental procedures were the same as in Example 50, and a white solid was obtained with a yield of 46.4%.1 H NMR (400MHz, DMSO-d6) δ11.32(s,1H),11.23(s,1H),7.71(s,1H),7.21(d,J=7.3Hz,1H),6.55(s,1H),5.15(s,1H),3.84(s,2H),3.78-3.73(m,1H) ,3.62-3.53(m,2H),3.58(s,3H),2.15–1.97(m,2H),1.77–1.71(m,2H),1 .60-1.55(m,2H),1.46-1.41(m,2H),1.38-1.32(m,2H).HRMS(ESI)calcd for C 19 H 24 N6O5[M+H] + :417.1808,found 417.1874

[0391] Example 54: 4-(3-(4-cyanoanilinoyloxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydropyridazine

[0392] Using 4-cyanophenyl isocyanate instead of isopropyl isocyanate, the synthesis method and experimental procedures were the same as in Example 50, yielding a white solid with a yield of 55.5%. 1 H NMR (400MHz, DMSO-d6) δ11.33(s,1H),11.24(d,J=6.0Hz,1H),10.24(s,1H),7.75(s,1H),7.73(s,1H),7.72(d,J=6.1Hz,1H),7.64(s,1H),7.62(s, 1H),6.59(s,1H),5.34(d,J=5.1Hz,1H),4.05-4.00(m,1H),3.94–3.89(m ,1H),3.66-3.56(m,2H),3.59(s,3H),2.27–2.10(m,2H).HRMS(ESI)calcd for C 21 H 19 N7O5[M+H] + :450.1448,found 450.1514

[0393] Example 55: 4-(3-(4-chloroanilinocarboxyloxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methyl-3-oxo-2,3-dihydropyridazine

[0394] Using 4-chlorophenyl isocyanate instead of isopropyl isocyanate, the synthesis method and experimental procedures were the same as in Example 50, yielding a white solid with a yield of 39.1%. 1 H NMR (400MHz, DMSO-d6) δ12.43(s,1H),11.31(d,J=2.0Hz,1H),11.18(d,J=6.2Hz,1H),9.87(s,1H),7.68(d,J=6.1Hz,1H),7.49(s,1H),7.47(s,1H) ,7.34(s,1H),7.31(s,1H),6.55(s,1H),5.31(s,1H),4.02-3.97(m,1H), 3.91-3.86(m,1H),3.65-3.56(m,2H),2.18–2.08(m,2H).HRMS(ESI)calcd for C 19 H 17 ClN6O5[M+H] + :445.0949,found 445.1022.

[0395] Example 56: 4-(3-(isopropylcarbamoyloxy)pyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0396] The synthesis method and experimental procedures were the same as in Example 50, using 4-bromo-6-chloro-3-oxo-2,3-dihydropyridazine instead of 4-bromo-6-chloro-2-methyl-3-oxo-2,3-dihydropyridazine, to obtain a white solid with a yield of 55.6%. 1 H NMR (400MHz, DMSO-d6) δ12.48(s,1H),11.35(s,1H),11.27(s,1H),7.74(s,1H),7.12(d,J=7.7Hz,1H),6.56(s,1H),5.15(s,1H),3 .84(s,2H),3.60-3.52(m,2H),2.10–2.04(m,1H),2.03-1.98(m,1H),1.04(d,J=2.7Hz,3H),1.02(d,J=2.7Hz,3H).HRMS(ESI)calcd for C 16 H 20 N6O5[M+H] + :377.1495,found377.1566

[0397] Example 57: 4-(3-(4-cyanoanilinocarboxyloxy)-2,2-difluoropropylamino)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0398] The synthesis method and experimental procedures were the same as in Example 50, using 4-cyanophenyl isocyanate instead of isopropyl isocyanate, 3-hydroxy-2,2-difluoropropylamine instead of 3-hydroxypyrrolidine, and 4-bromo-6-chloro-3-oxo-2,3-dihydropyridazine instead of 4-bromo-6-chloro-2-methyl-3-oxo-2,3-dihydropyridazine, to obtain a white solid with a yield of 38.8%. 1 H NMR (400MHz, DMSO-d6) δ12.78(s,1H),11.29(s,1H),11.20(s,1H),10.49(s,1H),7.76(d,J=2.0Hz,1H),7.75 (d,J=2.0Hz,1H),7.68–7.61(m,3H),6.84(s,1H),4.49(t,J=14.1Hz,2H),3.80–3.70(m,2H).HRMS(ESI)calcd for C 19 H 15 F2N7O5[M+H] + :460.1103,found 460.1174.

[0399] Example 58: 4-(3-(isopropylcarbamoyloxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0400] The synthesis method and experimental procedures were the same as in Example 50, using 4-(4,4-difluoro-3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one instead of 4-(3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylpyridazin-3(2H)-one to obtain a white solid in 40.7% yield. 1H NMR (400MHz, DMSO-d6) δ12.64(s,1H),11.34(s,1H),11.22(d,J=5.9Hz,1H),7.70 (d,J=6.0Hz,1H),7.51(d,J=7.7Hz,1H),6.61(s,1H),5.32-5.27(m,1H),4.22–4.1 4(m,1H),4.11–4.03(m,1H),3.99-3.95(m,1H),3.70(d,J=12.6Hz,1H),3.64–3.56 (m,1H),1.07(d,J=2.1Hz,3H),1.05(d,J=2.2Hz,3H).MS(ESI)m / e:[M+H]+=413.13

[0401] Example 59: (S)-4-(3-(isopropylcarbamoyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0402] The 4-(3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one was replaced with (S)-4-(4,4-difluoro-3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylpyridazin-3(2H)-one was synthesized using the same method and experimental procedures as in Example 50, yielding a white solid in 41.9% yield. MS(ESI) m / e: [M+H]+=413.13

[0403] Example 60: 4-(3-(tert-butylaminoformoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0404] The synthesis method and experimental procedures were the same as in Example 50, using tert-butyl isocyanate instead of isopropyl isocyanate and 4-(4,4-difluoro-3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one instead of 4-(3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylpyridazin-3(2H)-one, yielding a white solid in 37.6% yield. 1H NMR (400MHz, DMSO-d6) δ12.64(s,1H),11.35(s,1H),11.25(s,1H),7.70(d,J=6.1Hz,1H),7.36(s,1H),6.61(s,1H ),5.27(s,1H),4.23–4.00(m,2H),3.99-3.94(m,1H),3.71-3.66(m,1H),1.23(s,9H).MS(ESI)m / e:[M+H]+=427.15

[0405] Example 61: (S)-4-(3-(tert-butylaminoformoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0406] The synthesis was performed using tert-butyl isocyanate instead of isopropyl isocyanate, and (S)-4-(4,4-difluoro-3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one instead of 4-(3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylpyridazin-3(2H)-one, following the same synthetic method and experimental procedures as in Example 50. A white solid was obtained in 34.9% yield. MS (ESI) m / e: [M+H]+ = 427.15

[0407] Example 62: 4-(3-(cyclopropylcarbamoyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0408] Cyclopropyl isocyanate was used instead of isopropyl isocyanate, and 4-(4,4-difluoro-3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one was used instead of 4-(3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylpyridazin-3(2H)-one was used instead of 4-(4,4-difluoro-3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylpyridazin-3(2H)-one. The synthesis method and experimental procedures were the same as in Example 50, yielding a white solid in 37.7%. 1H NMR (400MHz, DMSO-d6) δ12.65(s,1H),11.35(s,1H),11.25(d,J=6.2Hz,1H) ,7.78(d,J=3.2Hz,1H),7.71(d,J=6.1Hz,1H),6.62(s,1H),5.31(s,1H),4. 21-4.16(m,1H),4.11-4.05(m,1H),4.01-3.95(m,1H),3.70(d,J=12.6Hz,1 H),0.59(dd,J=6.8,2.6Hz,2H),0.42(q,J=3.7,3.2Hz,2H).HRMS(ESI)calcd for C 16 H 16 F2N6O5[M+H] + :411.1150,found 411.1237.

[0409] Example 63: (S)-4-(3-(bicyclo[2,2,2]octane-1-carbamoylamino)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0410] The isopropyl isocyanate was replaced with bicyclo[2,2,2]octane-1-yl isocyanate, and the 4-(3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one was replaced with (S)-4-(4,4-difluoro-3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylpyridazin-3(2H)-one was synthesized using the same method and experimental procedures as in Example 50. A white solid was obtained in 21.8% yield. MS (ESI) m / e: [M+H]+ = 479.18

[0411] Example 64: 4-(3-(cyclopentanamide)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0412] Cyclopentyl isocyanate was used instead of isopropyl isocyanate, and 4-(3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one was used instead of 4-(3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylpyridazin-3(2H)-one was used. The synthetic method and experimental procedures were the same as in Example 50, yielding a white solid in 36.5% yield.1 H NMR (400MHz, DMSO-d6) δ12.66(s,1H),11.36(s,1H),11.26(s,1H),7.72(d,J=6.1Hz,1H),7.62(d,J=7.2Hz,1H),6.63(s,1H),5.31(s,1H),4.24– 4.06(m,2H),34.00-3.95(m,1H),3.81-3.76(m,1H),3.74-3.69(m,1H),1 .81-1.75(m,2H),1.64-1.59(m,2H),1.49-1.36(m,4H).HRMS(ESI)calcd for C 18 H 20 F2N6O5[M+H] + :439.1463,found 439.1525.

[0413] Example 65: (S)-4-(3-(cyclopentanamide)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0414] Cyclopentyl isocyanate was used instead of isopropyl isocyanate, and (S)-4-(4,4-difluoro-3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one was used instead of 4-(3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylpyridazin-3(2H)-one was used. The synthetic method and experimental procedures were the same as in Example 50, yielding a white solid in 40.5% yield. MS (ESI) m / e: [M+H]+=439.15

[0415] Example 66: 4-(3-(cyclohexylaminocarboxyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0416] Cyclohexyl isocyanate was used instead of isopropyl isocyanate, and 4-(4,4-difluoro-3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one was used instead of 4-(3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylpyridazin-3(2H)-one was used. The synthetic method and experimental procedures were the same as in Example 50, yielding a white solid in 34.2% yield. 1H NMR (500MHz, DMSO-d6) δ12.67(s,1H),11.37(s,1H),11.30(s,1H),7.72(d,J=6.1Hz,1H),7.55(d, J=7.9Hz,1H),6.63(s,1H),5.30(s,1H),4.26–4.16(m,1H),4.15–4.06(m,1H),3.98(dd,J=13.2,5 .9Hz,1H),3.71(d,J=12.8Hz,1H),3.26(dt,J=14.7,5.5Hz,1H),1.79–1.71(m,2H),1.67-1.62(m, 2H),1.55-1.50(m,1H),1.25-1.20(m,2H),1.19–1.12(m,2H),1.07-1.02(m,1H).HRMS(ESI)calcd for C 19 H 22 F2N6O5[M+H] + :453.1620, found 453.1680.

[0417] Example 67: (S)-4-(3-(cyclohexylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0418] Cyclohexyl isocyanate was used instead of isopropyl isocyanate, and (S)-4-(4,4-difluoro-3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one was used instead of 4-(3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylpyridazin-3(2H)-one was used. The synthetic method and experimental procedures were the same as in Example 50, yielding a white solid in 37.5% yield. MS (ESI) m / e: [M+H]+=453.17

[0419] Example 68: (S)-4-(3-(cyclohexylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0420] Cyclohexyl isocyanate was used instead of isopropyl isocyanate, and (S)-4-(4,4-difluoro-3-aminopyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one was used instead of 4-(3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylpyridazin-3(2H)-one was used. The synthetic method and experimental procedures were the same as in Example 50, yielding a white solid in 40.5% yield. MS (ESI) m / e: [M+H]+=452.18

[0421] Example 69: 4-(3-(4-chloroanilinocarboxyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0422] The synthesis method and experimental procedures were the same as in Example 50, using 4-chlorophenyl isocyanate instead of isopropyl isocyanate and 4-(4,4-difluoro-3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one instead of 4-(3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylpyridazin-3(2H)-one, to obtain a white solid with a yield of 49.8%. 1 H NMR (400MHz, DMSO-d6) δ12.66 (s, 1H), 11.35 (d, J = 2.0Hz, 1H), 11.23 (dd, J = 6 .1,2.0Hz,1H),10.22(s,1H),7.70(d,J=6.0Hz,1H),7.51(s,1H),7.49(s,1H ),7.37(d,J=2.2Hz,1H),7.36(d,J=2.1Hz,1H),6.65(s,1H),5.48-5.44(m,1 H),4.20-4.14(m,2H),4.07-4.03(m,1H),3.91–3.84(m,1H).HRMS(ESI)calcd for C 19 H 15 ClF2N6O5[M+H]+:481.0761,found 481.0827.

[0423] Example 70: (S)-4-(3-(4-chloroanilinocarboxyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0424] The synthesis was performed using 4-chlorophenyl isocyanate instead of isopropyl isocyanate, and (S)-4-(4,4-difluoro-3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one instead of 4-(3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylpyridazin-3(2H)-one, following the same synthetic method and experimental procedures as in Example 50. A white solid was obtained in 52.3% yield. MS (ESI) m / e: [M+H]+ = 481.08

[0425] Example 71: 4-(3-(4-trifluoromethylanilinecarboxyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0426] The synthesis method and experimental procedures were the same as in Example 50, using 4-trifluoromethylphenyl isocyanate instead of isopropyl isocyanate and 4-(4,4-difluoro-3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one instead of 4-(3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylpyridazin-3(2H)-one, to obtain a white solid with a yield of 19.8%. 1 H NMR (500MHz, DMSO-d6) δ12.69(s,1H),11.37(s,1H),11.25(d,J=6.1Hz,1H),10.51(s,1H),7.71(d,J=6.1Hz,1H),7.69(s ,4H),6.66(s,1H),5.50(d,J=6.9Hz,1H),4.25-4.16(m,2H),4.08-4.03(m,1H),3.91(d,J=12.9Hz,1H).HRMS(ESI)calcd for C 20 H 15 F5N6O5[M+H]+:515.1024,found515.1087.

[0427] Example 72, (S)-4-(3-(4-trifluoromethylanilinecarboxyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0428] The synthesis was performed using 4-trifluoromethylphenyl isocyanate instead of isopropyl isocyanate, and (S)-4-(4,4-difluoro-3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one instead of 4-(3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylpyridazin-3(2H)-one, following the same synthetic method and experimental procedures as in Example 50. A white solid was obtained in 23.3% yield. MS (ESI) m / e: [M+H]+=515.11

[0429] Example 73: (S)-4-(3-(4-fluoroanilinecarbamoylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0430] The synthesis was performed using 4-fluorophenyl isocyanate instead of isopropyl isocyanate, and (S)-4-(4,4-difluoro-3-aminopyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one instead of 4-(3-hydroxypyrrolidone-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methylpyridazin-3(2H)-one, following the same synthetic method and experimental procedures as in Example 50. A white solid was obtained in 27.3% yield. MS (ESI) m / e: [M+H]+ = 464.12

[0431] Example 74: 4-(3-(5-cyanopyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0432] By replacing 1-Boc-3-hydroxypyrrolidine with 1-Boc-3-hydroxy-4,4-difluoropyrrolidine and 4-cyanobenzyl bromide with 5-cyano-2-chloropyridine, and following the synthetic method and experimental procedures as described in Example 1, 4-(3-(5-cyanopyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine white solid was obtained in 11.5% yield. 1H NMR (500MHz, DMSO-d6) δ12.69(s,1H),11.36(s,1H),11.28(d,J=5.1Hz,1H),8.78(d,J=2.3Hz,1H),8.27(dd,J=8.7,2.3Hz,1H),7 .72(d,J=6.1Hz,1H),7.19(d,J=8.7Hz,1H),6.66(s,1H),5.90(s,1H),4.32-4.16(m,3H),3.86(d,J=12.7Hz,1H).HRMS(ESI)calcd for C 18 H 13 F2N7O4 430.0997, found 430.1076.

[0433] Example 75: (R)-4-(3-(3-chloro-4-cyanoanilinecarboxyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0434] Replacing 3-(4-cyanobenzoxy)-4,4-difluoropyrrolidine with (R)-3-(3-chloro-4-cyanoanilinoyl)-4,4-difluoropyrrolidine, and following the synthetic method and experimental procedures as described in Example 1, (R)-4-(3-(3-chloro-4-cyanobenzoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid, was obtained in yield of 33.5%. MS (ESI) m / e: [M+H]+=490.08

[0435] Example 76: (R)-4-(3-(4-cyanoanilinoyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine

[0436] Replacing 3-(4-cyanoanilinoyl)-4,4-difluoropyrrolidine with (R)-3-(4-cyanobenzyloxy)-4,4-difluoropyrrolidine, the synthesis method and experimental procedures were as described in Example 1, yielding (R)-4-(3-(4-cyanoanilinoyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine, a white solid with a yield of 35.1%. MS (ESI) m / e: [M+H]+=456.12

[0437] In vitro bioactivity evaluation

[0438] CD73 AMP-Glo TM Combined experiment

[0439] The in vitro molecular-level activity evaluation of the compounds was performed using the CD73 binding assay by Beijing Aisiyipu Technology Co., Ltd. CD73 enzyme activity was determined using the AMP-Glo ​​chemiluminescence detection method.

[0440] Experimental Procedure: The compound was serially diluted with DMSO in 384-well polypropylene compound dilution plates. 40 nanoliters of the compound were transferred to 384-well reaction microplates (Greiner, 784075) using an automated nanoparticle transfer system, Echo (LABCYTE, 655), ensuring a final DMSO concentration of 1% (double replicate). 4 μL of 2X CD73 solution (final concentration: 0.003 nM) was added to each well of the 384-well reaction microplate, and the plates were centrifuged at 1000 rpm for 1 minute. The plates were incubated at 25°C for 10 minutes. 4 μL of 2X AMP solution (final concentration: 5 μM) was added to each well, and the plates were centrifuged at 1000 rpm for 1 minute. The plates were incubated at 25°C for 120 minutes. 4 μL of AMP-Glo ​​Reagent I reagent was added to each well, and the plates were centrifuged at 1000 rpm for 1 minute. The plates were incubated at 25°C for 40 minutes. Add 8 μL of AMP-Glo ​​reagent II to each well, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes. Read the RLU (Relative Luminescence Unit) signal on a BMG (PHERAstar FSX) microplate reader. Wells containing 1% DMSO and the enzyme served as the high signal control, and wells containing 1% DMSO and AMP buffer served as the low signal control. The inhibition percentage of the compound-treated wells was normalized between the high and low signal control groups (% inhibition rate = (average high signal control wells - Ratio compound-treated well readings) / (average high signal control wells - average low signal control wells) * 100). Then, a four-parameter IC500 was fitted using XLfit 5.5.0. 50 Curve analysis, IC 50 This is the compound concentration corresponding to an inhibition rate of 50%.

[0441] Table 1. Inhibitory activity of the title compounds of the examples against CD73 at the enzyme level.

[0442] In the table, A represents less than or equal to 10 nM; B represents greater than 10 nM and less than or equal to 50 nM; and C represents greater than 50 nM and less than 500 nM.

[0443] Selective test

[0444] Experimental reagents and consumables

[0445] Experimental procedure:

[0446] 1) Dilute the test compound to 10 concentrations starting from 20 μM using DMSO. Take 24 μL of the compound and add it to 36 μL of buffer for a 3-fold dilution.

[0447] 2) Transfer 20 nL of the analyte to a 384 reaction plate using an Echo, with two replicates for each compound. Centrifuge at 1000 rpm for 1 minute. The final concentration of DMSO is 0.5%.

[0448] 3) Add 2 μL of NTPDase 1 to the 384 reaction plate and centrifuge at 1000 rpm for 1 minute.

[0449] 4) Add 2 μL of ATP to a 384 reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 37°C for 60 minutes.

[0450] 5) Add 4 μL of Reagent I to the 384 reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes.

[0451] 6) Add 8 μL of Reagent II to a 384 reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes.

[0452] 7) Read the Luminescence signal using the BMG high-throughput drug screening multi-functional microplate reader.

[0453] 8) Set the reading for the negative control (0.5% DMSO wells) to 0% inhibition rate and the reading for the positive control (positive drug wells) to 100% inhibition rate, and calculate the inhibition rate for each test solution. Use a nonlinear fitting formula to obtain the IC50 of the compound. 50 Value: Y = Bottom + (Top - Bottom) / (1 + 10) ^ ((LogIC 50 -X)*HillSlope)). X: compound concentration log value; Y: compound inhibition rate (%inh).

[0454] Selectivity results of compounds in some examples for related extracellular nucleotidases

Claims

1. A class of oxoaromatic heterocyclic derivatives of Formula I, their stereoisomers, and their pharmaceutically usable salts; In the formula: R1 is selected from hydrogen or methyl; R2 is selected from X and Y are arbitrarily selected from CH, N, and CF, respectively; R3 is selected from in: R4 is selected from hydrogen, Wherein R is selected from hydrogen, halogen, cyano, hydroxy, trifluoromethyl, hydroxymethyl, acetyl, trifluoroacetyl, ethynyl, vinyl, hydroxyethyl, amino, acetamido, hydroxyformyl, C1-C6 alkoxyformyl, nitro, methanesulfonyl, aminosulfonyl, carbamoyl, C1-C6 alkylaminoformyl, substituted C1-C6 alkyl, substituted C3-C10 cycloalkyl, substituted C1-C6 alicyclic, substituted C5-C10 aryl, substituted C1-C6 aromatic heterocyclic, substituted C1-C6 alkoxy, substituted C1-C6 alkylamino. The substituted C3-C10 cycloalkoxy group, substituted C3-C10 cycloalkylamino group, substituted C1-C6 aromatic heterocyclic oxy group, substituted C1-C6 aromatic heterocyclic amino group, substituted C1-C6 aliphatic heterocyclic oxy group, substituted C1-C6 aliphatic heterocyclic amino group, substituted C1-C6 alkoxycarbamoyl group, substituted C1-C6 alkylcarbamoyl group, wherein the substituents include hydrogen, halogen, cyano, hydroxyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, amino, acetamido, hydroxycarbamoyl, oxo, methanesulfonyl, aminosulfonyl, carbamoyl, and when there are multiple substitutions, R can be the same or different; n is selected from 1, 2, 3, 4, and 5.

2. The class of oxoaromatic heterocyclic derivatives and their pharmaceutically usable salts according to claim 1, characterized in that, The "C1-C6 alkyl" includes methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, neopentyl, and hexyl; the "C1-C6 alkoxy" includes methoxy, ethoxy, isopropoxy, propoxy, tert-butoxy, butoxy, isopentoxy, and pentoyloxy; the "C1-C6 alkylamino" includes methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, tert-butylamino, pentoamino, and neopentylamino; the halogens include fluorine, chlorine, and bromine; the "cycloalkanes" also include fused and spirocyclic polycyclics, such as adamantane, bicyclo[2,2,2]octane, and bicyclo[1,1,1]pentane; the "aliphatic heterocycles" also include fused and spirocyclic heterocycles; aliphatic heterocycles or aromatic heterocycles refer to a ring containing at least one heteroatom of nitrogen, oxygen, or sulfur.

3. A class of oxoaromatic heterocyclic derivatives and their pharmaceutically usable salts according to claim 1, characterized in that, The R2 mentioned is selected from General Formula II is obtained In the formula, the definitions of R1, R3, R4, R, X, Y, and n are the same as in claim 1.

4. A class of oxoaromatic heterocyclic derivatives and their stereoisomers and pharmaceutically acceptable salts according to any one of claims 1-3, wherein the compounds include, but are not limited to, the following compounds: 4-(3-(2-fluoro-4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine (S)-4-(3-(4-cyanobenzyloxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2,5-difluoro-4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-fluoro-4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-chloro-4-cyanobenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-cyanophenyl-difluoromethoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-trifluoromethylbenzyloxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-fluoro-4-trifluoromethylbenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-chloro-4-trifluoromethylbenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-fluoro-4-trifluoromethylbenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-trifluoromethylphenyl-difluoromethoxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-fluoro-4-difluoromethylbenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-chloro-4-difluoromethylbenzyloxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-difluoromethylbenzyloxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-difluoromethylphenyl-difluoromethoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-difluorochloromethylphenyl-difluoromethoxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-difluoromethylpyridin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-trifluoromethylpyridin-2-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-fluoro-5-trifluoromethylpyridin-2-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-trifluoromethylpyridin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-fluoro-6-trifluoromethylpyridin-3-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-chloro-6-trifluoromethylpyridin-3-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-amino-6-trifluoromethylpyridin-3-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-hydroxy-6-trifluoromethylpyridin-3-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyanopyridin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-amino-6-cyanopyridin-3-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-fluoro-6-cyanopyridin-3-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-fluoro-3-cyanopyridin-6-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-chloro-3-cyanopyridin-6-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-acetylbenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-hydroxyformylbenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-methoxycarboxybenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-carbamoylbenzyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-cyanopyridin-2-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-cyanopyrazin-2-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-cyanopyridazine-6-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-cyanopyrimidine-2-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyanopyrimidine-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-aminopyridin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-N,N-dimethylaminopyridin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-chloro-5-trifluoromethylpyridin-2-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyanopyridin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-difluoromethylpyridin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-trifluoromethyl-4-chloropyridin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-trifluoromethyl-4-fluoropyridine-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-trifluoromethylpyrimidin-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-trifluoromethylpyrazine-5-methoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-trifluoromethylphenoxymethyl)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-carboxyphenoxymethyl)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-carbamoylphenoxymethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-nitrophenoxymethyl)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-cyanophenoxymethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-cyanopyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-cyanopyrimidine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-amino-5-cyanopyrimidine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-methoxy-5-cyanopyrimidine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-methoxy-5-cyanopyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-trifluoromethyl-5-cyanopyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-methyl-5-cyanopyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-fluoro-5-cyanopyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-amino-3-cyanopyridin-6-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-N,N-dimethylamino-3-cyanopyridin-6-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-hydroxy-3-cyanopyridin-6-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-trifluoromethylpyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-trifluoromethylpyrimidin-2-oxomethyl)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-methylamino-5-trifluoromethylpyrimidin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-methoxy-5-trifluoromethylpyrimidin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-chloro-5-trifluoromethylpyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-fluoro-5-trifluoromethylpyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-fluoro-5-trifluoromethylpyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-difluoromethylpyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-boronic acid-5-trifluoromethylpyridin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-trifluoromethylpyrazine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-oxo-5-trifluoromethyl-1H-pyrimidin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-chloropyrimidin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-methylpyrimidin-2-oxomethyl)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-hydroxymethylpyrimidin-2-oxomethyl)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-cyanopyrazin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-cyano-6-methoxypyrazine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-cyano-6-aminopyrazine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-ethynylpyrazin-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-acetylpyrazine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-carbamoylpyrazine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-hydroxyformylpyrazine-2-oxomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-trifluoromethylphenoxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-cyanophenoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-nitrophenoxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-acetylphenoxy)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-methanesulfonylphenoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-cyanopyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-trifluoromethyl-5-cyanopyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-methoxy-5-cyanopyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-fluoro-5-cyanopyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-trifluoromethylpyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-fluoro-5-trifluoromethylpyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-methoxy-5-trifluoromethylpyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-amino-5-trifluoromethylpyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-fluoro-5-trifluoromethylpyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-fluoro-5-trifluoromethylformylpyridin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-trifluoromethylpyridin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-difluoromethyl-4-oxo-1H-pyridin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-trifluoromethyl-4-methylpyridin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyano-3-methylpyridin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyanopyridin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-carboxypyridin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-methoxypyridin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-acetylpyridin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-trifluoromethylpyrazine-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-alkynylpyrazin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyanopyrazin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-carbamoylpyrazine-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-carboxypyrazin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyano-3-aminopyrazine-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-acetylpyrazin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-trifluoromethylpyrimidin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-cyanopyrimidin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-amino-5-cyanopyrimidine-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-methoxy-5-cyanopyrimidine-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-carbamoylpyrimidin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-carboxypyrimidin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-alkynylpyrimidin-2-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyanopyrimidin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-alkynylpyrimidin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-trifluoromethylpyrimidin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-difluoromethylpyrimidin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-methoxypyrimidin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-carboxypyrimidin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(pyrimidin-5-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(pyridin-4-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(1-oxopyridin-4-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-chloropyridazine-6-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-cyanopyridazin-6-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-trifluoromethylpyridazine-6-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-carboxypyridazine-6-oxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-cyanoanilino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-cyanopyridin-2-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyanopyridin-5-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyanopyrimidine-5-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyanopyrazin-5-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-cyanopyrimidine-2-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-cyanopyridazine-6-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-trifluoromethylpyridazine-6-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-trifluoromethylphenylamino)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-trifluoromethylpyridin-5-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-trifluoromethylpyridin-2-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-trifluoromethylpyrazine-5-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-trifluoromethylpyrimidin-5-amino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-cyanobenzylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-trifluoromethylbenzylamino)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-alkynylbenzylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-fluoro-4-cyanobenzylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-fluoro-4-cyanobenzylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyanopyridin-5-methylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyano-3-fluoropyridine-5-methylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-alkynylpyridin-5-methylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyanopyrimidine-5-methylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyanopyrazin-5-methylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyanopyrazin-5-aminomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-cyanopyridin-2-aminomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-cyanophenylaminomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-cyanopyridazine-6-aminomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-cyanopyrimidine-2-aminomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyanopyrimidine-5-aminomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-trifluoromethylpyrazine-5-aminomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-trifluoromethylpyridin-2-aminomethyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(tert-butylaminoformoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(cyclopentanamide)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(cyclohexylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(bicyclo[1,1,1]pentan-1-carbamoyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(adamantaneaminoformoxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(bicyclo[2,2,2]oct-1-carbamoyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(cyclopentanamide)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(cyclohexylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(adamantaneamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(tert-butylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(bicyclo[1,1,1]pentan-1-carbamoylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(bicyclo[2,2,2]oct-1-carbamoylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-trifluoromethylpyridin-5-carbamoyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-trifluoromethylpyrimidin-5-carbamoyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-trifluoromethylphenylcarbamoyl)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-trifluoromethylbenzoylamino)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-fluoro-4-cyanobenzoamide)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-cyanoanilinoyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(pyrrolidine-1-formyloxy)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-cyanobenzamido)-4,4-difluoropyrrolidone-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-fluoro-4-cyanobenzoamido)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-fluoro-4-cyanobenzoamido)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-chloro-4-cyanobenzamido)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-cyanopyridin-2-carbamate)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-cyanopyrazin-2-carbamate)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyanopyridin-5-carbamate)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyanopyrimidine-5-carbamate)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(4-cyanoanilinoyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-fluoro-4-cyanoanilinecarboxyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-fluoro-4-cyanoanilinecarboxyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(3-chloro-4-cyanoanilinecarboxyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-cyanopyridin-2-carbamoyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-cyanopyrazin-2-carbamoyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyanopyridin-5-carbamoyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(2-cyanopyrimidin-5-carbamoyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxo-2,3-dihydropyridazine 4-(3-(5-cyanopyrimidine-2-carbamoyl)-4,4-difluoropyrrolidine-1-yl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl)-3-oxo-2,3-dihydropyridazine 5. A class of oxoaromatic heterocyclic derivatives and their stereoisomers and their pharmaceutically usable salts according to any one of claims 1-4, characterized in that, The medicinal salts include salts formed by combining with inorganic acids, organic acids, alkali metal ions, alkaline earth metal ions, or organic bases that can provide physiologically acceptable cations, as well as ammonium salts. The inorganic acids are selected from hydrochloric acid, hydrobromic acid, phosphoric acid, or sulfuric acid; the organic acids are selected from methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, citric acid, maleic acid, tartaric acid, fumaric acid, citric acid, or lactic acid; the alkali metal ions are selected from lithium ions, sodium ions, and potassium ions; the alkaline earth metal ions are selected from calcium ions and magnesium ions; and the organic bases that can provide physiologically acceptable cations are selected from methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris(2-hydroxyethyl)amine.

6. A method for preparing the class of oxoaromatic heterocyclic derivatives and their stereoisomers and pharmaceutically acceptable salts as described in any one of claims 1-4, wherein the synthetic route is as follows: In step (a), compound 1 is used as a raw material and undergoes a nucleophilic substitution reaction with compound R3H under an alkaline environment to generate compound 2 containing R3 substitution; in step (b), compound 2 undergoes a coupling reaction with R2-based boric acid R2B(OH)2 under a palladium catalytic environment to obtain target compound I containing R2 groups.

7. A method for preparing the class of oxoaromatic heterocyclic derivatives and their pharmaceutically acceptable salts as described in claims 1-4, wherein R2 is hour, Its characteristic synthetic route is as follows: (1) In step (a), using compound 1 as a raw material, compound R3H undergoes a nucleophilic substitution reaction with compound 1 under alkaline conditions to generate substituted compound 2; in step (b), under the action of palladium catalyst, compound 2 undergoes a coupling reaction with boric acid compound 3 to generate compound 4. In step (c), under acidic conditions, such as hydrochloric acid or boron tribromide, compound 4 undergoes demethylation and rearrangement to generate target compound II; (2) In step (a), compound 1 is used as a starting material and undergoes a nucleophilic substitution reaction with compound 5 under alkaline conditions to generate compound 6; in step (b), compound 6 undergoes a coupling reaction with compound 3 containing boric acid under palladium catalysis to obtain compound 7; in step (c), the hydroxyl group in compound 7 undergoes a nucleophilic substitution reaction with R4Br or R4Cl to generate compound 8; in step (d), the hydroxyl group in compound 6 undergoes a nucleophilic addition reaction with isocyanate R4NCO to generate compound 9; in step (e), under acidic conditions, such as hydrochloric acid or boron tribromide, compounds 8 and 9 are demethylated and rearranged to obtain target compound II; (3) In step (a), compound 1 is used as a starting material and undergoes a nucleophilic substitution reaction with compound 10 under alkaline conditions to generate compound 11; in step (b), under palladium catalysis, compound 11 undergoes a coupling reaction with compound 3 containing boric acid, and then loses Boc under acidic conditions to obtain compound 12; in step (c), the amino group in compound 12 undergoes a nucleophilic substitution reaction with R4Br or R4Cl to generate compound 13; in step (d), the amino group in compound 12 undergoes a nucleophilic addition reaction with R4NCO to generate compound 14; in step (e), under acidic conditions, such as hydrochloric acid or boron tribromide, compounds 13 and 14 are demethylated and rearranged to obtain target compound II; The definitions of R1, R2, R3, R4, X, and Y are the same as those of any one of claims 1-4.

8. A pharmaceutical composition, characterized in that, A class of oxoaromatic heterocyclic derivatives containing any one of claims 1-4, their stereoisomers, their pharmaceutically acceptable salts, and their pharmaceutically acceptable carriers.

9. The use of any one of the oxoaromatic heterocyclic derivatives of claims 1-4, their stereoisomers, and their pharmaceutically acceptable salts in the preparation of medicaments for the prevention and / or treatment of diseases related to CD73.

10. The application according to claim 9, characterized in that, The diseases associated with CD73 include those related to tumors, inflammation-related diseases, immune-related diseases, nervous system diseases, neurodegenerative diseases, central nervous system diseases, depression, Parkinson's disease, sleep disorders and fibrosis, and ischemic diseases of the brain and heart.

11. The application according to claim 9, characterized in that, The tumors mentioned are selected from liver cancer, kidney cancer, lung cancer, pancreatic cancer, stomach cancer, gallbladder cancer, colorectal cancer, colon cancer, bladder cancer, breast cancer, bile duct cancer, ovarian cancer, prostate cancer, thyroid cancer, leukemia, lymphoma, squamous cell carcinoma, glioblastoma, head and neck cancer, medulloblastoma, melanoma, glioma, and head and neck cancer.

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