Derivative as CD73 inhibitor and use thereof

Abstract

The present invention relates to a derivative as a CD73 inhibitor and a use thereof. Specifically, the present invention relates to a compound represented by formula I, a pharmaceutical composition containing the compound of formula I, and a use of the compound in the preparation of a drug for treating CD73-related diseases or inhibiting CD73.

Description

Derivatives of cd73 inhibitors and uses thereof TECHNICAL FIELD

[0001] The present invention relates to the field of medicinal chemistry; in particular, the present invention novel compounds, methods for their synthesis and their use as CD73 inhibitors in the preparation of medicaments for tumor-related diseases. BACKGROUND

[0002] Adenosine modulates the function of immune and inflammatory cells in a paracrine and autocrine manner by activating adenosine receptors expressed by tumor cells, endothelial cells or immune cells. Such as macrophages, dendritic cells, myeloid suppressor cells, T cells and natural killer cells (NK cells). ADO interferes with cell proliferation, apoptosis and angiogenesis. It makes the tumor microenvironment immunologically tolerant and plays a promoting role in the development of tumors.

[0003] Studies have shown that in vivo inhibition of CD73 can significantly inhibit extracellular adenosine levels. The production of extracellular adenosine is mainly due to the synergistic effect of CD39 and CD73. CD73 is a membrane-associated enzyme that is fixed on the cell surface by glycosylated phosphatidylinositol (GPI) at the C-terminal. It is ubiquitous in lymphocytes, endothelial cells and epithelial cells, and is highly expressed in the colon, kidney and brain. In normal tissues, acute elevation of adenosine dependent on CD73 expression is mainly used to protect ischemic and inflammatory tissues, and plays a physiological role in ion transport, barrier function maintenance, endothelial cell homeostasis and myocardial protection. In different tissues and cell types, CD73 can be shed from the membrane by phosphatidylinositol-specific phospholipase or proteolytic enzymes to produce soluble CD73 that retains catalytic activity. The protein is composed of two identical polypeptide chains, which form a non-covalent homodimer through a hinge, and the dimer exists in both open and closed conformations, with the conformation being changed by the rotation of the domain. First, extracellular adenosine triphosphate (ATP) is hydrolyzed to adenosine monophosphate (AMP) by CD39. CD73 catalyzes the synthesis of adenosine and phosphate. Adenosine triphosphate is a pro-inflammatory mediator. The dynamic balance of extracellular ATP and adenosine is an important part of immune homeostasis. Damaged and dying cells release adenosine triphosphate, which activates immune cells by binding to P2X and P2Y purinergic receptors, producing pro-inflammatory effects. Adenosine deaminase (ADA) is a negative regulator that can cause rapid inactivation of adenosine. Therefore, the adenosine balance maintained by the extracellular CD39-CD73-ADA system is crucial for maintaining immune balance. However, when there are malignant tumors or cells in the body, extracellular ATP is hydrolyzed to adenosine by CD39 and CD73 in large amounts, beyond the scope of ADA hydrolysis, which leads to a sustained increase in adenosine levels. In turn, adenosine limits the pro-apoptotic effects of extracellular ATP and affects the immune activity of immune cells in the body. This helps the growth, metastasis and survival of tumors and induces immune escape of tumor cells. Therefore, CD39 and CD73 have become popular targets for tumor treatment. Research on their inhibitors is increasing.

[0004] However, the research on CD39 inhibitors is less than that on CD73 inhibitors as a target for tumor inhibiting drugs. This may be due to the expression characteristics of CD39 in non-tumor cells limiting the effective anti-tumor targeting of CD39 inhibitors. There are also studies showing that the activity of CD39 is reversible in the presence of nucleoside diphosphate kinase (NDPK) and adenosine kinase. In contrast, the activity of CD73 is almost irreversible. Therefore, CD73 has become a key target for causing immunosuppression, and its inhibition is also considered a better method for tumor treatment. SUMMARY

[0005] The present application provides a compound represented by general formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof:

[0006] It is another object of the present application to provide pharmaceutical compositions comprising the above-mentioned compounds.

[0007] It is yet another object of the present application to provide use of the above-mentioned compounds in the manufacture of a medicament for treating CD73 associated diseases or inhibiting CD73.

[0008] In a first aspect, the present application provides a compound of general formula I:

[0009] wherein,

[0010] A is an optionally substituted phenyl ring, a 5 or 6 membered nitrogen, oxygen and sulfur containing heterocyclic ring;

[0011] M is an optionally substituted C8-C12 aryl or heteroaryl or heterocyclyl group;

[0012] Z1is selected from the group consisting of O, S, CR1R2or NR3, wherein R1, R2and R3are independently selected from the group consisting of: hydrogen, halogen, optionally substituted C1-C10alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C5-C6aryl, optionally substituted C5-C6heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O or S;

[0013] Z2is selected from the group consisting of CR4or N, wherein R4is hydrogen, halogen, optionally substituted C1-C10alkyl, optionally C3-C8cycloalkyl, optionally substituted C5-C6aryl, optionally substituted C5-C6heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O or S;

[0014] X is selected from CR5R6, NR7, O, S, carbonyl, sulfone or sulfoxide, wherein R5, R6and R7are independently selected from the group consisting of: H, halogen, optionally substituted C1-C10alkyl, optionally substituted C3-C8cycloalkyl;

[0015] Y is selected from CR8R9, NR 10 , O, S, carbonyl, sulfone or sulfoxide, wherein R8, R9and R 10 are independently selected from the group consisting of: H, halogen, optionally substituted C1-C10alkyl, optionally substituted C3-C8cycloalkyl; CH2, NH, O, S, carbonyl, sulfone or sulfoxide;

[0016] Q1and Q2are each independently selected from the group consisting of hydrogen, optionally substituted C1-C10alkyl (including but not limited to hydroxymethyl, hydroxyethyl, optionally substituted (e.g., deuterated) C1-C3alkoxymethyl, optionally substituted C1-C3alkoxyethyl), optionally substituted C3-C8cycloalkyl, optionally substituted C5-C6aryl, optionally substituted C5-C6heterocyclyl, optionally substituted phenyl C1-C5alkyl, optionally substituted C5-C6heterocyclyl C1-C5alkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, hydroxyl, optionally substituted C1-C3formyl (including but not limited to hydroxyformyl, C1-C3alkoxycarbonyl);

[0017] W1and W2are independently selected from the group consisting of NH, O, or S;

[0018] P1is H, optionally substituted C8-C12aryl and optionally substituted C8-C12aromatic heterocyclyl, optionally substituted C1-C10alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C1-C10alkylcarbonyloxymethyl; or, W1P1together constitutes an amino acid linked by a phosphoramidate linkage, an esterified amino acid linked by a phosphoramidate linkage, a phosphoric acid prodrug group;

[0019] P2is H, optionally substituted C8-C12aryl and optionally substituted C8-C12aromatic heterocyclyl, optionally substituted C1-C10alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C1-C10alkylcarbonyloxymethyl; W2P2together constitutes an amino acid linked by a phosphoramidate linkage, an esterified amino acid linked by a phosphoramidate linkage, a phosphoric acid prodrug group;

[0020] or P1, P2may form an optionally substituted 5-8 membered cyclic ether, lactone, lactam.

[0021] In a specific embodiment, the compound is as shown in Formula II:

[0022] wherein M, Z1, Z2, X, Y, Q1, Q2, W1, W2, P1, P2are as described above.

[0023] In a specific embodiment, the compound is as shown in Formula III:

[0024] wherein M, Q1, Q2, W1, W2, P1, P2are as described above.

[0025] In a preferred embodiment, M is as shown below:

[0026] wherein B is an optionally substituted C5-C6aromatic ring, an optionally substituted C5-C6heterocyclic ring containing N, O, or S;

[0027] A1, A2, A3, A4, A5 are each independently selected from CH or N;

[0028] R3 is selected from the group consisting of H, halogen (F, Cl or Br), nitro, cyano, optionally substituted C1-C10 alkyl (e.g. trifluoromethyl, hydroxymethyl), optionally substituted C3-C8 cycloalkyl, optionally substituted C5-C6 heterocyclyl C1-C5 alkyl (e.g. benzyl), optionally substituted C1-C5 alkoxy, optionally substituted C1-C5 alkoxycarbonyl, optionally substituted amino, optionally substituted C1-C5 alkylcarboxamido;

[0029] n is an integer selected from 1-5; preferably 1-3.

[0030] In a particular embodiment, the compound is as shown in Formula IV:

[0031] wherein B is an optionally substituted C5-C6 aromatic ring, an optionally substituted N-, O- or S-containing C5-C6 heterocyclic ring;

[0032] A1, A2, A3, A4, A5 are each independently selected from CH or N;

[0033] R3 is selected from the group consisting of H, halogen (F, Cl or Br), nitro, cyano, optionally substituted C1-C10 alkyl (e.g. trifluoromethyl, hydroxymethyl), optionally substituted C3-C8 cycloalkyl, optionally substituted C5-C6 heterocyclyl C1-C5 alkyl (e.g. benzyl), optionally substituted C1-C5 alkoxy, optionally substituted C1-C5 alkoxycarbonyl, optionally substituted amino, optionally substituted C1-C5 alkylcarboxamido;

[0034] n is an integer selected from 1-5; preferably 1-3.

[0035] Q1, Q2, W1, W2, P1, P2 are as described above.

[0036] In a particular embodiment, the compound is as shown in Formula V:

[0037] wherein A1, R3, Q1, Q2, W1, W2, P1, P2 and n are as described above.

[0038] In a particular embodiment, the present application provides a compound selected from the group consisting of:

[0039] Preferably, the compound is selected from the group consisting of:

[0040] In a second aspect, the present application provides a pharmaceutical composition comprising a compound of the first aspect, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0041] In preferred embodiments, the pharmaceutical composition is a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, powders.

[0042] In a third aspect, the present application provides use of a compound of the first aspect in the manufacture of a CD73 inhibitor.

[0043] In particular embodiments, the CD73 inhibitor is a medicament for treating or preventing a CD73-mediated disease, or inhibiting CD73.

[0044] In particular embodiments, the CD73-mediated disease is cancer.

[0045] In particular embodiments, the cancer is selected from the group consisting of breast cancer, multiple myeloma, bladder cancer as preferred, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumor, cholangiocellular carcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, schwannoma, lung squamous cell carcinoma, keratosis actinica, synovial sarcoma, skin cancer, adenocarcinoma, testicular cancer, or liposarcoma.

[0046] In a fourth aspect, the present application provides a method of treating or preventing a CD73-mediated disease, the method comprising administering to a subject in need of treatment or prevention of a CD73-mediated disease a therapeutically or prophylactically effective amount of a compound of the first aspect or a pharmaceutical composition of the second aspect.

[0047] In preferred embodiments, the CD73-mediated disease is cancer.

[0048] In preferred embodiments, the cancer includes but is not limited to breast cancer, multiple myeloma, bladder cancer as preferred, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumor, cholangiocellular carcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, schwannoma, lung squamous cell carcinoma, keratosis actinica, synovial sarcoma, skin cancer, adenocarcinoma, testicular cancer, or liposarcoma.

[0049] It should be understood that, within the scope of the present application, each of the technical features of the present application described above and each of the technical features specifically described hereinafter (e.g., in the examples) can be combined with each other to form a new or preferred technical solution. Due to the limited space, they will not be listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0050] Figure 1 shows the flow of in vivo pharmacodynamic evaluation;

[0051] Figure 2 shows the results of cytotoxicity evaluation of compounds 16, 31, 33 on HEK293 and L02. DETAILED DESCRIPTION

[0052] After extensive and in-depth research, the present inventors first accidentally discovered a structurally novel compound with CD73 inhibitory activity; the compound has excellent inhibitory activity on CD73; thus, it lays a new material foundation for the development of drugs that can inhibit CD73, has great industrialization and commercialization prospects and market value, and has significant economic benefits. On this basis, the present application is completed.

[0053] TERMINOLOGY

[0054] Some of the groups referred to herein are defined as follows:

[0055] Herein, "alkyl" refers to a saturated branched or straight chain or cyclic alkyl group having a carbon chain length of 1-10 carbon atoms, preferably alkyl includes alkyl having 1-5, 1-2, 1-6, 1-4, 3-8 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, heptyl, etc. The alkyl group can be substituted with one or more substituents, such as halogen or haloalkyl. For example, the alkyl group can be an alkyl group substituted with 1-4 fluorine atoms, or the alkyl group can be an alkyl group substituted with a fluoroalkyl group.

[0056] Herein, "alkenyl" generally refers to a monovalent hydrocarbon group having at least one double bond, typically containing 2-8 carbon atoms, preferably containing 2-6 carbon atoms, which can be straight or branched. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, etc.

[0057] Herein, "ester" generally refers to a carboxylic acid derivative having at least one ester group, typically containing 3-8 carbon atoms, preferably containing 3-6 carbon atoms, which can be straight or branched. Examples of ester include, but are not limited to, methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, etc.

[0058] As used herein, "hydroxy" refers to a branched or straight chain alcohol having a carbon chain length of 1 to 10 carbon atoms, typically having 1 to 10 carbon atoms, preferably having 1 to 6 carbon atoms, which can be straight or branched. Examples of ester hydroxy groups include, but are not limited to, 1-hydroxy n-butyl, 1-hydroxy iso-butyl, and the like.

[0059] As used herein, "amido" refers to a group of the formula "-R'-NH-C(O)-R" wherein R' can be selected from hydrogen or alkyl, and R can be selected from alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, halo-substituted alkyl, cyano-substituted alkenyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl. c R d substituted alkyl, substituted alkenyl, substituted alkynyl, halo-substituted alkyl, cyano-substituted alkenyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl. c R d substituted alkyl, substituted alkenyl, substituted alkynyl, halo-substituted alkyl, cyano-substituted alkenyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl. c R d substituted alkyl, substituted alkenyl, substituted alkynyl, halo-substituted alkyl, cyano-substituted alkenyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl. c R d may be selected from alkyl and alkenyl.

[0060] As used herein, "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic group having 6 to 14 carbon atoms, including phenyl, naphthyl, phenanthryl, anthryl, indenyl, fluorenyl, tetrahydronaphthyl, dihydroindenyl, and the like. The aryl group can be optionally substituted with 1 to 5 (e.g., 1, 2, 3, 4, or 5) substituents selected from halo, C 1-4 aldehyde, C 1-6 alkyl, cyano, nitro, amino, amido, hydroxy, hydroxymethyl, halo-substituted alkyl (e.g., trifluoromethyl), halo-substituted alkoxy (e.g., trifluoromethoxy), carboxy, C 1-4 alkoxy, carbethoxy, N(CH3), and C 1-4 acyl, and the like, heterocyclyl, or heteroaryl, and the like.

[0061] As used herein, "heterocyclyl" includes, but is not limited to, 5- or 6-membered heterocyclic groups containing 1 to 3 heteroatoms selected from O, S, or N, including, but not limited to, furanyl, thienyl, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, piperidinyl, morpholinyl, and the like.

[0062] As used herein, "aromatic heterocyclyl" refers to a ring system containing 5 to 14 ring atoms, and having 6, 10, or 14 electrons shared in the ring system. Further, the ring atoms contained are carbon atoms and optionally 1 to 3 heteroatoms from oxygen, nitrogen, and sulfur. Useful aromatic heterocyclyl groups include piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, thienyl, furanyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, and the like. The aromatic heterocyclyl group can be optionally substituted with 1 to 5 (e.g., 1, 2, 3, 4, or 5) substituents selected from halo, C 1-4 aldehyde, C1-6 straight or branched chain alkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halo-substituted alkyl (e.g., trifluoromethyl), halo-substituted alkoxy (e.g., trifluoromethoxy), carboxy, C 1-4 alkoxy, ethoxycarbonyl, N(CH3) and C 1-4 acyl.

[0063] As used herein, "alkoxy" refers to an oxygen radical substituted with an alkyl group. Preferred alkoxyl groups are alkoxy groups having from 1 to 6 carbon atoms, more preferably from 1 to 3 carbon atoms. Examples of alkoxyl groups include, but are not limited to, methoxy, ethoxy, propoxy and the like. The alkoxyl group can be substituted with one or more substituents, such as halo or haloalkyl. For example, the alkoxyl group can be an alkyl group substituted with from 1 to 4 fluorine atoms, or the alkyl group can be an alkyl group substituted with a fluoroalkyl group.

[0064] As used herein, "halo" refers to fluorine, chlorine, bromine or iodine.

[0065] As used herein, "optionally substituted" means that the substituent being modified can optionally be substituted with from 1 to 5 (e.g., 1, 2, 3, 4 or 5) substituents selected from the group consisting of: halo, C 1-4 aldehyde, C 1-6 straight or branched chain alkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halo-substituted alkyl (e.g., trifluoromethyl), halo-substituted alkoxy (e.g., trifluoromethoxy), carboxy, C 1-4 alkoxy, ethoxycarbonyl, N(CH3) and C 1-4 acyl.

[0066] As used herein, "amino acid linked via an amide bond" refers to the amino group of the amino acid forming a phosphoramidate linkage with the phosphate, thereby linking the amino acid to the main structure of the compound.

[0067] "Amidated amino acid" refers to an amino acid having its amino group amidated, i.e., linked to a carboxyl group via an amide bond.

[0068] "Phosphate prodrug group" refers to a prodrug group introduced in a drug containing a phosphate group to improve polarity.

[0069] Compounds of the Invention

[0070] In another embodiment, the present application provides a compound of Formula I:

[0071] wherein the substituents are as defined above.

[0072] In preferred embodiments, the present application further provides a compound of Formula II-V, or a pharmaceutically acceptable salt thereof:

[0073] wherein the definitions of the substituents are as described above.

[0074] In a specific embodiment, the present application provides a compound selected from the group consisting of:

[0075] Preferably, the compound is selected from the following compounds:

[0076] The present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0077] Examples of pharmaceutically acceptable salts of the compounds of the present application include, but are not limited to, inorganic and organic acid salts such as hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, and oxalate; and inorganic and organic base salts with bases such as sodium hydroxide, tris(hydroxymethyl)aminomethane (TRIS, tromethamine), and N-methylglucamine.

[0078] The pharmaceutical compositions of the present application can be formulated in dosage forms adapted to the various routes of administration, including, but not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial, intranasal, or topical routes of administration, for the treatment of tumors and other diseases. The amount administered is an amount effective to improve or eliminate one or more symptoms. For the treatment of a particular disease, an effective amount is an amount sufficient to improve or in some way diminish the symptoms associated with the disease. Such an amount can be administered as a single dose, or can be administered according to a regimen effective to treat the disease. The amount administered can cure the disease, but administration is usually to ameliorate symptoms of the disease. Repeated doses can be needed to achieve the desired amelioration of symptoms. The dosage of the drug will depend on the age, health, and weight of the patient, the kind of concurrent treatment, if any, the frequency of treatment, and the benefit sought.

[0079] The pharmaceutical formulations of the present application can be administered to any mammal which can benefit from the therapeutic effects of the compounds of the present application. Most importantly, these mammals include humans.

[0080] The compounds of the present application or pharmaceutical compositions thereof can be used in the treatment of various diseases mediated by CD73 involvement. The cancers include, but are not limited to, breast cancer, multiple myeloma, bladder cancer as preferred, the cancer is selected from the group consisting of breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumor, cholangiocellular carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, schwannoma, lung squamous cell carcinoma, Darier's disease, synovial sarcoma, skin cancer, adenocarcinoma, testicular cancer or liposarcoma.

[0081] The pharmaceutical preparations of the present application are manufactured in a manner which is known in itself, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. For oral therapeutic administration, the compounds can be incorporated with excipient and used in the form of tablets, capsules, dragees, etc. by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to give tablets or dragee cores.

[0082] Suitable excipients are, in particular, fillers such as sugar, lactose, sucrose, calcium phosphate, or sodium chloride; binders such as starch, gelatin, or acacia; lubricants such as magnesium stearate, stearic acid, or talc; disintegrants such as potato starch or sodium starch glycolate; or wetting agents such as sodium lauryl sulfate. If desired, the tablets can be coated by means of a drag coat and suitable organic solvents or solvent mixtures. To produce a gastric juice-resistant coating, a suitable cellulose solution, for example, cellulose acetate phthalate or hydroxypropyl methyl cellulose phthalate, can be used. Dyes or pigments can be added to the coating of the tablets or dragee cores. For example, for identification or in order to characterize the dosage of active ingredient.

[0083] The present application also includes the use of a compound of the present application for the manufacture of a medicament for the prevention or treatment of a CD73-mediated disease or for the inhibition of CD73 activity.

[0084] Advantages of the present application:

[0085] 1. The compounds provided by the present application are structurally novel compounds;

[0086] 2. The compound provided by the present application has excellent inhibitory activity on CD73;

[0087] 3. The compound provided by the present application lays a foundation for developing a drug capable of inhibiting CD73, has great industrialization and commercialization prospects and market value, and has significant economic benefits.

[0088] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application. The experimental methods in the following examples, if not specified, are generally carried out according to conventional conditions, for example, the conditions described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0089] The reagents and raw materials used in the present application are commercially available.

[0090] Example 1: Synthesis of CD73 inhibitor

[0091] (((6-(6-bromo-4-chloro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)methyl)phosphonic acid (Compound 1)

[0092] Step 1: 6-nitro-1H-indazole-3-carboxaldehyde (1-1)

[0093] The synthesis method is referred to RSC Adv 2018, 8(24), 13121-13128. Specifically, a 1L reaction bottle is taken, 600 mL of deionized water is added, NaNO2(21.83 g, 316.4 mmol) is added, and is assisted to dissolve under ultrasonic. After complete dissolution, 6-nitroindole (5.13 g, 3.16 mmol) is added in small amounts in batches to make it suspended, and after stirring for 5 min, 6N hydrochloric acid (46.5 mL, 284.7 mmol) is slowly dropped using a constant pressure dropping funnel for 30-40 min. After the dropping is completed, the reaction is carried out at room temperature for 2 h until the reaction is complete. The reaction liquid is filtered, the filter cake is washed twice with 100 mL of water, once with 50 mL of EA, and once with 100 mL of PE. After drying, 1-1 4.8 g is obtained. Yellow solid, the product does not need to be further purified. The product yield is 79.4%.

[0094] 1H NMR (400 MHz, DMSO-d6) δ 14.78 (s, 1H), 10.25 (s, 1H), 8.59 (d, J = 1.9 Hz, 1H), 8.32 (dd, J = 8.9, 0.7 Hz, 1H), 8.16 (dd, J = 8.9, 2.0 Hz, 1H). LC-MS / ESI [M-H] - 190.10.

[0095] Step 2: 6-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-3-carbaldehyde (1-2)

[0096] Compound 1-1 (4.3 g, 22.5 mmol) was dissolved in 50 mL of dichloromethane in a 250 mL reaction flask. Methylsulfonic acid (0.146 mL, 2.25 mmol) was added dropwise at 0 °C. 3,4-2H-pyran (5.14 mL, 56.2 mmol) was diluted with 20 mL of dichloromethane and added dropwise to the above reaction. The ice bath was removed and the reaction was allowed to proceed at room temperature for 8 h. The reaction was not complete so an additional 1.5 mL of 3,4-2H-pyran was added and the reaction was allowed to proceed for 1.5 h. The reaction was then concentrated to a brownish oil. 60 mL of acetonitrile was added and a solid precipitated. The product 1-2 was collected by filtration as a tan solid. The product was used without further purification. Yield 57.2 %.

[0097] 1 H NMR (400 MHz, DMSO-d6) δ 14.78 (s, 1H), 10.25 (s, 1H), 8.59 (d, J = 1.9 Hz, 1H), 8.32 (dd, J = 8.9, 0.7 Hz, 1H), 8.16 (dd, J = 8.9, 2.0 Hz, 1H). LC-MS / ESI [M-H]

[0098] Step 3: (6-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)methanol (1-3)

[0099] Compound 1-2 (16.5 g, 59.9 mmol) was dissolved in 200 mL THF, NaBH4(3.4 g 89.9 mmol) was added portion wise at 0 °C. The ice bath was removed and the reaction was allowed to proceed at room temperature for 30 min. After the reaction was complete, the reaction was quenched with 200 mL saturated ammonium chloride solution. After no more gas was generated, the reaction was extracted with 100 mL EA three times and the organic layers were combined. The organic layer was washed with water once and saturated NaCl once. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give 1-3 14 g as a white solid. The product was used without further purification. The product yield was 84.2%.

[0100] 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 8.01 (dd, J = 9.0, 2.0 Hz, 1H), 6.08 (dd, J = 9.7, 2.4 Hz, 1H), 5.51 (t, J = 5.8 Hz, 1H), 4.84 (d, J = 5.8 Hz, 2H), 3.92 - 3.78 (m, 2H), 2.39 (tdd, J = 13.4, 9.4, 3.4 Hz, 1H), 2.09 - 1.94 (m, 2H), 1.77 (tdd, J = 16.3, 9.4, 4.8 Hz, 1H), 1.59 (ddt, J = 9.2, 6.8, 3.9 Hz, 2H). LC-MS / ESI [M+H] + 278.10.

[0101] Step 4: ((6-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)methoxy)methyl) diethyl phosphonate (1-4)

[0102] NaH (3.98 g, 99.54 mmol) was taken in an oven dried two necked flask, anhydrous DMF 20 mL was added and cooled to 0 °C, (6-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)methanol (23.00 g, 82.95 mmol) in DMF 100 mL was added portion wise under N2atmosphere, after 1 h diethyl (p-tolylsulfonyloxy)methyl phosphonate (26.74 g, 82.95 mmol) in DMF 50 mL was added. After 10 min the ice bath was removed and the reaction was allowed to proceed at room temperature overnight. The reaction was diluted with 500 mL EA, 500 mL water was added and the organic layer was separated. The organic layer was washed with water three times and saturated NaCl once. The organic layer was dried over anhydrous Na2SO4. After concentration the residue was purified by column chromatography to give 1-4 14.5 g. The product was a colorless oil, yield 41%.

[0103] 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 1.8 Hz, 1H), 8.21 - 7.90 (m, 2H), 6.12 (dd, J = 9.6, 2.4 Hz, 1H), 4.98 (s, 2H), 4.04 (p, J = 7.3 Hz, 4H), 3.94 - 3.73 (m, 4H), 2.44 - 2.33 (m, 1H), 2.07 - 1.98 (m, 2H), 1.82 - 1.71 (m, 1H), 1.61 - 1.57 (m, 2H), 1.21 (t, J = 7.0 Hz, 6H).

[0104] Step 5: ((6-amino-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)methoxy)methyl) diethyl phosphonate (1-5)

[0105] Compound 1-4 (12.00 g, 28.08 mmol), reduced iron powder (7.84 g, 140.39 mmol) and ammonium chloride (6.01 g, 112.31 mmol) were taken in a reaction flask, 150 mL of ethanol and 150 mL of deionized water were added and the reaction was carried out at 85 °C under N2atmosphere for 4 h. After completion of the reaction, the reaction mixture was diluted with 500 mL of EA and passed through celite. The organic phase was washed with water once and saturated NaCl once. The organic layer was dried using anhydrous Na2S04. After concentration, the residue was purified by column chromatography to get 1-5 8.8 g. Brown oil, yield 79%.

[0106] 1 H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J = 8.5 Hz, 1H), 6.58 (s, 1H), 6.54 (dd, J = 8.6, 1.5 Hz, 1H), 5.52 (dd, J = 9.7, 2.5 Hz, 1H), 5.40 (s, 2H), 4.74 (s, 2H), 4.04 (p, J = 7.3 Hz, 4H), 3.89 - 3.80 (m, 3H), 3.68 - 3.61 (m, 1H), 2.39 - 2.30 (m, 1H), 2.10 - 1.83 (m, 2H), 1.76 - 1.68 (m, 1H), 1.58 - 1.53 (m, 2H), 1.21 (t, J = 7.0 Hz, 6H).

[0107] Step 6: ((6-((5-chloro-3-fluoro-2-nitrophenyl)amino)-l-(tetrahydro-2H-pyran-2-yl)-lH- indazol-3-yl)methoxy)methyl) diethyl phosphonate (1-6)

[0108] Take compound 1-5 (0.80 g, 2.01 mmol) and 5-chloro-1,3-difluoro-2-nitrobenzene (0.39 g, 2.01 mmol) in a reaction bottle, dissolve with 10 mL of DMSO, then add 10 mL of triethylamine, react at 100°C for 24 h. Dilute the reaction solution with 100 mL of EA, add 50 mL of water, separate the organic phase. The organic phase is washed with water three times and saturated NaCl once. Dry the organic layer with anhydrous Na2SO4. After concentration, the residue is purified by column chromatography to obtain 1-6 0.5 g. The product is a red-brown solid with a yield of 43%.

[0109] 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 1.7 Hz, 1H), 7.14 (dd, J = 10.7, 2.1 Hz, 1H), 7.11 (dd, J = 8.7, 1.8 Hz, 1H), 6.95 (t, J = 1.9 Hz, 1H), 5.77 (dd, J = 9.7, 2.4 Hz, 1H), 4.88 (s, 2H), 4.05 (p, J = 7.1 Hz, 4H), 3.90 - 3.85 (m, 3H), 3.76 - 3.67 (m, 1H), 2.40 - 2.31 (m, 1H), 2.12 - 1.90 (m, 2H), 1.77 - 1.66 (m, 1H), 1.62 - 1.50 (m, 2H), 1.21 (t, J = 7.1 Hz, 6H).

[0110] Step 7: ((6-((5-chloro-3-fluoro-2-aminophenyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-3-yl)methoxy)methyl)diethyl phosphonate (1-7)

[0111] Take compound 1-6 (0.45 g, 0.79 mmol), reduced iron powder (0.22 g, 3.94 mmol) and ammonium chloride (0.17 g, 3.15 mmol) in a reaction bottle, add 10 mL of ethanol and 10 mL of deionized water, react at 85°C for 4 h under N2 atmosphere. After the reaction is completed, dilute the reaction solution with 50 mL of EA and pass through silica gel. The organic phase is washed with water once and saturated NaCl once. Dry the organic layer with anhydrous Na2SO4. After concentration, the product is directly used in the next step without further purification.

[0112] Step 8: ((6-(6-chloro-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-3-yl)methoxy)methyl)diethyl phosphonate (1-8)

[0113] Take compound 1-7 (280 mg, 0.52 mmol) in a reaction bottle, add 5 mL of acetonitrile to dissolve. At room temperature, drop isopropyl nitrite (104 μL, 0.77 mmol). Move the reaction bottle to the 65 °C oil bath and react for 30 min, cool to room temperature, concentrate the residue and purify it by column chromatography to obtain 1-8 220 mg, white solid, yield 77%.

[0114] 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (dd, J = 1.8, 0.7 Hz, 1H), 8.15 (dd, J = 8.6, 0.7 Hz, 1H), 7.93 (d, J = 1.5 Hz, 1H), 7.70 (dd, J = 8.6, 1.7 Hz, 1H), 7.64 (dd, J = 10.1, 1.5 Hz, 1H), 6.04 (dd, J = 9.7, 2.4 Hz, 1H), 5.01 (s, 2H), 4.06 (dq, J = 8.2, 7.1 Hz, 4H), 3.95 (d, J = 8.4 Hz, 2H), 3.91 - 3.84 (m, 1H), 3.80 - 3.74 (m, 1H), 2.48 - 2.38 (m, 1H), 2.20 - 1.95 (m, 2H), 1.81 - 1.71 (m, 1H), 1.60 - 1.55 (m, 2H), 1.24 (t, J = 7.1 Hz, 6H).

[0115] Step 9: ((6-(6-chloro-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)methyl) diethyl phosphonate (1-9)

[0116] Take compound 1-8 (200 mg, 0.36 mmol) in a reaction bottle, add 3 mL of dichloromethane to dissolve. Stir at room temperature, drop 1.5 mL of trifluoroacetic acid, continue to stir for 2 h. After the reaction is completed, adjust the pH to 10 with saturated sodium carbonate solution, extract with 50 mL of EA, separate the organic phase. Wash the organic phase with water twice and saturated brine once, dry over anhydrous sodium sulfate. Spin dry, and purify the residue on a column. Obtain yellow solid 1-9 105 mg. Yield 62%.

[0117] 1H NMR (400 MHz, DMSO-d6) δ 13.45 (s, 1H), 8.13 (dd, J = 8.6, 0.7 Hz, 1H), 8.05 - 8.01 (m, 1H), 7.95 (d, J = 1.5 Hz, 1H), 7.64 (d, J = 1.7 Hz, 1H), 7.62 (t, J = 1.6 Hz, 1H), 5.01 (s, 2H), 4.05 (dq, J = 8.2, 7.0 Hz, 4H), 3.93 (d, J = 8.4 Hz, 2H), 1.23 (t, J = 7.0 Hz, 6H).

[0118] Step 10: (((6-(6-chloro-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-lH-indazol-3-yl)methoxy)methyl)phosphonic acid (1)

[0119] Compound 1-9 (75 mg, 0.16 mmol) was taken in a reaction flask, dissolved in 2 mL of 1,2-dichloroethane, trimethylsilyl bromide (317 μL, 2.40 mmol) was injected under N2protection, the reaction was warmed to 40 °C overnight. After the reaction was completed, 2 mL of methanol was added, the reaction liquid was spin dried, and the residue was recrystallized with methanol to obtain 35 mg of white solid powder, with a yield of 53%.

[0120] 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 8.6 Hz, 1H), 8.01 (d, J = 1.7 Hz, 1H), 7.95 (s, 1H), 7.78 - 7.55 (m, 2H), 4.99 (s, 2H), 3.67 (d, J = 8.8 Hz, 2H). LC-MS / ESI [M-H] - 410.00.

[0121] (((6-(5-chloropyrazolo[l,5-a]pyrimidin-3-yl)-lH-indazol-3-yl)methoxy)methyl)phosphonic acid (Compound 2)

[0122] Step 1: 6-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-3-carbaldehyde (2-1)

[0123] Compound 6-bromo-lH-indazole-3-carbaldehyde (10.00 g, 44.44 mmol) was placed in a 250 mL reaction flask, dissolved in 100 mL of dichloromethane, 3,4-2H-pyrane (10.14 mL, 111.09 mmol) was diluted with 20 mL of dichloromethane and added dropwise to the above reaction. Methyl sulfonic acid (0.29 mL, 4.44 mmol) was added dropwise, the reaction quickly turned from turbid to black, after 10 min the reaction was complete. The reaction was spin dried, 30 mL of EA was added, after stirring for 5 min it was suction filtered, the filter cake was washed twice with 20 mL of PE, dried to give 2-1 9 g of white solid, yield 65%.

[0124] 1 H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.57 (dd, J = 8.6, 1.6 Hz, 1H), 6.09 (dd, J = 9.5, 2.2 Hz, 1H), 4.03 - 3.72 (m, 2H), 2.43 - 2.33 (m, 1H), 2.16 - 1.99 (m, 2H), 1.81 - 1.70 (m, 1H), 1.64 - 1.58 (m, 2H).

[0125] Step 2: (6-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)methanol (2-2)

[0126] Compound 2-1 (6.20 g, 20.05 mmol) was dissolved in 100 mL of THF, NaBH4(1.14 g, 30.08 mmol) was added in portions at 0 °C. The ice bath was removed, the reaction was allowed to proceed at room temperature for 30 min, after the reaction was complete it was quenched with 200 mL of saturated ammonium chloride solution, after no more bubbles were generated it was extracted with 100 mL of EA three times, the organic phases were combined. Washed once with water, once with saturated NaCl. The organic layer was dried using anhydrous Na2S04, filtered and concentrated to give SCJ-17003 5.7 g, white solid. The product was used without further purification. Product yield 91%.

[0127] 1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 1.4 Hz, 1H), 7.81 (dd, J = 8.6, 0.6 Hz, 1H), 7.31 (dd, J = 8.5, 1.6 Hz, 1H), 5.82 (dd, J = 9.9, 2.5 Hz, 1H), 5.37 (t, J = 5.9 Hz, 1H), 4.76 (d, J = 5.9 Hz, 2H), 3.88 - 3.84 (m, 1H), 3.78 - 3.72 (m, 1H), 2.40 - 2.30 (m, 1H), 2.09 - 1.87 (m, 2H), 1.77 - 1.66 (m, 1H), 1.59 - 1.53 (m, 2H).

[0128] Step 3: ((6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methoxy)methyl) diethyl phosphonate (2-3)

[0129] NaH (0.80 g, 20.15 mmol) was taken in a dry two necked flask, anhydrous DMF 10 mL was added and cooled to 0 °C, under N2 atmosphere 2-2 (5.70 g, 18.32 mmol) in DMF 20 mL was added, after 1 h diethyl p-tolylsulfonyloxymethyl phosphonate (6.49 g, 20.15 mmol) in DMF 10 mL was added. After 10 min ice bath was removed and reaction was carried out at room temperature overnight. Reaction was diluted with 200 mL EA, water 200 mL was added, organic layer was separated. Organic layer was washed with water three times, saturated NaCl once. Organic layer was dried using anhydrous Na2S04. After concentration residue was purified by column chromatography to get 2-3 2.0 g. Product was colorless oil, yield 23.7%.

[0130] NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 1.3 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.36 (dd, J = 8.5, 1.6 Hz, 1H), 5.87 (dd, J = 9.8, 2.5 Hz, 1H), 4.90 (s, 2H), 4.02 (dq, J = 8.2, 7.1 Hz, 4H), 3.91 - 3.83 (m, 3H), 3.79 - 3.72 (m, 1H), 2.43 - 2.25 (m, 1H), 2.11 - 1.85 (m, 2H), 1.81 - 1.48 (m, 3H), 1.21 (t, J = 7.1 Hz, 6H).

[0131] Step 4: ((1-(tetrahydro-2H-pyran-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazol-3-yl)methoxy)methyl) diethyl phosphonate (2-4)

[0132] To a reaction flask containing compound 2-3 (2.00 g, 4.34 mmol) was added bis(pinacolato)diboron (1.65 g, 6.50 mmol), Pd(dppf)Cl2(0.32 g, 0.43 mmol) and potassium acetate (0.85 g, 8.67 mmol). After three nitrogen purges, 1,4-dioxane was added and the reaction was refluxed for 2 h. The reaction was monitored by TLC. After cooling to room temperature, 100 mL of water was added and the reaction was extracted with 150 mL of EA. The organic layer was separated and washed with water twice, saturated brine once and dried over anhydrous sodium sulfate. The crude product was obtained after rotary evaporation and the residue was columned to give yellow solid 1.0 g in 45% yield.

[0133] 1 H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.85 (dd, J = 8.1, 0.9 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 5.98 (dd, J = 9.6, 2.5 Hz, 1H), 4.91 (s, 2H), 4.02 (dq, J = 8.2, 7.0 Hz, 5H), 3.88 (d, J = 8.4 Hz, 2H), 3.86 - 3.75 (m, 2H), 2.46 - 2.32 (m, 1H), 2.09 - 1.90 (m, 2H), 1.83 - 1.73 (m, 1H), 1.63 - 1.47 (m, 2H), 1.33 (s, 12H), 1.25 - 1.17 (m, 6H).

[0134] Step 5: ((6-(5-chloropyrazolo[l,5-a]pyrimidin-3-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH- indazol-3-yl)methoxy)methyl)diethyl phosphonate (2-5)

[0135] To a reaction flask containing compound 2-4 (400 mg, 0.79 mmol) was added 5-chloro-3-iodopyrazolo[l,5-a]pyrimidine (242 mg, 0.87 mmol), Pd(dppf)Cl2(57 mg, 0.079 mmol) and potassium phosphate (334 mg, 1.57 mmol). After three nitrogen purges, 1,4-dioxane 10 ml and water 2 mL were added and the reaction was refluxed overnight. The reaction was monitored by TLC. After cooling to room temperature, 80 mL of water was added and the reaction was extracted with 50 mL of EA. The organic layer was separated and washed with water twice, saturated brine once and dried over anhydrous sodium sulfate. The crude product was obtained after rotary evaporation and the residue was columned to give yellow solid 80 mg in 19% yield.

[0136] 1H NMR (400 MHz, DMSO-d6) δ 9.24 (d, J = 7.3 Hz, 1H), 8.96 (s, 1H), 8.44 (t, J = 1.1 Hz, 1H), 7.98 (dd, J = 8.4, 1.3 Hz, 1H), 7.90 (dd, J = 8.5, 0.8 Hz, 1H), 7.23 (d, J = 7.3 Hz, 1H), 5.86 (dd, J = 9.9, 2.4 Hz, 1H), 4.91 (s, 2H), 4.04 (dq, J = 8.3, 7.1 Hz, 4H), 3.97 (d, J = 11.6 Hz, 1H), 3.91 (d, J = 8.4 Hz, 2H), 3.86 - 3.72 (m, 1H), 2.48 - 2.35 (m, 1H), 2.11 - 1.98 (m, 2H), 1.85 - 1.72 (m, 1H), 1.68 - 1.54 (m, 2H), 1.22 (t, J = 7.0 Hz, 6H).

[0137] Step 6: ((6-(5-chloropyrazolo[1,5-a]pyrimidin-3-yl)-1 H-indazol-3-yl)methoxy)methyl) diethyl phosphonate (2-6)

[0138] Compound 2-5 (75 mg, 0.14 mmol) was dissolved in 4 mL of dichloromethane in a reaction bottle. 2 mL of trifluoroacetic acid was added dropwise at room temperature and stirred for 3 h. After the reaction was completed, the pH was adjusted to 10 with saturated sodium carbonate solution, extracted with 50 mL of EA, and the organic phase was separated. The organic phase was washed with water twice and saturated brine once, and dried over anhydrous sodium sulfate. After rotary evaporation, the residue was columned. 55 mg of yellow solid was obtained. Yield 87%.

[0139] 1 H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 9.25 (d, J = 7.2 Hz, 1H), 8.94 (s, 1H), 8.30 (t, J = 1.1 Hz, 1H), 7.95 - 7.65 (m, 2H), 7.23 (d, J = 7.2 Hz, 1H), 4.92 (s, 2H), 4.03 (dq, J = 8.1, 7.1 Hz, 4H), 3.89 (d, J = 8.4 Hz, 2H), 1.22 (t, J = 7.0 Hz, 6H).

[0140] Step 7: (((6-(5-chloropyrazolo[1,5-a]pyrimidin-3-yl)-1 H-indazol-3-yl)methoxy)methyl) phosphonic acid (2)

[0141] Into a reaction vial was placed compound 2-6 (50 mg, 0.11 mmol) dissolved in 2 mL of 1,2-dichloroethane, and trimethylsilyl bromide (0.22 mL, 1.67 mmol) was added under N2protection. The reaction was then warmed to 40 °C overnight. After the reaction was completed, 2 mL of methanol was added, and the reaction was dried down. The residue was recrystallized with methanol to give a light yellow solid powder 21 mg in 48% yield.

[0142] 1 H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 9.24 (d, J = 7.2 Hz, 1H), 8.93 (s, 1H), 8.28 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.80 (dd, J = 8.5, 1.4 Hz, 1H), 7.23 (d, J = 7.3 Hz, 1H), 4.91 (s, 2H), 3.63 (d, J = 8.8 Hz, 2H). LC-MS / ESI [M-H] - 392.05.

[0143] (((6-(6-chloroimidazo[l,2-b]pyridazin-3-yl)-lH-indazol-3-yl)methoxy)methyl)phosphonic acid (Compound 3)

[0144] Synthesis method is the same as Example 2. Light yellow solid powder 44 mg in 81% yield. 1 H NMR (600 MHz, DMSO-d6) δ 13.25 (s, 1H), 8.50 (s, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.37 (d, J = 9.5 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.77 (dd, J = 8.5, 1.5 Hz, 1H), 7.52 (dd, J = 9.4, 1.5 Hz, 1H), 4.94 (s, 2H), 3.65 (d, J = 8.8 Hz, 2H). LC-MS / ESI [M-H] - 392.05.

[0145] (((6-(6-chloroimidazo[l,2-a]pyrimidin-3-yl)-lH-indazol-3-yl)methoxy)methyl)phosphonic acid (Compound 4)

[0146] Synthesis method is the same as Example 2. Light yellow solid powder 10 mg in 38% yield. 1H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 9.25 (d, J = 2.5 Hz, 1H), 8.63 (d, J = 2.5 Hz, 1H), 8.10 (s, 1H), 8.07 - 8.00 (m, 1H), 7.85 (t, J = 1.1 Hz, 1H), 7.45 (dd, J = 8.3, 1.4 Hz, 1H), 4.95 (s, 2H), 3.63 (d, J = 8.9 Hz, 2H). LC-MS / ESI [M-H] - 392.05.

[0147] (((6-(5-chlorothieno[3,2-b]pyridin-3-yl)-lH-indazol-3-yl)methoxy)methyl)phosphonic acid (Compound 5)

[0148] Synthesis method same as Example 2. Light yellow solid powder 36 mg, yield 82%. 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.67 (d, J = 8.6 Hz, 1H), 8.60 (s, 1H), 8.36 (t, J = 1.1 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.73 - 7.65 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 4.94 (s, 2H), 3.64 (d, J = 8.9 Hz, 2H). LC-MS / ESI [M-H] - 408.00.

[0149] (((6-(5-chlorothieno[3,2-b]pyridin-3-yl)-lH-indazol-3-yl)methoxy)methyl)phosphonic acid (Compound 5)

[0150] Synthesis method same as Example 2. Light yellow solid powder 36 mg, yield 36%. 1 H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 9.07 (s, 1H), 8.55 (s, 1H), 8.25 (d, J = 8.7 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.76 (dd, J = 8.5, 1.3 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 4.93 (s, 2H), 3.64 (d, J = 8.9 Hz, 2H). LC-MS / ESI [M-H] - 392.00.

[0151] (((6-(5-chlorothieno[3,2-b]pyridin-3-yl)-lH-indazol-3-yl)methoxy)methyl)phosphonic acid (Compound 5)

[0152] Synthetic procedure same as Example 2. Product was a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.41 (s, 1H), 13.07 (s, 1H), 8.06 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 1.3 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.38 (dd, J = 8.6, 1.7 Hz, 1H), 4.94 (s, 2H), 3.64 (d, J = 8.9 Hz, 2H). LC-MS / ESI [M-H] - 435.00.

[0153] (((6-(5-amino-lH-pyrazolo[4,3-b]pyridin-3-yl)-lH-indol-3-yl)methoxy)methyl)phosphonic acid (Compound 8)

[0154] Synthetic procedure same as Example 2. Product was a light tan solid. 1 H NMR (600 MHz, Methanol-d4) δ 8.24 (dd, J = 9.4, 2.4 Hz, 1H), 8.06 (dd, J = 8.5, 3.0 Hz, 1H), 7.94 (s, 1H), 7.58 (dd, J = 8.3, 1.4 Hz, 1H), 7.03 (d, J = 9.5 Hz, 1H), 5.06 (s, 2H), 3.85 (d, J = 9.3 Hz, 2H). LC-MS / ESI [M-H] - 373.00.

[0155] (((6-(5-acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-lH-indol-3-yl)methoxy)methyl)phosphonic acid (Compound 9)

[0156] Synthetic procedure same as Example 2. Product was a light tan solid. 1H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 7.86 (dd, J = 8.5, 2.8 Hz, 1H), 7.63 (s, 1H), 7.38 (dd, J = 9.9, 6.5 Hz, 2H), 4.88 (s, 2H), 4.56 (d, J = 13.8 Hz, 2H), 3.79 (t, J = 5.7 Hz, 1H), 3.75 (t, J = 5.7 Hz, 1H), 3.61 (d, J = 8.8 Hz, 2H), 2.90 (t, J = 5.7 Hz, 1H), 2.77 (t, J = 5.7 Hz, 1H), 2.12 (s, 3H). LC-MS / ESI [M-H] - 420.10.

[0157] (((6-(2-oxo-l,2-dihydropyridin-3-yl)-lH-indazol-3-yl)methoxy)methyl)phosphonic acid (Compound 10)

[0158] Synthetic procedure same as Example 2. Product was a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.07 (s, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.79 (dd, J = 7.0, 2.0 Hz, 1H), 7.54 - 7.31 (m, 2H), 6.35 (t, J = 6.7 Hz, 1H), 4.92 (s, 2H), 3.63 (d, J = 8.9 Hz, 2H). LC-MS / ESI [M-H] - 334.00.

[0159] (((6-(l-methyl-6-oxo-l,6-dihydropyridazin-3-yl)-lH-indazol-3-yl)methoxy)methyl)phosphonic acid (Compound 11)

[0160] Synthetic procedure same as Example 2. Product was a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.23 (s, 1H), 8.18 (d, J = 9.7 Hz, 1H), 8.04 - 7.90 (m, 2H), 7.71 (dd, J = 8.6, 1.5 Hz, 1H), 7.09 (d, J = 9.7 Hz, 1H), 4.94 (s, 2H), 3.79 (s, 3H), 3.65 (d, J = 8.9 Hz, 2H). LC-MS / ESI [M-H] - 349.05.

[0161] (((6-(6-methylpyridazin-3-yl)-lH-indazol-3-yl)methoxy)methyl)phosphonic acid (Compound 12)

[0162] Synthetic procedure same as Example 2. Product was a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 8.50 (d, J = 8.8 Hz, 1H), 8.30 (s, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.97 - 7.88 (m, 2H), 4.97 (s, 2H), 3.66 (d, J = 8.9 Hz, 2H), 2.75 (s, 3H). LC-MS / ESI [M-H] - 333.05.

[0163] (((6-(6-bromopyridazin-3-yl)-lH-indazol-3-yl)methoxy)methyl)phosphonic acid (Compound 13)

[0164] Synthetic procedure same as Example 2. Product was a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 8.34 (d, J = 9.0 Hz, 1H), 8.29 (s, 1H), 8.13 (d, J = 9.0 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.96 - 7.87 (m, 1H), 4.95 (s, 2H), 3.64 (d, J = 8.8 Hz, 2H). LC-MS / ESI [M-H] - 396.95.

[0165] (((6-([l,2,4]triazolo[4,3-a]pyridin-5-yl)-lH-indazol-3-yl)methoxy)methyl)phosphonic acid (Compound 14)

[0166] Synthetic procedure same as Example 2. Methanol recrystallization, product was a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.26 (s, 1H), 9.35 (s, 1H), 9.07 (s, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.96 (s, 2H), 7.85 (s, 1H), 7.51 (d, J = 8.1 Hz, 1H), 4.95 (s, 2H), 3.66 (s, 2H). LC-MS / ESI [M-H] - 358.05.

[0167] (((6-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)-1H-indol-3-yl)methoxy)methyl)phosphonic acid (Compound 15)

[0168] Synthesis procedure same as Example 2. Product was a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H), 8.76 (s, 1H), 8.17 (d, J = 9.6 Hz, 1H), 8.08 (dd, J = 9.5, 1.6 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 1.5 Hz, 1H), 7.54 (dd, J = 8.4, 1.5 Hz, 1H), 4.95 (s, 2H), 3.64 (d, J = 8.9 Hz, 2H). LC-MS / ESI [M-H] - 426.05.

[0169] (((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indol-3-yl)methoxy)methyl)phosphonic acid (Compound 16)

[0170] Synthesis procedure same as Example 1. White solid (90 mg, 197.3 pmol), 89.44% yield. 1 H NMR (600 MHz, DMSO-d6) δ 13.38 (s, 1H), 8.16 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 1.4 Hz, 1H), 8.01 (d, J = 1.7 Hz, 1H), 7.71 (dd, J = 9.8, 1.4 Hz, 1H), 7.60 (dd, J = 8.6, 1.8 Hz, 1H), 6.37 (s, 2H), 4.99 (s, 2H), 3.67 (d, J = 8.8 Hz, 2H). LC-MS / ESI [M-H] - 454.00.

[0171] (((6-(6-bromo-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indol-3-yl)methoxy)methyl)phosphonic acid (Compound 17)

[0172] Synthesis procedure same as Example 1. White solid. LC-MS / ESI [M-H] - 436.00.

[0173] (((6-(6-cyano-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-lH-indol-3-yl)methoxy)methyl)phosphonic acid (Compound 18)

[0174] Synthesis procedure same as Example 1. White solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 1.1 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.06 (dd, J = 3.9, 1.7 Hz, 1H), 7.97 (dd, J = 10.3, 1.1 Hz, 1H), 7.64 (dd, J = 8.6, 1.8 Hz, 1H), 5.00 (s, 2H), 3.68 (d, J = 8.9 Hz, 2H). LC-MS / ESI [M-H] - 401.05.

[0175] (((6-(6-(trifluoromethyl)-lH-benzo[d][l,2,3]triazol-l-yl)-lH-indol-3-yl)methoxy)methyl)phosphonic acid (Compound 19)

[0176] Synthesis procedure same as Example 1. White solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.41 (s, 1H), 8.48 (d, J = 8.7 Hz, 1H), 8.38 - 8.29 (m, 1H), 8.18 (d, J = 8.6 Hz, 1H), 8.06 (d, J = 1.7 Hz, 1H), 7.86 (dd, J = 8.8, 1.6 Hz, 1H), 7.66 (dd, J = 8.6, 1.8 Hz, 1H), 5.00 (s, 2H), 3.68 (d, J = 8.8 Hz, 2H). LC-MS / ESI [M-H] - 426.05.

[0177] (((6-(6-bromo-5-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-lH-indol-3-yl)methoxy)methyl)phosphonic acid (Compound 20)

[0178] Synthesis procedure same as Example 1. White solid. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 5.8 Hz, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.16 (d, J = 8.6 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.62 (dd, J = 8.6, 1.8 Hz, 1H), 4.99 (s, 2H), 3.68 (s, 2H). LC-MS / ESI [M-H] - 454.00.

[0179] (((6-(6-bromo-7-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)methyl)phosphonic acid (Compound 21)

[0180] Synthesis as in Example 1. White solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 5.8 Hz, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.16 (d, J = 8.6 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.62 (dd, J = 8.6, 1.8 Hz, 1H), 4.99 (s, 2H), 3.68 (s, 2H). LC-MS / ESI [M-H] - 454.00.

[0181] (((6-(6-bromo-7-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)methyl)phosphonic acid (Compound 21)

[0182] Synthesis as in Example 1. White solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 5.8 Hz, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.16 (d, J = 8.6 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.62 (dd, J = 8.6, 1.8 Hz, 1H), 4.99 (s, 2H), 3.68 (s, 2H). LC-MS / ESI [M-H] - 470.00.

[0183] (((6-(5,6-dichloro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)methyl)phosphonic acid (Compound 23)

[0184] Synthesis as in Example 1. White solid. 1H NMR (600 MHz, DMSO-d6) δ 13.38 (s, 1H), 8.65 (s, 1H), 8.35 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.62 (dd, J = 8.5, 1.8 Hz, 1H), 4.99 (s, 2H), 3.67 (d, J = 8.8 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 145.14, 142.66, 141.03, 134.14, 132.37, 132.03, 128.17, 122.75, 122.29, 121.34, 116.61, 113.43, 105.79, 67.07 (d, J C-O-C-P = 12.5 Hz), 66.09 (d, J C-P = 161.2 Hz). LC-MS / ESI [M-H] - 426.00.

[0185] (((6-(5-bromo-3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-lH-indol-3-yl)methoxy)methyl)phosphonic acid (Compound 24)

[0186] Synthesis as in Example 1. White solid. 1 H NMR (600 MHz, DMSO-d6) δ 13.42 (s, 1H), 8.70 (d, J = 8.6 Hz, 1H), 8.35 (d, J = 1.8 Hz, 1H), 8.16 (d, J = 8.6 Hz, 1H), 7.89 (dd, J = 8.7, 1.8 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 4.99 (s, 2H), 3.67 (d, J = 8.8 Hz, 2H). LC-MS / ESI [M-H] - 437.00.

[0187] (((6-(6-bromo-lH-[l,2,3]triazolo[4,5-b]pyridin-l-yl)-lH-indol-3-yl)methoxy)methyl)phosphonic acid (Compound 25)

[0188] Synthesis as in Example 1. White solid. 1H NMR (600 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.24 (s, 1H), 7.84 - 7.79 (m, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 1.8 Hz, 1H), 6.98 (dd, J = 8.6, 1.9 Hz, 1H), 4.86 (s, 2H), 3.62 (d, J = 8.8 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 147.96, 142.22, 139.67, 131.24, 126.99, 125.64, 122.05, 118.63, 115.34, 105.26, 99.32, 67.21 (d, J C-O-C-P = 12.6 Hz), 66.10 (d, J C-P = 161.5 Hz). LC-MS / ESI [M-H] - 437.00.

[0189] (((6-(6-chloro-lH-[l,2,3]triazolo[4,5-c]pyridin-l-yl)-lH-indazol-3-yl)methoxy)methyl)phosphonic acid (Compound 26)

[0190] Synthesis method same as Example 1. White solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.40 (s, 1H), 9.49 (d, J = 1.1 Hz, 1H), 8.19 (d, J = 1.1 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.64 (dd, J = 8.6, 1.9 Hz, 1H), 4.99 (s, 2H), 3.67 (d, J = 8.8 Hz, 2H). LC-MS / ESI [M-H] - 393.00.

[0191] (l-((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-lH-indazol-3-yl)methoxy)-2-hydroxyethyl)phosphonic acid (Compound 27)

[0192] Step 1: 3-(((tert-butyldimethylsilyloxy)methyl)-6-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (27-1)

[0193] Take 6-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-3-methanol 25 g, 90.16 mmol in a flask, dissolve in anhydrous DMF, add (30.69 g, 450.81 mmol) imidazole, protect N2, replace gas several times, place in ice bath, and wait for the temperature to drop to 0°C, then add (33.97 g, 225.40 mmol) tert-butyldimethylsilyl chloride, transfer to room temperature reaction, and after about half an hour, monitor the reaction completion by TLC. Remove DMF by rotary evaporation, extract with ethyl acetate and water, concentrate the organic phase, add a small amount of ethyl acetate and dichloromethane to make a slurry, and precipitate 3-(((tert-butyldimethylsilyl)oxy)methyl)-6-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole white block solid (29.14 g, 79.84 mmol), yield 88.55%.

[0194] 1 H NMR (400 MHz, DMSO-d6) δ 8.74-8.70 (m, 1H), 8.05-7.98 (m, 2H), 6.09 (dd, J = 9.5, 2.4 Hz, 1H), 5.05 (s, 2H), 3.84 (tdd, J = 15.6, 11.5, 4.7 Hz, 2H), 2.43-2.29 (m, 1H), 2.01 (tq, J = 16.5, 3.8 Hz, 2H), 1.82-1.70 (m, 1H), 1.58 (ddt, J = 12.2, 8.7, 3.8 Hz, 2H), 0.86 (s, 9H), 0.09 (s, 6H).

[0195] Step 2: 3-(((tert-butyldimethylsilyloxy)methyl)-6-amino-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (27-2)

[0196] Take 3-(((tert-butyldimethylsilyl)oxy)methyl)-6-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (29 g, 74.42 mmol) in a reaction flask, add 3 g of 10% Pd / C, dissolve in methanol and dichloromethane, replace H2 several times, and react at room temperature. After about 30 minutes, monitor the reaction completion by TLC. After suction filtration with celite, collect the filtrate, remove the solvent by rotary evaporation, and obtain 3-(((tert-butyldimethylsilyl)oxy)methyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-6-amine red-brown oily liquid (24.85 g, 68.73 mmol), which is directly used in the next step without purification, yield 92.35%.

[0197] 1H NMR (400 MHz, DMSO-d6) δ 7.40 (d, J = 8.6 Hz, 1H), 6.59 (d, J = 1.8 Hz, 1H), 6.54 (dd, J = 8.6, 1.8 Hz, 1H), 5.51 (dd, J = 9.7, 2.5 Hz, 1H), 5.37 (s, 2H), 4.85 (s, 2H), 3.93 - 3.83 (m, 1H), 3.71 - 3.59 (m, 1H), 2.35 (dq, J = 12.7, 5.5, 4.2 Hz, 1H), 2.03 (d, J = 15.6 Hz, 1H), 1.89 (d, J = 13.1 Hz, 1H), 1.72 (d, J = 10.1 Hz, 1H), 1.56 (s, 2H), 0.88 (s, 9H), 0.08 (d, J = 2.1 Hz, 6H).

[0198] Step 3: N-(5-bromo-3-fluoro-2-nitrophenyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)- 1 -(tetrahydro-2H-pyran-2-yl)-1 H-indazole-6-carboxamide (27-3)

[0199] To 3-(((tert-butyldimethylsilyl)oxy)methyl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H- indazole-6-carboxamide (15.5 g, 42.87 mmol) in a reaction flask, add 2,5-difluoro-4- bromonitrobenzene (11.22 g, 47.16 mmol), triethylamine 75 ml, DMSO 75 ml, dissolve, heat to reflux at 100 °C. After TLC monitoring reaction no remaining, extract with ethyl acetate and water, collect the organic phase, dry over anhydrous sodium sulfate, concentrate to get the crude product, separate by silica gel column chromatography (PE / EA = 10 / 1) to get N-(5-bromo-3-fluoro-2-nitrophenyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H-indazole-6-carboxamide yellow-brown oily liquid (4.665 g, 258.37, 8.08 mmol), yield 18.78%.

[0200] 1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.67 (s, 1H), 7.39 (dd, J = 10.3, 2.1 Hz, 1H), 7.27 - 7.16 (m, 2H), 5.91 - 5.83 (m, 1H), 5.10 (d, J = 3.1 Hz, 2H), 4.01 (d, J = 11.5 Hz, 1H), 3.83 (d, J = 12.3 Hz, 1H), 2.50 (d, J = 14.6 Hz, 1H), 2.13 (s, 1H), 2.08 (d, J = 13.3 Hz, 1H), 1.86 (s, 1H), 1.70 (s, 2H), 1.02 (d, J = 3.2 Hz, 9H), 0.24 (d, J = 3.4 Hz, 6H).

[0201] Step 4: 5-bromo-N 1 (3-(((tert-butyldimethylsilyl)oxy)methyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-6- yl)-3-fluorobenzene-l,2-diamine (27-4)

[0202] To N-(5-bromo-3-fluoro-2-nitrophenyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-l- (tetrahydro-2H-pyran-2-yl)-lH-indazol-6-amine (4.6 g, 7.94 mmol), ammonium chloride (4.25 g, 79.37 mmol) in a reaction flask, add 10 ml water and 40 ml ethanol to dissolve and suspend, slowly add iron powder (2.22 g, 39.69 mmol) under stirring, heat to reflux at 85 °C, the reaction is complete after about an hour. Remove the iron powder by celite suction filtration, collect the filtrate, extract with EA and water, remove the solvent by rotary evaporation, concentrate to get the crude product, separate by silica gel column chromatography to get 5-bromo-N 1 (3-(((tert-butyldimethylsilyl)oxy)methyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-6- yl)-3-fluorobenzene-l,2-diamine yellow oily liquid (4.247 g, 7.73 mmol), yield 97.36%.

[0203] 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.03 (dd, J = 9.0, 1.9 Hz, 2H), 6.97 (d, J = 1.8 Hz, 1H), 6.81 (dd, J = 8.7, 1.8 Hz, 1H), 5.60 (dd, J = 9.5, 2.6 Hz, 1H), 4.98 (s, 2H), 4.89 (s, 2H), 3.85 (d, J = 11.3 Hz, 1H), 3.64 (ddd, J = 11.3, 9.4, 3.9 Hz, 1H), 2.39 - 2.25 (m, 1H), 2.05 - 1.85 (m, 2H), 1.71 (d, J = 11.6 Hz, 1H), 1.54 (t, J = 4.6 Hz, 2H), 0.87 (s, 9H), 0.08 (d, J = 1.5 Hz, 6H).

[0204] Step 5: 6-Bromo-l-(3-(((tert-butyldimethylsilyl)oxy)methyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-6-yl)-4-fluoro-lH-benzo[d][l,2,3]triazole (27-5)

[0205] To 5-bromo-Nl-(3-(((tert-butyldimethylsilyl)oxy)methyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-6-yl)-3-fluorobenzene-l,2-diamine (4.2 g, 7.64 mmol) in a reaction flask, 50 ml acetonitrile was added to dissolve, dropwise added isoamyl nitrite (1.34 g, 11.46 mmol), heated and stirred at 65 °C. After about 1 hour, TLC monitoring reaction was complete, the solvent was removed by rotary evaporation, the crude product was purified by silica gel column chromatography (PE / EA = 12 / 1) to give 6-bromo-l-(3-(((tert-butyldimethylsilyl)oxy)methyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-6-yl)-4-fluoro-lH-benzo[d][l,2,3]triazole, black oily liquid (2.186 g, 3.90 mmol), yield 51.03%.

[0206] 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 1.8 Hz, 1H), 8.12 - 8.05 (m, 2H), 7.75 (dd, J = 9.9, 1.4 Hz, 1H), 7.69 (dd, J = 8.5, 1.8 Hz, 1H), 6.03 (dd, J = 9.6, 2.3 Hz, 1H), 5.15 - 5.05 (m, 2H), 3.89 (d, J = 11.6 Hz, 1H), 3.78 (dt, J = 12.0, 6.8 Hz, 1H), 2.44 (d, J = 11.6 Hz, 1H), 2.03 (d, J = 15.7 Hz, 2H), 1.77 (s, 1H), 1.66 - 1.56 (m, 2H), 0.92 (s, 9H), 0.15 (d, J = 1.5 Hz, 6H).

[0207] Step 6: (6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-l-(tetrahydro-2H-pyran-2- yl)-lH-indazol-3-yl)methanol (27-6)

[0208] To 6-bromo-l-(3-(((tert-butyldimethylsilyl)oxy)methyl)-l-(tetrahydro-2H-pyran-2-yl)-lH- indazol-6-yl)-4-fluoro-lH-benzo[d][l,2,3]triazole (3.63 g, 6.48 mmol) in a reaction flask, add 50 mL of tetrahydrofuran, dissolve, stir the reaction at room temperature, after about 30 minutes, monitor the reaction by TLC, extract with EA and water, collect the organic phase, dry over anhydrous sodium sulfate, concentrate to get (6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3- yl)methanol, black oil (1.748 g, 3.92 mmol), yield 60.48%, without purification, directly to the next step.

[0209] Step 7: 2-((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH- indazol-3-yl)methoxy)-2-(diethoxyphosphoryl)acetic acid ethyl ester (27-7)

[0210] To a reaction flask was taken ((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-lH-indazol-3-yl)methoxy)methyl)phosphonic acid (1 g, 2.24 mmol) dissolved in 10 mL of toluene, 2-diazo-2-(diethoxyphosphoryl)acetic acid ethyl ester (673 mg, 2.69 mmol) was added drop wise, 10 mg of rhodium dimeric acetate was added, heated to reflux at 100 °C overnight, after completion of the reaction monitored by TLC, toluene was removed by rotary evaporation, the crude product was purified by column chromatography on silica gel to get 2-((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)methoxy)-2-(diethoxyphosphoryl)acetic acid ethyl ester as brownish oil (965 mg, 1.44 mmol), 64.43 % yield.

[0211] 1 H NMR (400 MHz, DMSO-d6) δ 8.34 - 8.24 (m, 2H), 8.07 (d, J = 1.5 Hz, 1H), 7.75 (ddd, J = 8.3, 6.9, 1.6 Hz, 2H), 6.06 (dt, J = 9.6, 2.1 Hz, 1H), 5.13 - 4.97 (m, 2H), 4.89 (dd, J = 19.2, 1.6 Hz, 1H), 4.13 - 4.06 (m, 6H), 3.91 - 3.75 (m, 2H), 2.41 (d, J = 20.0 Hz, 1H), 2.08 - 1.99 (m, 2H), 1.77 (d, J = 12.6 Hz, 1H), 1.61 (q, J = 9.0, 6.5 Hz, 2H), 1.25 - 1.22 (m, 9H).

[0212] Step 8: (l-((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)methoxy)-2-hydroxyethyl)phosphonic acid diethyl ester (27-8)

[0213] To a reaction vial was added 2-((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-l- (tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)methoxy)-2-(diethoxyphosphoryl)acetic acid ethyl ester (207 mg, 309.67 umol) dissolved in 2 mL THF and placed in an ice bath and stirred until the temperature dropped to 0 °C. A solution of LiBH4 in tetrahydrofuran (2 M, 620 uL, 1.24 mmol) was added dropwise and the reaction was allowed to warm to room temperature. After about 2 hours, the reaction was monitored by TLC and was complete. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate and water. The organic phase was collected and dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation to give (l-((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-l- (tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)methoxy)-2-hydroxyethyl)diethyl phosphonate as a yellow oily liquid (152 mg, 242.65 umol) in 78.36% yield.

[0214] 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 1.4 Hz, 1H), 7.75 (dd, J = 9.9, 1.4 Hz, 1H), 7.69 (dd, J = 8.5, 1.7 Hz, 1H), 6.04 (d, J = 8.7 Hz, 1H), 5.13 (t, J = 8.8 Hz, 3H), 4.12 - 4.04 (m, 5H), 3.88 (s, 1H), 3.81 (d, J = 8.5 Hz, 2H), 3.66 (dd, J = 12.8, 6.7 Hz, 1H), 2.44 (s, 1H), 2.06 (s, 2H), 1.77 (s, 1H), 1.60 (s, 2H), 1.24 (ddd, J = 7.1, 2.9, 1.3 Hz, 6H).

[0215] Step 9: (l-((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-lH-indazol-3- yl)methoxy)-2-hydroxyethyl)diethyl phosphonate (27-9)

[0216] Take (1-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methoxy)-2-hydroxyethyl)phosphonic acid diethyl ester (73 mg, 116.54 μmol) in a reaction bottle, dissolve in 2 mL of dichloromethane, stir in an ice bath, and drop 1 mL of trifluoroacetic acid when the temperature drops to 0°C. TLC monitoring reaction complete for about 30 minutes. Quench with saturated sodium bicarbonate solution, extract with EA, collect the organic phase, dry over anhydrous sodium sulfate, and rotary evaporate to remove the solvent to obtain the crude product. The crude product is separated and purified by silica gel column chromatography to obtain (1-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)-2-hydroxyethyl)phosphonic acid diethyl ester, yellow oil (50 mg, 92.20 μmol), yield 79.12%.

[0217] Step 10: (1-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)-2-hydroxyethyl)phosphonic acid (27)

[0218] Take (1-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methoxy)-2-hydroxyethyl)phosphonic acid diethyl ester (50 mg, 92.20 μmol) in a reaction bottle, dissolve in 2 mL of anhydrous 1,2-dichloroethane, and protect with nitrogen. Stir in an ice bath until the temperature drops to 0°C, then slowly drop trimethylsilyl bromide (424 mg, 2.77 mmol), and move to room temperature for reaction. After TLC monitoring reaction complete, rotary evaporate to remove the solvent, and purify the crude product by soaking in dichloromethane and ethyl acetate to obtain (1-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)-2-hydroxyethyl)phosphonic acid, yellow solid (16 mg, 32.91 μmol), yield 35.69%.

[0219] 1H NMR (600 MHz, DMSO-d6) δ 13.28 (s, 1H), 8.30 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 1.4 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.72 (dd, J = 9.9, 1.4 Hz, 1H), 7.57 (dd, J = 8.5, 1.8 Hz, 1H), 5.21 (d, J = 11.2 Hz, 1H), 5.06 (d, J = 11.2 Hz, 1H), 3.82 - 3.79 (m, 2H), 3.75 - 3.72 (m, 2H), 3.60 (ddd, J = 11.9, 8.9, 4.4 Hz, 2H).

[0220] (1-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methoxy)-2-methoxyethyl)phosphonic acid diethyl ester (28-1)

[0221] Step 1: (1-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methoxy)-2-methoxyethyl)phosphonic acid diethyl ester (28-1)

[0222] To a reaction flask containing (1-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methoxy)-2-hydroxyethyl)phosphonic acid diethyl ester (136 mg, 265 μmol) was added 1,8-bisdimethylaminonaphthalene (228 mg, 1.06 mmol), trimethyl oxonium tetrafluoroborate (118 mg, 795 μmol) and molecular sieves, dissolved in 2.5 mL of anhydrous dichloromethane, protected from N2, and allowed to react at room temperature. After 2 hours, the reaction was monitored by TLC and was complete. The reaction was quenched with sodium bicarbonate and extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography to give (1-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methoxy)-2-methoxyethyl)phosphonic acid diethyl ester as a white solid (68 mg, 106 μmol, 40.07% yield).

[0223] 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 1.8 Hz, 1H), 8.21 (dd, J = 8.6, 2.6 Hz, 1H), 8.06 (d, J = 1.4 Hz, 1H), 7.73 (ddd, J = 18.8, 9.2, 1.5 Hz, 2H), 6.07 - 6.00 (m, 1H), 5.24 - 4.99 (m, 2H), 4.24 (ddt, J = 10.4, 8.2, 2.4 Hz, 1H), 4.10 (dq, J = 9.4, 7.2 Hz, 4H), 3.89 (dd, J = 11.1, 4.0 Hz, 1H), 3.79 (dt, J = 11.8, 6.6 Hz, 1H), 3.73 - 3.58 (m, 2H), 3.33 (s, 3H), 2.48 - 2.33 (m, 1H), 2.03 (dt, J = 16.3, 5.6 Hz, 2H), 1.61 (d, J = 8.0 Hz, 2H), 1.25 (tt, J = 3.1, 1.5 Hz, 6H).

[0224] Synthesis of steps 2 and 3 was the same as steps 9 and 10 of Example 27. Yield 40.44%. 1 H NMR (600 MHz, DMSO-d6) δ 13.30 (s, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.99 (d, J = 1.7 Hz, 1H), 7.72 (d, J = 9.8 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.20 (d, J = 11.3 Hz, 1H), 5.02 (d, J = 11.2 Hz, 1H), 3.93 - 3.86 (m, 2H), 3.68 (d, J = 11.5 Hz, 2H), 3.56 (m, J = 11.7, 8.9, 3.3 Hz, 2H), 3.27 (s, 3H).

[0225] (2-((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-lH-indazol-3-yl)methoxy)-l- hydroxy-3-methoxypropan-2-yl)phosphonic acid (Compound 29)

[0226] Step 1: Ethyl 2-((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-l-(tetrahydro-2H-pyran- 2-yl)-lH-indazol-3-yl)methoxy)-2-(diethoxyphosphoryl)-3-methoxypropanoate (29-1)

[0227] Take 2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)methoxy)-2-(diethoxyphosphoryl)acetic acid ethyl ester (130 mg, 194.48 μmol) in a reaction bottle, dissolve in 2 mL of anhydrous THF, protect under N2, place the system in -15°C, slowly drop sodium bis(trimethylsilyl)amide (253 μL, 253 μmol), stir for 30 min, then add tetrabutylammonium iodide (36 mg, 97.24 μmol), immediately drop chloromethyl methyl ether (56 μL, 680.67 μmol) dropwise. Stir the solution at this temperature for 2 h, monitor the reaction completion by TLC, quench with saturated aqueous ammonium chloride solution, extract with ethyl acetate, collect the organic phase, dry over anhydrous sodium sulfate, remove the solvent by rotary evaporation, purify the crude product by silica gel column chromatography to obtain 2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)methoxy)-2-(diethoxyphosphoryl)-3-methoxypropanoic acid ethyl ester, yellow oily product (137 mg, 131.93 μmol), yield 67.84%.

[0228] 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 8.6 Hz, 1H), 8.26 (s, 1H), 8.05 (s, 1H), 7.71 (dd, J = 15.7, 9.2 Hz, 2H), 6.03 (dd, J = 9.6, 2.3 Hz, 1H), 5.17 (qd, J = 10.8, 3.1 Hz, 2H), 4.28 (q, J = 7.1, 6.6 Hz, 2H), 4.15 - 4.05 (m, 6H), 4.02 (t, J = 5.4 Hz, 2H), 3.91 - 3.73 (m, 2H), 3.36 (s, 3H), 2.43 (d, J = 11.8 Hz, 1H), 1.99 (s, 2H), 1.76 (s, 1H), 1.58 (s, 2H), 1.28 - 1.17 (m, 13H).

[0229] Step 2: (2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)methoxy)-1-ethoxy-3-methoxypropan-2-yl)diethyl phosphonate (29-2)

[0230] Take 2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)methoxy)-2-(diethoxyphosphoryl)-3-methoxypropanoic acid ethyl ester (129 mg, 181.05 μmol) in a reaction bottle, add calcium dichloride (61 mg, 543.15 μmol), dissolve in ethanol, place in an ice bath, and slowly add sodium borohydride (21 mg, 543.15 μmol) to the solution after the temperature drops to 0°C, transfer to room temperature reaction, about half an hour later, TLC monitoring reaction is complete, saturated ammonium chloride solution is quenched, extracted with ethyl acetate and water, collect the organic phase, dry over anhydrous sodium sulfate, concentrate and mix the sample, the crude product is separated and purified by silica gel column chromatography to obtain (2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)methoxy)-1-ethoxy-3-methoxypropan-2-yl) diethyl phosphonate yellow oil (95 mg, 138.00 μmol), yield 75.12%.

[0231] 1 H NMR (400 MHz, DMSO-d6) δ 8.29 - 8.22 (m, 2H), 8.03 (d, J = 1.4 Hz, 1H), 7.74 - 7.63 (m, 2H), 6.00 (d, J = 9.2 Hz, 1H), 5.21 - 5.08 (m, 3H), 4.15 - 3.97 (m, 6H), 3.93 - 3.71 (m, 7H), 2.47 - 2.33 (m, 1H), 2.01 (d, J = 18.1 Hz, 3H), 1.75 (s, 1H), 1.58 (s, 2H), 1.31 - 1.14 (m, 9H).

[0232] The synthesis of steps 3 and 4 is the same as steps 9 and 10 of Example 27. Yield 54.45%. 1 H NMR (600 MHz, DMSO-d6) δ 13.23 (s, 1H), 8.29 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 1.4 Hz, 1H), 7.96 (s, 1H), 7.71 (d, J = 9.9, 1.4 Hz, 1H), 7.55 (d, J = 8.5, 1.8 Hz, 1H), 5.21 - 5.13 (m, 2H), 4.03 (q, J = 7.1 Hz, 1H), 3.87 - 3.81 (m, 4H), 3.77 (d, J = 10.5, 8.6 Hz, 2H), 3.34 (s, 3H).

[0233] (2-((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-l-(tetrahydro-2H-pyran-2-yl)- lH-indol-3-yl)methoxy)-l-hydroxypropan-2-yl)phosphonic acid (Compound 30)

[0234] Step 1: Ethyl 2-((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-l-(tetrahydro-2H- pyran-2-yl)-lH-indol-3-yl)methoxy)-2-(diethoxyphosphoryl)propanoate (30-1)

[0235] To a reaction flask containing ethyl 2-((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l- yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indol-3-yl)methoxy)-2-(diethoxyphosphoryl)propanoate (350 mg, 523.59 pmol) was added cesium carbonate (683 mg, 2.09 mmol) in DMF and iodomethane (372 mg, 2.62 mmol) was added under stirring at 40 °C. The reaction was monitored by TLC and upon completion, the reaction mixture was extracted with ethyl acetate and water. The organic layer was collected and dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography to obtain ethyl 2-((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indol-3- yl)methoxy)-2-(diethoxyphosphoryl)propanoate as a yellow liquid (266 mg, 389.75 pmol, 74.44% yield).

[0236] 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (dd, J = 8.5, 3.2 Hz, 1H), 8.29 (s, 1H), 8.06 (t, J = 1.8 Hz, 1H), 7.74 (m, J = 14.2, 9.3, 1.6 Hz, 2H), 6.04 (d, J = 9.3 Hz, 1H), 5.07 - 4.93 (m, 2H), 4.29 (p, J = 6.9 Hz, 3H), 3.91 - 3.75 (m, 2H), 3.66 (d, J = 11.1 Hz, 1H), 2.44 (d, J = 14.9 Hz, 1H), 1.77 (d, J = 15.9 Hz, 5H), 1.60 (s, 3H), 1.39 - 1.31 (m, 9H).

[0237] The synthesis of steps 2, 3 and 4 was same as example 29. Yield 70.84%. 1H NMR (600 MHz, DMSO-d6) δ 13.22 (s, 1H), 8.31 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 1.4 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.71 (dd, J = 9.9, 1.4 Hz, 1H), 7.54 (dd, J = 8.5, 1.8 Hz, 1H), 5.10 (s, 2H), 3.94 - 3.90 (m, 1H), 3.69 - 3.61 (m, 2H), 3.45 - 3.41 (m, 1H), 1.43 (d, J = 14.6 Hz, 3H).

[0238] (2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H-indol-3-yl)methoxy)-3-phenylpropan-2-yl)phosphonic acid (Compound 31)

[0239] To a reaction flask containing 2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H-indol-3-yl)methoxy)-2-(diethoxyphosphoryl)acetic acid ethyl ester (27-7, 150 mg, 224.40 pmol) was added cesium carbonate (146 mg, 448.79 pmol) in DMF and benzyl bromide (115 mg, 673.19 pmol) was added dropwise. The reaction was stirred at room temperature and monitored by TLC. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and water. The organic layer was collected and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography to give 2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H-indol-3-yl)methoxy)-2-(diethoxyphosphoryl)-3-phenylpropanoic acid ethyl ester as a yellow oily liquid (31-1 90 mg, 118.64 pmol) in 53% yield.

[0240] 1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.05 (d, J = 4.7 Hz, 1H), 7.83 - 7.73 (m, 2H), 7.51 (d, J = 8.7 Hz, 1H), 7.25 - 7.13 (m, 5H), 6.03 (d, J = 9.7 Hz, 1H), 5.33 - 5.18 (m, 2H), 4.29 - 4.20 (m, 7H), 3.84 (d, J = 33.5 Hz, 2H), 3.46 (d, J = 13.4 Hz, 1H), 2.43 (s, 1H), 2.05 (s, 2H), 1.81 (d, J = 31.1 Hz, 1H), 1.60 (s, 2H), 1.34 (m, J = 7.2, 3.5 Hz, 9H).

[0241] The synthesis of steps 2, 3 and 4 is the same as in example 29. Yield 80%. 1 H NMR (600 MHz, DMSO-d6) δ 8.06 - 8.01 (m, 2H), 7.96 (d, J = 1.8 Hz, 1H), 7.71 (dd, J = 9.8, 1.4 Hz, 1H), 7.48 (dd, J = 8.5, 1.8 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.26 - 7.13 (m, 3H), 5.31 (d, J = 10.9 Hz, 1H), 5.18 (d, J = 10.9 Hz, 1H), 3.72 (t, J = 11.1 Hz, 1H), 3.64 - 3.58 (m, 1H), 3.27 (dd, J = 14.0, 10.9 Hz, 1H), 3.18 (dd, J = 14.0, 8.0 Hz, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 153.19, 151.46, 143.83, 141.07, 136.95, 136.89, 136.41, 136.36, 135.56, 135.44, 133.89, 131.49, 131.42, 128.03, 127.87, 126.48, 123.62, 122.47, 122.17, 122.12, 116.33, 113.96, 113.82, 111.23, 111.19, 106.01, 80.22, 79.22, 61.66, 61.62, 60.83, 36.35, 36.31. LC-MS / ESI [M-H] - 630.1

[0242] (1-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)-2- ethoxy-2-oxoethyl)phosphonic acid (Compound 32)

[0243] Yield 96.29%. 1 H NMR (400 MHz, DMSO-d6) δ 13.39 (s, 1H), 8.34 (d, J = 8.6 Hz, 1H), 8.06 (s, 1H), 7.98 (s, 1H), 7.71 (d, J = 10.0 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 5.19 (d, J = 11.4 Hz, 1H), 4.94 (d, J = 11.3 Hz, 1H), 4.28 (d, J = 19.2 Hz, 1H), 3.79 (d, J = 9.5 Hz, 4H), 1.04 (t, J = 7.0 Hz, 3H).

[0244] ((((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)methyl)(phenoxy)phosphoryl)-D-alanin isopropyl ester (compound 33)

[0245] Step 1: ethyl hydrogen (((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)methyl)phosphonate (33-1)

[0246] Take compound 1-9 (220 mg, 0.43 mmol), lithium hydroxide monohydrate (180 mg, 4.20 mmol) in a reaction bottle, add 5 mL THF and 1.2 mL water, after reaction at room temperature for 2 d, add 20 mL water to dilute the reaction solution, adjust pH = 5 with 1N hydrochloric acid, 50 mL EA extraction. Collect the organic phase, dry over anhydrous sodium sulfate, rotary evaporation to remove the solvent, get 33-1 white solid 150 mg, the product does not need to be further purified. The product yield is 72.1%.

[0247] 1 H NMR (400 MHz, DMSO-d6) δ 13.50 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 1.4 Hz, 1H), 8.08 (d, J = 1.8 Hz, 1H), 7.78 (dd, J = 10.0, 1.4 Hz, 1H), 7.67 (dd, J = 8.6, 1.8 Hz, 1H), 5.05 (s, 2H), 4.02 (p, J = 7.2 Hz, 2H), 3.81 (d, J = 8.6 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H).

[0248] Step 2: phenyl (((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-lH-indazol-3-yl)methoxy)methyl) phosphonate (33-2)

[0249] To a reaction vial was placed compound 33-1 (100 mg, 0.21 mmol), added was DCM 1 mL, after injection of thionyl chloride (45 μL, 0.62 mmol), one drop of DMF was added as catalyst. After 1 h, the reaction was roto-evaporated to dryness, phenol (39 mg, 0.41 mmol) was added, the reaction was re-dissolved in 1 mL of dry DCM, triethylamine (200 μL, 1.45 mmol) was added dropwise, after 2 h of reaction at room temperature, the solvent was removed by roto-evaporation, the residue was loaded on a column to give 33-2 as a white solid 55 mg. The product yield was 56.2%.

[0250] 1 H NMR (400 MHz, DMSO-d6) δ 13.52 (s, 1H), 8.17 (d, J = 8.6 Hz, 1H), 8.10 (dd, J = 10.6, 1.6 Hz, 2H), 7.78 (dd, J = 9.9, 1.4 Hz, 1H), 7.67 (dd, J = 8.6, 1.8 Hz, 1H), 7.47 - 7.36 (m, 2H), 7.30 - 7.15 (m, 3H), 5.11 (d, J = 1.7 Hz, 2H), 4.25 (tt, J = 8.3, 6.5 Hz, 2H), 4.17 (dd, J = 8.1, 2.8 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H).

[0251] Step 3: phenyl ((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-lH-indazol-3- yl)methoxy)methyl) hydrogen phosphonate (33-3)

[0252] To a reaction vial was placed compound 33-2 (60 mg, 0.11 mmol), added was DCM 2 mL, after injection of TMS-Br (71 μL, 0.55 mmol), the reaction was allowed to proceed overnight at room temperature, 2 mL of methanol was added, the solvent was removed by roto-evaporation, EA was added to slurry the product, which was filtered to give 33-3 as a white solid 50 mg. The product yield was 87.7% without further purification.

[0253] Step 4: isopropyl ((((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-lH-indazol-3- yl)methoxy)methyl)(phenoxy)phosphoryl)-D-alaninate (33)

[0254] Take compound 33-3 (100 mg, 0.19 mmol) in a reaction bottle, add anhydrous DCM 1 mL, after injecting oxalyl chloride (48 μL, 0.56 mmol), drop in a drop of DMF catalyst, the reaction is rapid bubble. 1 h after spin dry reaction liquid, add L-alanine isopropyl ester hydrochloride (63 mg, 0.38 mmol), redissolve the reaction with 1 mL of anhydrous DCM, drop in anhydrous triethylamine (104 μL, 0.75 mmol), room temperature reaction overnight, rotary evaporation to remove the solvent, the residue on the column to get 33 white solid 32 mg.

[0255] Product yield 26.4%. 1 H NMR (400 MHz, DMSO-d6) δ 13.50 (s, 1H), 8.16 (d, J = 7.1 Hz, 1H), 8.05 (d, J = 8.9 Hz, 2H), 7.75 (d, J = 9.8 Hz, 1H), 7.69 - 7.56 (m, 1H), 7.35 (t, J = 8.0 Hz, 2H), 7.18 (q, J = 7.7, 6.9 Hz, 3H), 5.77 (q, J = 11.9 Hz, 1H), 5.06 (d, J = 11.2 Hz, 2H), 4.84 (dt, J = 11.9, 5.9 Hz, 1H), 4.02 - 3.79 (m, 3H), 1.29 - 1.09 (m, 9H). LC-MS / ESI [M-H] - 643.05

[0256] 2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)-1- hydroxy-3-(2H-tetrazol-5-yl)propan-2-yl)phosphonic acid (34)

[0257] Step 1: ethyl 2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazole-5-carboxylate (34-2)

[0258] Compound 34-1 (10.00 g, 70.36 mmol) was dissolved in THF, NaH (2.03 g, 84.43 mmol) was added under ice bath condition, followed by SEM-Cl (14.08 g, 84.43 mmol). Reaction at room temperature, TLC monitoring reaction complete, add water to quench the reaction liquid, ethyl acetate extraction, to get intermediate 34-2 (20.00 g, 73.43 mmol), yield 98%.

[0259] 1H NMR (400 MHz, DMSO-d6) δ 6.14 (s, 2H), 4.49 (q, J = 7.0 Hz, 2H), 3.73 (t, J = 7.5 Hz, 2H), 1.40 (t, J = 5.8 Hz, 3H), 0.92 (t, J = 9.4 Hz, 2H), -0.00 (s, 9H).

[0260] Step 2: (2-((2-(Trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)methanol (34-3)

[0261] Compound 34-2 (1.00 g, 4.30 mmol) was dissolved in MeOH, NaBH4(0.33 g, 8.60 mmol) was added under ice bath condition. The reaction was stirred at room temperature until TLC showed the reaction was completed. The reaction was quenched with water, extracted with ethyl acetate, to give intermediate 34-3 (0.80 g, 3.47 mmol) in 80% yield.

[0262] 1 H NMR (400 MHz, DMSO-d6) δ 6.14 (s, 2H), 4.49 (q, J = 7.0 Hz, 2H), 3.73 (t, J = 7.5 Hz, 2H), 1.40 (t, J = 5.8 Hz, 3H), 0.92 (t, J = 9.4 Hz, 2H), -0.00 (s, 9H).

[0263] Step 3: 5-(Bromomethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazole (34-4)

[0264] Compound 34-3 (0.20 g, 0.87 mmol), PPh3(0.46 g, 1.74 mmol) was dissolved in DCM, NBS (0.31 g, 1.74 mmol) was added. The reaction was monitored by TLC until it was completed. The reaction was quenched with water, extracted with ethyl acetate, purified by column chromatography to give intermediate 34-4 (0.40 g, 0.17 mmol) in 40% yield.

[0265] 1 H NMR (400 MHz, DMSO-d6) δ 6.14 (s, 2H), 4.49 (q, J = 7.0 Hz, 2H), 3.73 (t, J = 7.5 Hz, 2H), 1.40 (t, J = 5.8 Hz, 3H), 0.92 (t, J = 9.4 Hz, 2H), -0.00 (s, 9H).

[0266] Step 4: Ethyl 2-((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-l- (tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)methoxy)-2-(diethoxyphosphoryl)-3- (2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)propanoate (34-5)

[0267] Compound 27-7 (0.27 g, 0.40 mmol) was dissolved in toluene (5 mL), TBAI (75 mg, 0.20 mmol) was added under ice bath condition, followed by intermediate 34-4 (0.23 g, 0.80 g), 50% KOH solution (1 mL), the reaction was stirred at room temperature, TLC was used to monitor the completion of the reaction, the reaction was quenched by saturated ammonium chloride solution, extracted by ethyl acetate to give intermediate 34-5 (0.15 g, 0.17 mmol) as yellow oil, yield 42%.

[0268] 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 1.9 Hz, 1H), 8.17 - 8.02 (m, 2H), 7.86 (dd, J = 9.9, 1.4 Hz, 1H), 7.69 (dt, J = 8.6, 1.6 Hz, 1H), 6.15 - 5.98 (m, 3H), 5.49 (dd, J = 10.8, 4.6 Hz, 1H), 5.30 (d, J = 11.1 Hz, 1H), 4.47 - 4.29 (m, 5H), 4.15 (d, J = 7.1 Hz, 1H), 4.02 - 3.85 (m, 3H), 3.85 - 3.76 (m, 1H), 3.70 (ddd, J = 9.2, 7.5, 2.0 Hz, 2H), 2.58 - 2.47 (m, 1H), 2.14 (s, 2H), 1.86 (d, J = 9.2 Hz, 1H), 1.70 (s, 2H), 1.29 - 1.40 (m, 9H), 0.96 - 0.81 (m, 2H), 0.00 (s, 9H).

[0269] Step 5: (2-((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-l-(tetrahydro-2H- pyran-2-yl)-lH-indazol-3-yl)methoxy)-l-ethoxy-l-oxo-3-(2-((2- (trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)propan-2-yl)phosphonic acid triethylammonium salt (34-6)

[0270] Compound 34-5 (117 mg, 0.13 mmol) was dissolved in CH3CN (5 mL), followed by the addition of TEA (0.27 g, 2.65 mmol) and TMSBr (0.30 g, 1.95 mmol). The reaction was carried out at room temperature, and the reaction was monitored by TLC until it ended. The reaction solution was evaporated to dryness to obtain intermediate 34-6, which did not require purification.

[0271] Step 6: (2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)-1-ethoxy-1-oxo-3-(2H-tetrazol-5-yl)prop-2-yl)phosphonate triethylammonium salt (compound 34)

[0272] The crude compound 34-6 obtained in the previous step was dissolved in methanol (1 mL), and 2 mL of hydrochloric acid methanol solution was added. The reaction was monitored by TLC until complete. The reaction solution was evaporated to dryness and purified by preparative liquid chromatography to obtain a pale yellow solid compound 34 (40 mg, 0.07 mmol), with a yield of 50%.

[0273] m / z(ESI, -ve ion) = 608.0, [MH] - , 1 H NMR (400MHz, DMSO) δ13.25(s,1H),10.32(s,1H),8.01(d,J=1.3Hz,1H),7.90(d,J=9.5Hz,2H ),7.76–7.67(m,1H),7.41(d,J=8.7Hz,1H),5.21(d,J=10.5Hz,1H),5.06(d,J=10.6Hz,1H), 4.26(t,J=9.0Hz,1H),4.16(d,J=10.3Hz,1H),3.87(d,J=16.3Hz,1H),3.72(d,J=7.9Hz,1H) ,3.22(s,1H),3.17(s,1H),3.10–3.02(m,4H),1.24(t,J=7.1Hz,3H),1.20(t,J=7.3Hz,6H).. 13 C NMR(151MHz,DMSO)δ171.52,152.26(d,J CF =261.2Hz),143.64,140.96,136.30,135.42(d,J CF =18.1Hz),133.70,123.69,122.35,122.08(d,J CF =7.1Hz), 116.02, 113.83 (d, J) CF= 18.3 Hz), 111.07, 105.76, 82.33, 62.59, 61.05, 45.69, 29.48, 14.47, 8.80.

[0274] (2-((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-lH-indazol-3-yl)methoxy)-l- hydroxy-3-(2H-tetrazol-5-yl)propan-2-yl)phosphonic acid triethylammonium salt (Compound 35)

[0275] Step 1: Diethyl (2-((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-l-(tetrahydro- 2H-pyran-2-yl)-lH-indazol-3-yl)methoxy)-l-hydroxy-3-(2-((2-(trimethylsilyl)ethoxy)methyl)- 2H-tetrazol-5-yl)propan-2-yl)phosphonate (35-1)

[0276] Intermediate 27-2 (0.34 g, 0.40 mmol) was dissolved in ethanol (5 mL), CaCl2(75 mg, 0.20 mmol) was added under ice bath condition, NaBH4(67 mg, 1.79 mmol) was added. The reaction was stirred at room temperature until TLC showed the reaction was completed. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate to give intermediate 35-1 (0.53 g, 0.63 mmol) in 86% yield.

[0277] 1 H NMR (400 MHz, DMSO) δ 8.33 (d, J = 1.9 Hz, 1H), 8.29 - 8.23 (m, 1H), 8.11 (d, J = 1.4 Hz, 1H), 7.83 (dd, J = 9.9, 1.4 Hz, 1H), 7.70 (dd, J = 8.6, 1.8 Hz, 1H), 6.10 (dd, J = 9.7, 2.3 Hz, 1H), 6.03 (s, 2H), 5.40 (dd, J = 5.1, 3.6 Hz, 2H), 4.21 - 4.06 (m, 6H), 3.96 (d, J = 11.5 Hz, 1H), 3.90 - 3.83 (m, 1H), 3.72 (t, J = 8.0 Hz, 2H), 3.63 (dt, J = 12.3, 3.2 Hz, 2H), 2.50 (m, 1H), 2.14 (m, 2H), 1.84 (m, 1H), 1.68 (m, 2H), 1.28 (m, 6H), 0.94 - 0.88 (m, 2H), 0.00 (s, 9H).

[0278] Steps 2, 3 same as synthesis of Example 34

[0279] Yield 36%, pale yellow solid.

[0280] m / z (ESI, -ve ion) = 566.0 [M-H] - . 1 H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 10.32 (s, 1H), 8.01 (d, J = 1.3 Hz, 1H), 7.90 (d, J = 9.5 Hz, 2H), 7.70 (dd, J = 9.9, 1.3 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 5.21 (d, J = 10.5 Hz, 1H), 5.06 (d, J = 10.6 Hz, 1H), 4.27 (d, J = 10.7 Hz, 1H), 4.20 - 4.13 (m, 1H), 3.87 (d, J = 16.8 Hz, 1H), 3.72 (d, J = 7.9 Hz, 1H), 3.17 (s, 1H), 3.06 (s, 1H), 1.24 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, DMSO) δ 152.31 (d, J = 259.7 Hz), 143.99, 140.97, 136.35, 135.48 (d, J = 18.1 Hz), 133.83, 123.48, 122.41, 122.11 (d, J = 9.1 Hz), 116.19, 113.93, 113.80 (d, J = 22.5 Hz), 111.19, 105.87, 78.83, 77.86 (d, J = 146.5 Hz), 62.31, 60.20, 46.10, 9.05. CF = 259.7 Hz), 111.19, 105.87, 78.83, 77.86 (d, J = 146.5 Hz), 62.31, 60.20, 46.10, 9.05. CF = 259.7 Hz), 111.19, 105.87, 78.83, 77.86 (d, J = 146.5 Hz), 62.31, 60.20, 46.10, 9.05. CF = 259.7 Hz), 111.19, 105.87, 78.83, 77.86 (d, J = 146.5 Hz), 62.31, 60.20, 46.10, 9.05. CF = 259.7 Hz), 111.19, 105.87, 78.83, 77.86 (d, J = 146.5 Hz), 62.31, 60.20, 46.10, 9.05. PC = 259.7 Hz), 111.19, 105.87, 78.83, 77.86 (d, J = 146.5 Hz), 62.31, 60.20, 46.10, 9.05.

[0281] (2-((6-(6-bromo-4-fluoro-(1-((2H-tetrazol-5-yl)methoxy)-2-((6-(6-bromo-4-fluoro-1H- benzo[d][1,2,3]triazol-1-yl)-1 H-indol-3-yl)methoxy)-3-(2H-tetrazol-5-yl)prop-2-yl)phosphonic acid triethylammonium salt (Compound 36)

[0282] Step 1: Diethyl (2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1- (tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)methoxy)-1-(2-((2-(trimethylsilyl)ethoxy)methyl)- 2H-tetrazol-5-yl)-3-((2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)methoxy)propan- 2-yl)phosphonate (36-1)

[0283] Compound 35-1 (0.10 g, 0.12 mmol), 34-4 (0.17 g, 0.60 mmol) were dissolved in DMF (4 mL) under ice-bath condition, then NaH (60%, 12 mg, 0.30 mmol) was added, and the reaction was stirred for 30 min under ice-bath condition. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, dried under reduced pressure, and purified by column chromatography (PE:EA = 20:80) to obtain 36-1 (0.25 g, 0.24 mmol) as a light yellow oil at a yield of 64%.

[0284] 1 H NMR (400 MHz, DMSO-d6) δ 8.39 - 8.33 (m, 1H), 8.24 (dd, J = 8.6, 4.1 Hz, 1H), 8.13 (d, J = 1.4 Hz, 1H), 7.85 (dd, J = 9.9, 1.3 Hz, 1H), 7.69 (dd, J = 8.5, 1.8 Hz, 1H), 6.12 (dd, J = 9.8, 2.4 Hz, 1H), 6.09 (s, 2H), 6.06 (s, 2H), 5.43 (dd, J = 10.3, 5.4 Hz, 1H), 5.32 (dd, J = 10.8 Hz, 1H), 5.06 (t, J = 2.6 Hz, 2H), 4.33 - 4.25 (m, 1H), 4.21 - 4.11 (m, 6H), 3.98 (d, J = 10.6 Hz, 1H), 3.93 - 3.84 (m, 1H), 3.77 (d, J = 7.6 Hz, 2H), 3.73 (d, J = 7.5 Hz, 2H), 3.66 - 3.55 (m, 1H), 2.58 - 2.47 (m, 1H), 2.22 - 2.12 (m, 2H), 1.95 - 1.82 (m, 1H), 1.70 (s, 2H), 1.31 - 1.29 (m, 3H), 1.28 - 1.27 (m, 3H), 0.98 - 0.88 (m, 4H), 0.03 (s, 9H), -0.00 (s, 9H).

[0285] Steps 2, 3 are the same as those in Synthetic Example 34.

[0286] Yield: 64%, light yellow solid. m / z (ESI, -ve ion) = 608.0, 1 H NMR (400 MHz, DMSO-d6) δ 13.21 (s, 1H), 9.10 (s, 0.2H), 8.02 (d, J = 1.3 Hz, 1H), 7.98 - 7.86 (m, 2H), 7.70 (dd, J = 9.9, 1.4 Hz, 1H), 7.38 (dd, J = 8.7, 1.7 Hz, 1H), 5.32 (d, J = 10.9 Hz, 1H), 5.08 (d, J = 11.0 Hz, 1H), 4.99 (dd, 2H), 4.12 (t, 1H), 4.0 (t, 1H), 3.56 (s, 1H), 3.39 (s, 1H), 3.09 (d, J = 7.1 Hz, 1H), 1.17 (t, J = 7.3 Hz, 2H). 13 C NMR (151 MHz, DMSO) δ 155.37, 152.32 (d, J = 261.2 Hz), 143.70, 140.96, 136.35 (d, J = 3.0 Hz), 135.49 (d, J = 18.1 Hz), 133.82, 123.32, 122.33, 122.14 (d, J = 7.6 Hz), 116.19, 113.88 (d, J = 21.1 Hz), 111.19 (d, J = 6.0 Hz), 105.88, 78.83 (d, J = 3.0 Hz), 72.87, 63.37, 60.91, 46.23, 9.06 CF CF CF CF CF CF PC

[0287] (1-((2H-Tetrazol-5-yl)methoxy)-2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)-3-hydroxypropan-2-yl) triethylammonium phosphonate (Compound 37)

[0288] Step 1: Ethyl 2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methoxy)-2-(diethoxyphosphoryl)-3-(2-(trimethylsilyl)ethoxy)propanoate (37-1)

[0289] ​​​​​​​Compound 27-2 (1.50 mmol, 1.00 g) was dissolved in THF (25 mL) at -15 °C, NaHMDS (1 N, 2 mL) was added slowly dropwise. After 25 min, TBAI (tetra butyl ammonium iodide) (0.75 mmol, 0.28 g) was added, followed by SEM-Cl (2-(trimethylsilyl)ethoxymethyl chloride) (4.4 mmol, 0.75 g) immediately. The reaction was continued at -15 °C for 2.5 h. After the reaction was completed, it was quenched with saturated ammonium chloride and extracted with ethyl acetate, and purified by column chromatography (PE:EA = 120:80) to give yellow oil 37-1 (0.60 g, 0.76 mmol) in 51% yield.

[0290] 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (td, J = 8.5, 1.0 Hz, 1H), 8.29 (d, J = 1.8 Hz, 1H), 8.04 (t, J = 1.7 Hz, 1H), 7.76 (dd, J = 9.9, 1.4 Hz, 1H), 7.70 (dd, J = 8.6, 1.8 Hz, 1H), 6.05 (dd, J = 9.7, 2.4 Hz, 1H), 5.29 - 5.17 (m, 2H), 4.30 (qd, J = 6.9, 1.6 Hz, 2H), 4.20 - 4.05 (m, 6H), 3.90 (d, J = 11.3 Hz, 1H), 3.80 (td, J = 11.1, 6.9 Hz, 1H), 3.66 (m, 1H), 3.54 (td, J = 9.3, 7.1 Hz, 1H), 2.48 - 2.37 (m, 1H), 2.07 (s, 2H), 1.77 (d, J = 6.9 Hz, 1H), 1.61 (s, 2H), 1.32 - 1.23 (m, 9H), 0.90 (m, 2H), -0.00 (s, 9H).

[0291] Steps 2, 3, 4, 5 are the same as synthesis example 36.

[0292] (2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)-1,3- dihydroxypropan-2-yl) triethylammonium phosphonate salt (Compound 38)

[0293] Steps 1, 2 are as per synthesis example 37.

[0294] Yield 50%, pale yellow solid. m / z (ESI, -ve ion) = 596.0 [M-H] - . 1H NMR (600 MHz, DMSO) δ 13.24 (s, 1H), 9.26 (s, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 1.4 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.71 (dd, J = 9.8, 1.4 Hz, 1H), 7.54 (dd, J = 8.5, 1.8 Hz, 1H), 5.21 (s, 2H), 3.96 - 3.88 (m, 4H), 3.12 - 3.07 (m, 8H), 1.19 (t, J = 7.3 Hz, 12H). 13 C NMR (151 MHz, DMSO) δ 152.32 (d, J = 243.9 Hz), 144.15, 141.08, 136.40 (d, J = 7.1 Hz), 135.49 (d, J = 16.9 Hz), 133.92, 123.85, 122.69, 122.15 (d, J = 8.46 Hz), 116.40, 113.90 (d, J = 18.3 Hz), 111.22 (d, J = 4.2 Hz), 106.01, 79.67 (d, J = 139.6 Hz), 60.95 (d, J = 9.1 Hz), 60.38, 46.07, 9.02. CF CF CF CF CF CF PC PC

[0295] (1-((2H-Tetrazol-5-yl)methoxy)-2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indol-3-yl)methoxy)-3-(2-methoxyethoxy)propan-2-yl) triethylphosphonium salt (Compound 39)

[0296] Synthetic procedure same as Example 37.

[0297] Yield 50%, pale yellow solid. m / z (ESI, -ve ion) = 654.1 [M-H] - . 1 ​​​​​​​​H NMR (600 MHz, DMSO) δ 13.21 (s, 1H), 9.67 (s, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.02 (s, 1H), 7.92 (s, 1H), 7.69 (d, J = 10.0 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 5.27 (d, J = 10.7 Hz, 1H), 5.12 (d, J = 10.8 Hz, 1H), 4.96 (q, J = 12.0 Hz, 2H), 4.08 (dd, J = 11.3, 4.4 Hz, 1H), 4.05 - 4.01 (m, 1H), 4.00 - 3.97 (m, 1H), 3.83 (dd, J = 11.4, 3.4 Hz, 1H), 3.63 - 3.58 (m, 2H), 3.47 (t, J = 4.8 Hz, 2H), 3.08 (q, J = 7.3 Hz, 6H), 1.18 (t, J = 7.3 Hz, 11H). 13 C NMR (151 MHz, DMSO) δ 155.70, 152.31 (d, J = 261.2 Hz), 143.99, 141.02, 136.34 (d, J = 7.6 Hz), 135.48 (d, J = 18.1 Hz), 133.84, 123.62 (d, J = 15.1 Hz), 122.55, 122.14 (d, J = 7.6 Hz), 116.20, 113.87 (d, J = 15.1 Hz), 111.16 (d, J = 4.2 Hz), 105.89, 81.57 (d, J = 151.0 Hz), 72.65, 71.75 (d, J = 10.6 Hz), 70.72 (d, J = 6.0 Hz), 69.86 (d, J = 10.6 Hz), 63.86, 60.62, 58.62, 46.01, 8.98. CF CF CF CF CF CF CF PC PC PC PC

[0298] (1-(BENZYLOXY)-2-((6-(6-BROMO-4-FLUORO-1H-BENZO[D][1,2,3]TRIAZOL-1-YL)-1H-INDAZOL-3-YLMETHOXY)-3-(2-METHOXYETHOXY)PRO PAN-2-YL)PHOSPHONIC ACID TRIETHYLAMMONIUM SALT (COMPOUND 40)

[0299] Synthesis method refers to Example 39.

[0300] ​​​​​​​​​​​Yield 45%, pale yellow solid. m / z (ESI, -ve ion) = 662.0 [M-H] - . 1 H NMR (400 MHz, DMSO) δ 13.25 (s, 1H), 8.39 (s, 1H), 7.93 (d, J = 15.3 Hz, 2H), 7.77 - 7.15 (m, 7H), 5.25 (s, 2H), 4.56 (s, 2H), 4.02 - 3.84 (m, 4H), 3.59 (s, 4H), 3.16 - 2.76 (m, 23H), 1.47 - 0.84 (m, 33H). 13 CNMR (151 MHz, DMSO) δ 152.33 (d, J = 261.3 Hz), 144.70, 141.07, 139.28, 135.55, 133.81, 129.08, 128.57, 127.89, 127.68, 122.08, 115.90, 113.94, 111.08, 105.82, 73.12, 71.79 (d, J = 25.7 Hz), 70.68, 60.58, 58.60, 51.89, 45.95, 8.87. CF CNMR (151 MHz, DMSO) δ 152.33 (d, J = 261.3 Hz), 144.70, 141.07, 139.28, 135.55, 133.81, 129.08, 128.57, 127.89, 127.68, 122.08, 115.90, 113.94, 111.08, 105.82, 73.12, 71.79 (d, J = 25.7 Hz), 70.68, 60.58, 58.60, 51.89, 45.95, 8.87. PC CNMR (151 MHz, DMSO) δ 152.33 (d, J = 261.3 Hz), 144.70, 141.07, 139.28, 135.55, 133.81, 129.08, 128.57, 127.89, 127.68, 122.08, 115.90, 113.94, 111.08, 105.82, 73.12, 71.79 (d, J = 25.7 Hz), 70.68, 60.58, 58.60, 51.89, 45.95, 8.87.

[0301] (2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)-1- hydroxy-3-(2-methoxyethoxy)propan-2-yl)phosphonic acid triethylammonium salt (Compound 41)

[0302] Synthetic procedure refers to Example 39.

[0303] Yield 40%, pale yellow solid. m / z (ESI, -ve ion) = 572.0 [M-H]-. 1H NMR (400 MHz, DMSO) δ 13.23 (s, 1H), 8.34 (d, J = 8.6 Hz, 1H), 8.03 (d, J = 1.5 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 10.0 Hz, 1H), 7.52 (dd, J = 8.6, 1.8 Hz, 1H), 5.23 (d, J = 10.8 Hz, 1H), 5.16 (d, J = 10.1 Hz, 1H), 3.98 (dd, J = 10.7, 6.3 Hz, 1H), 3.92 - 3.81 (m, 3H), 3.69 - 3.58 (m, 2H), 3.53 - 3.44 (m, 2H), 3.26 (s, 3H), 3.09 (q, J = 7.2 Hz, 1H), 1.18 (t, J = 7.3 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 152.32 (d, J = 261.6 Hz), 144.12, 141.09, 136.38 (d, J = 8.1 Hz), 135.49 (d, J = 19.2 Hz), 133.91, 123.90, 122.70, 122.11 (d, J = 8.1 Hz), 116.33, 113.86 (d, J = 20.2 Hz), 111.17, 105.94, 79.59 (d, J = 151.5 Hz), 71.73, 70.81, 61.30, 60.53, 58.63, 46.09, 9.04. CF CF CF CF CF PC

[0304] (((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methyl) sulfonyl)methyl)phosphonic acid (Compound 42)

[0305] Step 1: (6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-3-yl)methanethiol (42-1)

[0306] ​​​​​​Compound 42-1 (0.12 g, 0.27 mmol), yield: 25% was obtained as yellow oil.1H NMR (400 MHz, DMSO) δ 8.30 - 8.16 (m, 2H), 8.05 (d, J = 1.3 Hz, 1H), 7.74 (dd, J = 9.9, 1.5 Hz, 1H), 7.66 (dd, J = 8.6, 1.8 Hz, 1H), 5.98 (dd, J = 9.8, 2.3 Hz, 1H), 4.18 (d, J = 7.8 Hz, 2H), 3.88 (d, J = 12.1 Hz, 1H), 3.82 - 3.70 (m, 1H), 3.16 (t, J = 7.8 Hz, 1H), 2.46 - 2.38 (m, 1H), 2.12 - 2.02 (m, 2H), 1.74 (t, J = 6.2 Hz, 1H), 1.64 - 1.51 (m, 2H).

[0307] m / z (ESI, -ve ion) = 460.0 [M-H] - m / z (ESI, +ve ion) = 378.0 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.30 - 8.16 (m, 2H), 8.05 (d, J = 1.3 Hz, 1H), 7.74 (dd, J = 9.9, 1.5 Hz, 1H), 7.66 (dd, J = 8.6, 1.8 Hz, 1H), 5.98 (dd, J = 9.8, 2.3 Hz, 1H), 4.18 (d, J = 7.8 Hz, 2H), 3.88 (d, J = 12.1 Hz, 1H), 3.82 - 3.70 (m, 1H), 3.16 (t, J = 7.8 Hz, 1H), 2.46 - 2.38 (m, 1H), 2.12 - 2.02 (m, 2H), 1.74 (t, J = 6.2 Hz, 1H), 1.64 - 1.51 (m, 2H).

[0308] Step 2: (((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methyl)thio)methyl)dimethyl phosphonate (42-2)

[0309] Intermediate 42-1 (0.34 g, 0.74 mmol, 1.0 eq) was dissolved in DMF (5 mL) and stirred at -10 °C for 30 min, then diethyl methylphosphonate iodomethide (0.31 g, 1.11 mmol, 1.5 eq) was added, after 15 min at reaction temperature, the reaction was stirred at room temperature for 1 h, after completion of the reaction, it was quenched with saturated ammonium chloride, extracted with ethyl acetate, the organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, purified by column chromatography (gradient elution PE:EA = 50:50 - 100% EA) to give pale yellow oil 42-2 (0.10 g, 0.16 mmol), yield: 22%.

[0310] m / z (ESI, +ve ion) = 612.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.26 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 1.5 Hz, 1H), 7.74 (d, J = 9.8 Hz, 1H), 7.68 (dd, J = 8.6, 1.8 Hz, 1H), 6.01 (d, J = 7.4 Hz, 1H), 4.36 (s, 2H), 4.10 - 4.02 (m, 6H), 2.92 (d, J = 12.8 Hz, 2H), 2.51 - 2.53 (m, 1H), 2.08 - 2.04 (m, 2H), 1.77 - 1.74 (m, 1H), 1.60 - 1.58 (m, 2H), 1.25 - 1.24 (m, 6H).

[0311] Step 3: (((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methyl) sulfonyl)methyl) diethyl phosphonate (42-3)

[0312] Intermediate 42-2 (0.10 g, 0.16 mmol, 1.0 eq) was dissolved in MeOH:H2O:THF (1:1:2, 1 mL, 1 mL, 2 mL) mixed solvent, then oxone (0.56 g, 1.63 mmol, 10.0 eq) was added, the reaction was carried out overnight, the reaction solution was quenched with NaHCO3, extracted with ethyl acetate, the organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, purified by preparative TLC plate to give pale yellow solid 42-3 (60 mg, 0.10 mmol), yield: 58%.

[0313] m / z (ESI, -ve ion) = 642.0 [M-H] - . 1H NMR (400 MHz, DMSO) δ 8.32 (d, J = 2.3 Hz, 1H), 8.18 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 1.5 Hz, 1H), 7.74 (dd, J = 8.5, 1.7 Hz, 2H), 6.08 (dd, J = 9.5, 2.3 Hz, 1H), 5.24 (s, 2H), 4.34 (dd, J = 16.7, 2.1 Hz, 2H), 4.22 - 4.12 (m, 4H), 4.08 - 3.99 (m, 1H), 3.95 - 3.87 (m, 1H), 2.45 - 2.42 (m, 1H), 2.10 - 2.04 (m, 2H), 1.80 - 1.75 (m, 1H), 1.63 - 1.56 (m, 2H), 1.30 (t, J = 7.0 Hz, 6H).

[0314] Step 4: (((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-lH-indazol-3-yl)methyl) sulfonyl)methyl)phosphonic acid (Compound 42)

[0315] Compound 42-3 (0.06 g, 0.09 mmol, 1 eq) was dissolved in DCE (5 mL), followed by the addition of TMSI (0.28 g, 1.40 mmol), and the reaction was allowed to proceed at room temperature for 24 h. The reaction was then concentrated and triturated with methanol to give white solid 42 (20 mg, 0.16 mmol), m / z (ESI, -ve ion) = 501.9 [M-H] - .

[0316] 1 H NMR (600 MHz, DMSO) δ 13.64 (s, 1H), 8.20 (d, J = 8.6 Hz, 1H), 8.13 - 8.01 (m, 2H), 7.70 (d, J = 10.3 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 5.22 (s, 2H), 3.87 (d, J PC = 16.1 Hz, 2H). 13 CNMR (151 MHz, DMSO) δ 152.30 (d, J CF = 243.9 Hz), 140.98, 136.31 (d, J CF = 5.6 Hz), 135.51 (d, J CF = 16.9 Hz), 135.00, 134.17, 123.47, 123.17, 122.23 (d, J CF = 7.1 Hz), 117.23, 113.94 (d, J CF = 18.3 Hz), 111.23 (d, JCF = 4.2 Hz), 106.30, 52.49, 51.33 (d, J = 121.3 Hz). PC = 4.2 Hz), 106.30, 52.49, 51.33 (d, J = 121.3 Hz).

[0317] (((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methyl)thio)methyl)phosphonic acid (Compound 43)

[0318] Synthetic Method Referenced to Example 42. Yield: 55%, white solid. m / z (ESI, -ve ion) = 470.0 [M-H] - . 1 HNMR (600 MHz, DMSO) δ 13.32 (s, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.08 (s, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.71 (d, J = 9.8 Hz, 1H), 7.59 (dd, J = 8.5, 1.8 Hz, 1H), 4.33 (s, 2H), 2.64 (d, J = 13.3 Hz, 2H). PC = 13.3 Hz, 2H). 13 C NMR (151 MHz, DMSO) δ 152.31 (d, J = 242.5 Hz), 143.21, 141.10, 136.33, 135.51 (d, J = 16.9 Hz), 134.05, 122.71, 122.21, 121.89, 116.51, 113.92 (d, J = 18.3 Hz), 111.27, 106.21, 28.34, 27.58 (d, J = 132.5 Hz). FC = 13.3 Hz, 2H). FC = 13.3 Hz, 2H). FC = 13.3 Hz, 2H). PC = 13.3 Hz, 2H).

[0319] (2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)-1- ethoxy-3-(4-fluorophenyl)-1-oxopropan-2-yl)phosphonic acid (Compound 44)

[0320] Step 1 : Ethyl 2-((6-(6-bromo-4-fluoro-1 -(tetrahydro-2H-pyran-2-yl)-1H-indazol-3- yl)methoxy)-2-(diethoxyphosphoryl)-3-(4-fluorophenyl)propanoate (44-1 )

[0321] Compound 27-2 (0.20 g, 0.29 mmol, 1.0 eq), cesium carbonate (0.28 g, 0.87 mmol, 3.0 eq) were dissolved in DMF, followed by the addition of 4-F-benzyl bromide (0.12 g, 0.60 mmol, 2.0 eq) at room temperature overnight, the reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate. Purified by column chromatography to obtain yellow oil 44-1 (0.18 g, 0.23 mmol), yield 80%, m / z (ESI, +ve ion) = 776.2 [M+H] + .

[0322] 1 H NMR (400 MHz, DMSO) δ 8.25 (d, J = 1.8 Hz, 1H), 8.04 (dd, J = 4.2, 1.4 Hz, 1H), 7.82 (dd, J = 8.6, 2.3 Hz, 1H), 7.74 (dd, J = 9.9, 1.4 Hz, 1H), 7.53 (ddd, J = 8.6, 4.8, 1.7 Hz, 1H), 7.21 - 7.11 (m, 2H), 7.03 (td, J = 8.9, 2.9 Hz, 2H), 6.02 (dd, J = 9.9, 2.7 Hz, 1H), 5.22 (dd, J = 12.4, 5.6 Hz, 2H), 4.29 - 4.18 (m, 6H), 3.92 - 3.74 (m, 2H), 3.29 - 3.20 (m, 2H), 2.46 - 2.37 (m, 1H), 2.11 - 2.00 (m, 2H), 1.83 - 1.71 (m, 1H), 1.64 - 1.52 (m, 2H), 1.36 - 1.28 (m, 6H), 1.24 (t, J = 7.0 Hz, 3H).

[0323] Step 2: (2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-3-yl)methoxy)-1-ethoxy-3-(4-fluorophenyl)-1-oxopropan-2-yl)phosphonic acid (44-2)

[0324] Intermediate 44-1 (50 mg, 0.06 mmol, 1.0 eq) was dissolved in DCE (2 mL), followed by the addition of triethylamine (0.12 g, 1.20 mmol, 20.0 eq) and TMSI (2.96 g, 19.35 mmol, 15 eq) at room temperature for 24 h, the reaction solution was rotary evaporated, without further purification, directly into the next step, m / z (ESI, -ve ion) = 868.2 [M-H] - .

[0325] Step 3: (2-((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-lH-indazol-3-yl)methoxy)-l- ethoxy-3-(4-fluorophenyl)-l-oxopropan-2-yl)phosphonic acid triethylammonium salt (Compound 44)

[0326] The crude intermediate 44-2 from previous step was dissolved in methanol (2 mL), followed by the addition of con. HC1 (0.25 mL) and the reaction was stirred at room temperature for 2 d. The reaction was concentrated and the solid was washed with water to give pale yellow solid 44 (25 mg, 0.04 mmol) in 66% yield, m / z (ESI, -ve ion) = 634.0 [M-H] - .

[0327] 1 H NMR (600 MHz, DMSO) δ 13.21 (s, 1H), 9.78 (s, 1H), 8.07 - 7.99 (m, 1H), 7.93 (dd, J = 5.2, 3.2 Hz, 2H), 7.69 (dd, J = 9.8, 1.3 Hz, 1H), 7.39 - 7.31 (m, 1H), 7.12 (dd, J = 8.4, 5.6 Hz, 2H), 6.95 (t, J = 8.6 Hz, 2H), 5.44 (d, J = 11.0 Hz, 1H), 5.37 (d, J = 11.1 Hz, 1H), 4.07 - 4.13 (m, 1H), 4.16 - 4.20 (m, 1H), 3.54 (t, J = 10.1 Hz, 1H), 3.26 (dd, J = 14.1, 7.3 Hz, 1H), 3.08 (q, J = 7.3 Hz, 2H), 1.19 (t, J = 7.3 Hz, 7H). 13 C NMR (151 MHz, DMSO) δ 171.06, 161.55 (d, J = 227.0 Hz), 152.33 (d, J = 243.9 Hz), 144.33, 141.19, 136.24, 135.52 (d, J = 16.9 Hz), 133.82, 132.39 (d, J = 7.1 Hz), 124.31, 122.45, 122.13 (d, J = 7.1 Hz), 115.64, 114.80 (d, J = 18.3 Hz), 113.88 (d, J = 19.6 Hz), 111.19, 105.70, 84.37, 83.43, 63.58, 60.92 (d, J = 7.0 Hz). CF CF CF CF CF CF CF PC ​​​​​​​= 375.1 Hz), 45.99, 29.48, 14.56, 9.00.

[0328] (2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)-1- (methoxy-d3)-3-(2H-tetrazol-5-yl)propan-2-yl)phosphonic acid triethylammonium salt (Compound 46)

[0329] Step 1 refers to Example 44 Step 1, Step 2 refers to Example 35 Step 1, Step 3 refers to Example 42 Step 4.

[0330] (2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)-1- (methoxy-d3)-3-(2H-tetrazol-5-yl)propan-2-yl)phosphonic acid triethylammonium salt (Compound 46)

[0331] Step 1: Diethyl (2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-3-yl)methoxy)-1-(methoxy-d3)-3-(2-((2-(trimethylsilyl)ethoxy)methyl)- 2H-tetrazol-5-yl)propan-2-yl)phosphonate (46-1)

[0332] Compound 35-1 (0.22 g, 0.26 mmol, 1 eq), CD3I (0.38 g, 2.62 mmol, 10 eq) were dissolved in DMF (5 mL) under ice-bath condition, then NaH (60%, 32 mg, 0.79 mmol, 3.0 eq) was added, the reaction was carried out under ice-bath condition for 3 h, after the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, the organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, dried under reduced pressure, purified by column chromatography (PE:EA = 30:70) to obtain 46-1 (0.18 g, 1.29 mmol) as a light yellow oil, yield: 95%.

[0333] 1H NMR (400MHz, DMSO) δ8.35(d,J=1.8Hz,1H),8.24–8.19(m,1H),8.12(d,J=1.4Hz,1H),7.84(dd,J=9.9,1.5Hz ,1H),7.72(dd,J=8.6,1.8Hz,1H),6.10(d,J=9.0Hz,1H),6.05(s,2H),5.46–5.37(m,1H),5.28(d,J=10.8Hz, 1H),4.27–4.10(m,4H),4.01–3.81(m,4H),3.73(t,J=8.2Hz,3H),3.63–3.56(m,1H),2.58–2.40(m,1H),2.15 –2.07(m,2H),1.94–1.75(m,-1H),1.74–1.63(m,2H),1.31–1.27(m,6H),0.92(t,J=8.9Hz,2H),0.00(s,9H).

[0334] For steps 2 and 3, refer to synthesis example 34.

[0335] Yield 50%, white solid. m / z(ESI, -ve ion) = 583.0 [MH] - . 1 H NMR (400MHz, DMSO) δ13.25 (s, 1H), 8.11–8.00 (m, 2H), 7.94 (d, J = 1.8Hz, 1H), 7.70 (dd, J =9.9,1.4Hz,1H),7.48(dd,J=8.6,1.8Hz,1H),5.35(d,J=11.0Hz,1H),5.09(d,J=10.8H z,1H),3.94(dd,J=10.8,7.7Hz,1H),3.77(dd,J=10.8,5.7Hz,1H),3.55(dd,J=15.3,12 .1Hz,1H),3.44(dd,J=15.2,11.2Hz,1H),3.10(q,J=7.2Hz,1H),1.18(t,J=7.9Hz,2H). 13 C NMR(101MHz,DMSO)δ152.33(d,J CF =261.6Hz),143.67,141.06,136.41,135.59,133.93,123.45,122.40,122.09,116.35,113.88(d,J CF =20.2Hz),111.17,105.94,78.80,77.27(d,J PC= 77.5 Hz), 71.97, 61.01, 46.18, 27.17, 9.08.

[0336] (2-((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-lH-indazol-3-yl)methoxy)- 1 -methoxy-3-(2H-tetrazol-5-yl)propan-2-yl)phosphonic acid triethylammonium salt (Compound 47)

[0337] The procedure was the same as in Example 46.

[0338] Yield 73%, pale yellow solid. ESI, -ve ion) = 583.0 [M-H]". H NMR (400 MHz, DMSO) δ 8.10 - 7.97 (m, 2H), 7.92 (d, J = 1.7 Hz, 1H), 7.70 (dd, J = 9.9, 1.4 Hz, 1H), 7.46 (dd, J = 8.6, 1.8 Hz, 1H), 5.35 (d, J = 10.9 Hz, 1H), 5.03 (d, J = 10.9 Hz, 1H), 4.00 (dd, J = 11.0, 6.4 Hz, 1H), 3.75 (dd, J = 11.0, 4.4 Hz, 1H), 3.60 (t, J = 15.1 Hz, 1H), 3.39 (dd, J = 14.9, 11.3 Hz, 1H), 3.33 (s, 3H), 3.10 (q, J = 7.2 Hz, 1H), 1.18 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, DMSO) δ 159.41, 152.50 (d, J = 299.0 Hz), 143.77, 141.04, 136.40, 135.50 (d, J = 19.2 Hz), 133.90, 123.48, 122.42, 122.09, 116.30, 113.87 (d, J = 20.2 Hz), 111.18, 105.89, 78.14 (d, J = 152.5 Hz), 72.09, 60.94, 59.15, 46.12, 27.34, 9.05. CF C NMR (101 MHz, DMSO) δ 159.41, 152.50 (d, J = 299.0 Hz), 143.77, 141.04, 136.40, 135.50 (d, J = 19.2 Hz), 133.90, 123.48, 122.42, 122.09, 116.30, 113.87 (d, J = 20.2 Hz), 111.18, 105.89, 78.14 (d, J = 152.5 Hz), 72.09, 60.94, 59.15, 46.12, 27.34, 9.05. CF C NMR (101 MHz, DMSO) δ 159.41, 152.50 (d, J = 299.0 Hz), 143.77, 141.04, 136.40, 135.50 (d, J = 19.2 Hz), 133.90, 123.48, 122.42, 122.09, 116.30, 113.87 (d, J = 20.2 Hz), 111.18, 105.89, 78.14 (d, J = 152.5 Hz), 72.09, 60.94, 59.15, 46.12, 27.34, 9.05. CF C NMR (101 MHz, DMSO) δ 159.41, 152.50 (d, J = 299.0 Hz), 143.77, 141.04, 136.40, 135.50 (d, J = 19.2 Hz), 133.90, 123.48, 122.42, 122.09, 116.30, 113.87 (d, J = 20.2 Hz), 111.18, 105.89, 78.14 (d, J = 152.5 Hz), 72.09, 60.94, 59.15, 46.12, 27.34, 9.05. PC C NMR (101 MHz, DMSO) δ 159.41, 152.50 (d, J = 299.0 Hz), 143.77, 141.04, 136.40, 135.50 (d, J = 19.2 Hz), 133.90, 123.48, 122.42, 122.09, 116.30, 113.87 (d, J = 20.2 Hz), 111.18, 105.89, 78.14 (d, J = 152.5 Hz), 72.09, 60.94, 59.15, 46.12, 27.34, 9.05.

[0339] ((((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-lH-indazol-3-yl)methoxy)methyl) phosphoryl)bis(oxy))bis(methylene)bis(2-methylpropanoate) (Compound 48)

[0340] Step 1: (((((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-l-(tetrahydro-2H-pyran-2- yl)-lH-indazol-3-yl)methoxy)methyl)phosphoryl)oxy)methylene)dimethyl phosphate (Compound 48-1)

[0341] Compound 48-1 (0.20 g, 0.37 mmol), Cs2C03(0.18 g, 11 mmol) were dissolved in NMP (10 mL) and reacted at 80 °C for 3 min, then chloromethyl isobutyrate (3 mL, 11 mmol) was added, after 10 min, the reaction solution was quenched with saturated ammonium chloride, and the reaction solution was extracted with ethyl acetate, and purified by column chromatography (PE:EA = 50:50) to obtain yellow oil 48-2 (0.33 g, 0.44 mmol), yield: 82%.

[0342] m / z (ESI, +ve ion) = 740.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.28 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.73 (d, J = 9.9 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 6.03 (d, J = 8.3 Hz, 1H), 5.66 (s, 2H), 5.62 (s, 2H), 5.01 (s, 2H), 4.05 (d, J = 8.4 Hz, 2H), 3.94 - 3.86 (m, 1H), 3.81 - 3.75 (m, 1H), 2.60 - 2.54 (m, 2H), 2.46 - 2.37 (m, 1H), 2.08 - 2.01 (m, 2H), 1.82 - 1.73 (m, 1H), 1.62 - 1.55 (m, 2H), 1.08 (s, 6H), 1.07 (s, 6H).

[0343] Step 2: (((((6-(6-bromo-4-fluoro-lH-benzo[d][l,2,3]triazol-l-yl)-lH-indazol-3-yl)methoxy)methyl) phosphoryl)oxy)methylene)dimethyl phosphate (Compound 48)

[0344] Compound 48-2 (0.33 g, 0.44 mmol) was dissolved in DCM (10 mL) at room temperature, then TFA (1.50 g, 13.16 mmol) was added, the reaction was completed, the reaction solution was rotary evaporated, and purified by column chromatography (PE:EA = 50:50) to obtain yellow oil 48 (0.16 g, 0.24 mmol), yield: 55%.

[0345] m / z (ESI, +ve ion) = 656.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 13.47 (s, 1H), 8.12 (d, J = 8.6 Hz, 1H), 8.03 (d, J = 7.3 Hz, 2H), 7.71 (d, J = 11.4 Hz, 1H), 7.61 (dd, J = 8.6, 1.8 Hz, 1H), 5.65 (s, 2H), 5.62 (s, 2H), 5.01 (s, 2H), 4.02 (d, J = 8.2 Hz, 2H), 2.59 - 2.54 (m, 2H), 1.08 (d, J = 1.5 Hz, 6H), 1.06 (d, J = 1.5 Hz, 6H). 13 C NMR (101 MHz, DMSO) δ 175.23, 152.35 (d, J = 261.6 Hz), 142.10, 141.08, 136.35 (d, J = 8.1 Hz), 135.53 (d, J = 19.2 Hz), 134.09, 122.51, 122.36, 122.23, 116.99, 113.92 (d, J = 20.2 Hz), 111.18, 106.30, 81.86, 67.43, 64.10 (d, J = 163.6 Hz), 33.45, 18.75. CF = 261.6 Hz), 142.10, 141.08, 136.35 (d, J = 8.1 Hz), 135.53 (d, J = 19.2 Hz), 134.09, 122.51, 122.36, 122.23, 116.99, 113.92 (d, J = 20.2 Hz), 111.18, 106.30, 81.86, 67.43, 64.10 (d, J = 163.6 Hz), 33.45, 18.75. CF = 261.6 Hz), 142.10, 141.08, 136.35 (d, J = 8.1 Hz), 135.53 (d, J = 19.2 Hz), 134.09, 122.51, 122.36, 122.23, 116.99, 113.92 (d, J = 20.2 Hz), 111.18, 106.30, 81.86, 67.43, 64.10 (d, J = 163.6 Hz), 33.45, 18.75. CF = 261.6 Hz), 142.10, 141.08, 136.35 (d, J = 8.1 Hz), 135.53 (d, J = 19.2 Hz), 134.09, 122.51, 122.36, 122.23, 116.99, 113.92 (d, J = 20.2 Hz), 111.18, 106.30, 81.86, 67.43, 64.10 (d, J = 163.6 Hz), 33.45, 18.75. CF = 261.6 Hz), 142.10, 141.08, 136.35 (d, J = 8.1 Hz), 135.53 (d, J = 19.2 Hz), 134.09, 122.51, 122.36, 122.23, 116.99, 113.92 (d, J = 20.2 Hz), 111.18, 106.30, 81.86, 67.43, 64.10 (d, J = 163.6 Hz), 33.45, 18.75. PC = 261.6 Hz), 142.10, 141.08, 136.35 (d, J = 8.1 Hz), 135.53 (d, J = 19.2 Hz), 134.09, 122.51, 122.36, 122.23, 116.99, 113.92 (d, J = 20.2 Hz), 111.18, 106.30, 81.86, 67.43, 64.10 (d, J = 163.6 Hz), 33.45, 18.75.

[0346] ((((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)methyl)(hydroxy)phosphoryl)oxy)methyl isobutyrate triethylammonium salt (Compound 49)

[0347] Step 1: (((((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methoxy)methyl)(hydroxy)phosphoryl)oxy)methyl isobutyrate (49-1)

[0348] Compound 48-1 (0.20 g, 0.37 mmol), TEA (0.97 g, 9.62 mmol) were dissolved in NMP (10 mL) and reacted at 80 °C for 3 min, then chloromethyl isobutyrate (3 mL, 11 mmol) was added, after 10 min, the reaction solution was quenched with saturated ammonium chloride, and the reaction solution was extracted with ethyl acetate. Without purification, it was directly used in the next step.

[0349] m / z (ESI, -ve ion) = 746.1 [M-H] - , m / z (ESI, +ve ion) = 748.2 [M+H] + .

[0350] Step 2 The same as that in Synthetic Example 48, Step 2.

[0351] Yield: 40%, pale yellow oil. m / z (ESI, -ve ion) = 554.0 [M-H] - . 1 H NMR (400 MHz, DMSO) δ 13.41 (s, 1H), 8.15 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 1.5 Hz, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.71 (dd, J = 9.9, 1.4 Hz, 1H), 7.60 (dd, J = 8.5, 1.9 Hz, 1H), 5.54 (d, J = 12.6 Hz, 2H), 4.99 (s, 2H), 3.78 (d, J = 8.4 Hz, 2H), 3.19 - 3.14 (m, 6H), 2.55 - 2.52 (m, 1H), 1.05 (d, J = 7.0 Hz, 6H), 0.94 (t, J = 7.3 Hz, 11H). 13 C NMR (151 MHz, DMSO) δ 175.84, 152.29 (d, J = 261.2 Hz), 143.38, 141.14, 136.23, 135.49 (d, J = 18.1 Hz), 133.74, 123.16, 122.48, 122.13 (d, J = 7.6 Hz), 116.21, 113.86 (d, J = 21.1 Hz), 111.25 (d, J = 6.0 Hz), 106.05, 83.57 (d, J = 4.5 Hz), 68.53 (d, J = 154.0 Hz), 66.85, 66.78 (d, J = 4.5 Hz), 57.96, 33.68, 18.97, 13.95. CF CF CF CF CF PC PC PC

[0352] (6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methanol (Compound 50)

[0353] ​​​​​​​​Step 1: (6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3- yl)methanol (Compound 50)

[0354] Compound 8d-1 (0.40 g, 0.90 mmol) was dissolved in methanol (2 mL), then concentrated hydrochloric acid (2 mL) was added, and the reaction was stirred at room temperature for 12 h. The solid was filtered off and washed with water to give compound 50 (0.16 g, 0.24 mmol) as a red solid in 93% yield. m / z (ESI, -ve ion) = 360.0 [M-H] - . 1 H NMR (400 MHz, DMSO) δ 8.16 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 1.4 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.70 (dd, J = 9.9, 1.6 Hz, 1H), 7.57 (dd, J = 8.7, 1.8 Hz, 1H), 4.88 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 152.37 (d, J = 261.6 Hz), 146.64, 141.22, 136.35 (d, J = 7.1 Hz), 135.56 (d, J = 18.2 Hz), 133.91, 123.12, 122.25, 122.15 (d, J = 4.04 Hz), 116.31, 113.94 (d, J = 20.2 Hz), 111.23 (d, J = 5.1 Hz), 106.04, 57.20. CF CF CF CF CF CF

[0355] (2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)-1- hydroxy-3-(4-(trifluoromethyl)phenyl)propan-2-yl)phosphonic acid (Compound 51)

[0356] Synthetic method refers to Example 45. Yield: 78%, light yellow solid. m / z (ESI, -ve ion) = 642.0 [M-H] - . 1 ​​​​​​H NMR (600 MHz, DMSO) δ 13.26 (s, 1H), 8.10 - 8.00 (m, 2H), 7.97 (s, 1H), 7.71 (d, J = 11.3 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.46 (dd, J = 8.5, 1.8 Hz, 1H), 5.31 (d, J = 10.9 Hz, 1H), 5.19 (d, J = 10.9 Hz, 1H), 3.81 - 3.69 (m, 2H), 3.30 (d, J = 11.1 Hz, 2H). 13 CNMR (151 MHz, DMSO) δ 152.34 (d, J = 261.2 Hz), 143.82, 142.33, 141.09, 136.36 (d, J = 7.6 Hz), 135.51 (d, J = 18.1 Hz), 133.93, 132.21, 127.71, 127.35 (q, J = 9.1 Hz), 124.83 (q, J = 329.9 Hz), 124.64 (q, J = 96.6 Hz), 122.45, 122.15 (d, J = 9.1 Hz), 116.23, 113.91 (d, J = 19.6 Hz), 111.17 (d, J = 4.5 Hz), 106.01, 79.91 (d, J = 152.5 Hz), 61.16 (d, J = 7.6 Hz), 60.79, 36.81. CF CF CF CF CF CF CF CF CF PC PC

[0357] (2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indol-3-yl)methoxy)-1-(3- fluorophenyl)-3-hydroxypropan-2-yl)phosphonic acid (Compound 52)

[0358] Synthetic method refers to Example 45. Yield: 78%, light yellow solid. m / z (ESI, -ve ion) = 592.0 [M-H] - . 1 ​​​​​​​​​​​H NMR (600MHz, DMSO) δ8.09–8.01(m,2H),7.97(d,J=2.5Hz,1H),7.70(d,J=9.9Hz,1H),7.49(dd,J=8.5,1.8Hz,1H),7.29–7.23(m,1H),7.22–7.15(m,2H ),7.03–6.98(m,1H),5.31(d,J=10.9Hz,1H),5.19(d,J=10.9Hz,1H),3.76 (dd,J=11.7,9.1Hz,1H),3.69(dd,J=14.3,11.7Hz,1H),3.30–3.19(m,2H). 13 C NMR(151MHz,DMSO)δ162.14(d,J CF =241.6Hz), 152.18(d,J) CF =261.2Hz),143.80,141.09,139.96(d,J CF =9.1Hz), 136.38(d,J) CF =7.1Hz), 135.50(d,J CF =16.9Hz), 133.91, 129.59 (d, J) CF =9.1Hz),127.59,123.53,122.46,122.15(d,J CF =9.1Hz), 118.04(d,J CF =21.1Hz), 116.32, 113.88 (d, J) CF =19.6Hz), 113.23(d,J CF =19.6Hz), 111.17(d,J CF =4.5Hz), 106.03, 79.82 (d, J) PC =149.5Hz),61.37,60.75,36.40.

[0359] (2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)-1-hydroxy-3-(4-(trifluoromethoxy)phenyl)prop-2-yl)phosphonic acid (compound 53)

[0360] Synthesis method is described in Example 45. Yield: 56%, pale yellow solid. m / z (ESI, -ve ion) = 658.0 [MH] - . 1H NMR (600 MHz, DMSO) δ 13.25 (s, 1H), 8.15 - 7.90 (m, 3H), 7.70 (d, J = 9.9 Hz, 1H), 7.49 (d, J = 8.6 Hz, 3H), 7.20 (d, J = 8.4 Hz, 2H), 5.32 (d, J = 10.9 Hz, 1H), 5.20 (d, J = 10.9 Hz, 1H), 3.80 - 3.74 (m, 1H), 3.72 - 3.66 (m, 1H), 3.26 (dd, J = 10.7, 4.9 Hz, 2H). 13 C NMR (151 MHz, DMSO) δ 152.33 (d, J = 261.2 Hz), 147.27, 143.81, 141.09, 136.69 (d, J = 9.1 Hz), 136.34 (d, J = 7.6 Hz), 135.50 (d, J = 18.1 Hz), 133.92, 133.15, 123.56, 122.30 (d, J = 42.3 Hz), 121.42, 120.44, 119.73, 116.23, 113.89 (d, J = 19.6 Hz), 111.15 (d, J = 4.5 Hz), 105.99, 79.79 (d, J = 151.0 Hz), 61.26 (d, J = 7.6 Hz), 60.79, 36.04. CF CF CF CF CF CF CF PC PC

[0361] (1-([1,1'-Biphenyl]-4-yl)-2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indol-3-yl)methoxy)-3-hydroxypropan-2-yl)phosphonic acid (Compound 54)

[0362] Synthetic method refers to Example 45. Yield: 48%, light yellow solid. m / z (ESI, -ve ion) = 650.1 [M-H] - . 1 ​​​​​​​​​H NMR (600MHz, DMSO) δ8.08–8.00(m,2H),7.96(d,J=1.9Hz,1H),7.70(d,J=11.3Hz,1H),7.62 (d,J=7.9Hz,2H),7.51(d,J=8.4Hz,2H),7.49–7.43(m,3H),7.40(t,J=7.7Hz,2H),7.30(t,J =7.4Hz,1H),5.34(d,J=10.8Hz,1H),5.22(d,J=10.9Hz,1H),3.78(dd,J=12.0,6.0Hz,1H), 3.69(dd,J=15.6,11.6Hz,1H), 3.31(dd,J=14.1,11.1Hz,1H), 3.24(dd,J=14.0,8.6Hz,1H). 13 C NMR(151MHz,DMSO)δ152,.32(d,J CF =261.2Hz),143.89,141.09,140.55,138.30,136.35(d,J CF =6.0Hz), 135.49(d,J CF =18.1Hz),133.89,132.02,129.29,127.56,126.90,126.28,123.65,122.49,122.15(d,J CF =9.1Hz), 116.33, 113.89 (d, J) CF =19.6Hz),111.17,105.97,80.35,79.35,61.22(d,J PC =107.2Hz), 36.09.

[0363] (2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)-1-(4-chlorophenyl)-3-hydroxypropyl-2-yl)phosphonic acid (compound 55)

[0364] Synthesis method is described in Example 45. Yield: 54%, pale yellow solid. m / z (ESI, -ve ion) = 608.1 [MH] - . 1H NMR (600MHz, DMSO) δ8.07–8.01(m,2H),8.00–7.95(m,1H),7.70(dd,J=9.8,1. 4Hz,1H),7.49(dd,J=8.5,1.8Hz,1H),7.41–7.35(m,2H),7.30–7.24(m,2H),5. 29(dd,J=10.1,0.5Hz,1H),5.17(dd,J=11.0,1.2Hz,1H),3.75(dd,J=11.7,8. 8Hz,1H),3.69(dd,J=14.1,11.7Hz,1H),3.26–3.21(m,1H),3.21–3.18(m,1H). 13 C NMR(151MHz,DMSO)δ152.33(d,J CF =261.2Hz),143.84,141.09,136.35(d,J CF =7.6Hz), 136.16(d,J) CF =9.1Hz), 135.52(d,J CF =18.3Hz),133.93,133.26,131.22,127.86,123.61,122.44,122.17(d,J CF =7.1Hz), 116.21, 113.90 (d, J) CF =12.1Hz), 111.18(d,J CF =4.5Hz), 105.99, 79.80 (d, J) PC =152.5Hz), 61.20(d,J PC =7.6Hz), 60.79, 36.10.

[0365] (2-((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)-1-(4-cyanophenyl)-3-hydroxypropyl-2-yl)phosphonic acid (compound 56)

[0366] For the synthesis method, refer to Example 45.

[0367] Yield: 56%, pale yellow solid. m / z(ESI, -ve ion) = 599.0 [MH] - . 1H NMR (600 MHz, DMSO) δ 13.25 (s, 1H), 8.15 - 7.90 (m, 3H), 7.70 (d, J = 9.9 Hz, 1H), 7.49 (d, J = 8.6 Hz, 3H), 7.20 (d, J = 8.4 Hz, 2H), 5.32 (d, J = 10.9 Hz, 1H), 5.20 (d, J = 10.9 Hz, 1H), 3.80 - 3.74 (m, 1H), 3.72 - 3.66 (m, 1H), 3.26 (dd, J = 10.7, 4.9 Hz, 2H). 13 C NMR (151 MHz, DMSO) δ 152.33 (d, J = 261.2 Hz), 147.27, 143.81, 141.09, 136.69 (d, J = 9.1 Hz), 136.34 (d, J = 7.6 Hz), 135.50 (d, J = 18.1 Hz), 133.92, 133.15, 123.56, 122.30 (d, J = 42.3 Hz), 121.42, 120.44, 119.73, 116.23, 113.89 (d, J = 19.6 Hz), 111.15 (d, J = 4.5 Hz), 105.99, 79.79 (d, J = 151.0 Hz), 61.26 (d, J = 7.6 Hz), 60.79, 36.04. CF CF CF CF CF CF CF PC PC

[0368] (4S)-2-(((6-(6-bromo-4-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1H-indazol-3-yl)methoxy)methyl)-4-(2-chlorophenyl)-1,3,2-dioxaphosphorin-2-oxide (Compound 57)

[0369] Compound x-1 (120 mg, 0.26 mmol), (S)-1-(3-chlorophenyl)propane-1,3-diol (147 mg, 0.79 mmol) and dicyclohexylmethane diamine (163 mg, 0.79 mmol) were weighed in a 25 mL reaction vial, after dissolved in 5 mL N,N-dimethylformamide and 1 mL pyridine, reaction at 70 °C for 4 h, after the reaction was complete, the solvent was spin dried, after adding ethyl acetate, white solid precipitated, after suction filtration, 1M HCl solution was added dropwise to the filtrate, extracted with ethyl acetate and saturated brine 3 times, the organic phase was dried with anhydrous sodium sulfate, separated by PLC preparation plate to obtain 42 mg of white solid powder, the yield was 26%.​​​​​​​​​

[0370] 1 H NMR (600 MHz, DMSO-d6) δ 13.44 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.02 (dd, J = 9.4, 1.6 Hz, 2H), 7.71 (dd, J = 9.8, 1.4 Hz, 1H), 7.56 (dd, J = 8.5, 1.8 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.40 - 7.32 (m, 3H), 5.69 (dt, J = 10.8, 2.4 Hz, 1H), 5.13 - 4.93 (m, 2H), 4.54 (tt, J = 11.2, 3.7 Hz, 1H), 4.38 (dddd, J = 15.3, 10.9, 4.6, 2.3 Hz, 1H), 4.05 (qd, J = 14.3, 8.5 Hz, 2H), 2.23 - 2.06 (m, 2H). LC-MS / ESI [M+H] + :606.00.

[0371] Test Example:

[0372] Biological activity test

[0373] Test Example 1: CD73 small molecule compound molecular level and cell level enzyme activity test scheme of the present patent disclosure

[0374] Principle of experiment: AMP is removed by catalysis of CD73 to generate adenosine, phosphate and molybdate generate phosphomolybdate acid association under acidic conditions, and then form a green complex with malachite green. The higher the enzyme activity, the higher the content of inorganic phosphate produced, the stronger the signal intensity of wave absorption, and after adding the inhibitor, the enzyme activity will be weakened, so as to indirectly reflect the inhibition activity of the inhibitor.

[0375] Molecular level activity test scheme:

[0376] Activity test system:

[0377] 1. Prepare malachite green color developing agent.

[0378] The ratio of Regent A to Regent B is 100:1, and after preparation, it is stable for more than 12 hours in the dark.

[0379] 2. Prepare the substrate (AMP, 250 μM, about 15x final concentration)

[0380] Weigh 18.26 mg of AMP (M = 365.2) in a beaker, and dilute with ultrapure water to 200 ml. Stir to completely dissolve, then 1.5 ml per tube, and store in a -20°C refrigerator.

[0381] 3. Prepare the assay buffer (0.22 μm filter) at the molecular level:

[0382] Prepare 200 ml at a time. The components are as follows: 1 mM CaCl2, 1 mM MgCl2, 200 mM NaCl, 10 mM KC1, 100 mM Tris-HCl, pH 8.0.

[0383] 4. Prepare the blank control (0.5% DMSO buffer)

[0384] 5. Dispense the test compound, dilute it by 3-fold gradient, and obtain 11 concentrations.

[0385] 5. Dilute the protein (15 ng / ml)

[0386] 6. Plate: Add 70 μl of protein to each well of the sample and positive wells, and add 70 μl of buffer to the blank wells.

[0387] 7. Add the drug to the sample wells, 5 μl per well, and incubate at room temperature for 30 min. Add 0.5% DMSO buffer to the positive and blank wells.

[0388] 8. Add the substrate (AMP) and incubate in an oven for 30 min

[0389] 9. Add the malachite green reagent and develop color at room temperature for 30 min

[0390] 10. Read at 620 nm using a microplate reader

[0391] 11. Calculate the initial velocity V0 of the enzymatic reaction. To test the activity of the inhibitor, add different concentrations of the inhibitor to the above reaction, and calculate the initial velocity V1 of the enzymatic reaction. The inhibition rate of the compound is calculated by the formula (1-V1 / V0) x 100%. Three sets of parallel controls are prepared for each experiment.

[0392] Cell level:

[0393] Assay system:

[0394] 1. Prepare the malachite green developing reagent. Same as at the molecular level.

[0395] 2. Prepare the substrate (AMP, 250 μM, about 10 x final concentration). Same as at the molecular level.

[0396] 3. Prepare the assay buffer (0.22 μm filter) at the cell level:

[0397] Typically 200 ml is prepared at one time. The components are as follows: 20 mM HEPES, pH 7.4, 137 mM NaCl2, 5.4 mM KCl, 1.3 mM CaCl, 4.2 mM NaHCO3, 0.1% glucose.

[0398] 4. Prepare blank control (0.5% DMSO buffer).

[0399] 5. Prepare drug, test compound: 3-fold dilution gradient, 11 concentrations.

[0400] 6. Take cells to plating: when the cell density of MDA-MB-231 reaches 80%-90% and the cell viability is more than 95%, the compound screening can be performed. Take the cell culture dish out of the carbon dioxide cell incubator, discard the culture medium, add 2 mL D-hank's to wash the residual medium and dead cells, discard the D-hank's, and then add 500 μL of 0.25% trypsin to the surface of the cells, put the cells into a 37°C cell incubator for one minute to digest the cells. After the cells are digested, add 2 mL of fresh 1640 complete medium, and use a pipette gun to blow the cells completely from the cell culture dish. Transfer the cell suspension to a 15 mL sterile centrifuge tube, and centrifuge at 1000 rpm for three minutes. Discard the medium, resuspend the cells with 4 mL of phosphate-free activity test buffer, and then centrifuge at 1000 rpm for three minutes. Repeat the above operation three times. After the last washing, resuspend the cells with 1 mL of activity test buffer, blow evenly, and take 10 μL of the cell suspension to an EP tube, add 10 μL of 0.4% trypan blue dyeing solution and blow evenly, take 10 μL of the above mixed solution to a cell counting plate, insert the cell counting plate into a cell counter, and count and record the cell concentration. Dilute the cell suspension with the activity test buffer, and add 80 μl of 3000 cells to each well of the sample and positive control wells in the 96-well plate. Add the corresponding amount of buffer to the blank wells.

[0401] 7. Add 10 μl of drug to each well of the sample, and incubate in the oven for 30 min,

[0402] 8. Add 10 μl of substrate (AMP) to each well, and incubate in the oven for 30 min

[0403] 9. After the incubation, centrifuge at 230 x g for 5 min using a blank centrifuge, and then transfer the supernatant to a flat-bottom 96-well plate. Then add 20 μl of malachite green color developing agent to each well, and develop the color at room temperature for 30 min.

[0404] 10. Read at 620 nm using a microplate reader.

[0405] 11. Calculate the initial velocity of the enzymatic reaction V0, and then add different concentrations of the inhibitor to the above reaction to calculate the initial velocity of the enzymatic reaction V1. The inhibition rate of the compound is calculated by the formula (1-V1 / V0) x 100%. Each experiment is done in triplicate.

[0406] The results of the enzyme activity test at the molecular level and the cellular level of CD73 molecules (compounds 34-41, 44, 46-47, and 49 were tested as triethylammonium salts) are indicated by A, B, C, and D, where A: IC50≤0.5 nM, B: 0.5 nM < IC50≤1 nM, C: 1 nM < IC50≤100 nM, and D: IC50>100 nM.

[0407] Test Example 2: In vivo pharmacodynamic evaluation

[0408] The compounds of the present application that have a B or higher result in the enzyme activity test at the molecular level or the cellular level of CD73 were evaluated for in vivo pharmacodynamic properties, and it was found that these compounds all have excellent in vivo pharmacodynamic properties.

[0409] 1 Expansion of E.G7-OVA mouse T lymphoma cells

[0410] The mouse T lymphoma cells (E.G7-OVA) in the cell bank of the research group were thawed. First, turn on the water bath, wait for the temperature to rise to 37℃, and then immediately put the cells into the water bath for about 5 minutes. At the same time, turn on the biosafety cabinet and prepare the complete RPMI1640 medium needed for resuscitation, and transfer 4 mL of medium to a 15 mL sharp-bottom centrifuge tube. After the cell liquid is thawed, spray alcohol and then put it into the biosafety cabinet. Use a pipette to transfer the cell liquid to the 15 ml centrifuge tube containing the medium, mix gently with 1 mL of pipette, and then centrifuge at 1000 rpm for 3 minutes. Discard the supernatant and add 1 mL of complete medium to resuspend the cell pellet. According to the amount of frozen cells, transfer to a culture dish of appropriate size, and add an appropriate volume of medium. Then shake the culture dish in a cross shape to evenly distribute the cells in the culture dish. Then, place the culture dish in a cell culture incubator for culture. After 2 days, observe the cell state and change the liquid or passage the cells. When the cells grow well, passage them according to a 2-day interval at a ratio of 1:3.

[0411] 2 Modeling (E.G7-OVA subcutaneous tumor model)

[0412] (1) Preparation of tumor cell suspension: The purchased Matrigel was previously frozen in the 4℃ refrigerator and at the same time a box of sterilized 1 mL gun head was pre-cooled, and the expanded cells were collected by centrifugation, the supernatant was discarded, and the cells were resuspended with serum-free RPIM1640 medium, then centrifuged, and the washing was repeated 3 times to remove the FBS in the complete medium. After the last time, the supernatant was discarded, and the appropriate volume of serum-free RPIM1640 medium was resuspended, and the cells were mixed with a pipette gun. 10 μL was transferred to a 1.5 mL centrifuge tube, then 10 μL of trypan blue was added to the centrifuge tube and mixed, 10 μL was injected into a cell counting plate, and then the counting plate was inserted into a cell counter. After focusing, start counting. According to the counting density, adjust the cell density to 2 times the target density with medium, then add an equal volume of Matrigel and mix by blowing. The prepared cell suspension was placed on ice for tumor transplantation;

[0413] (2) Tumor transplantation: When transplanting tumors, a 1 mL sterile syringe was used. First, the cell suspension was transferred to the syringe, and the bubbles were removed, then 100 μL of cell suspension was injected subcutaneously into the right dorsal neck of C57BL / 6 mice. According to the previous experience of the research group in constructing this model, 5 × 10 4 E.G7-OVA mouse lymphoma cells were transplanted into each mouse. After tumor transplantation, the state of the mice was observed every day, and when the tumor reached about 100 mm 3 , drug administration was performed. Body weight and tumor volume were measured every other day during the entire study. The tumor growth inhibition rate (TGI) was calculated according to the formula: TGI (%) = [1-(T i -T0) / (C i -C0)] × 100, where Ti is the average tumor volume of the drug-treated group on a certain day, T0 is the initial average tumor volume of the drug-treated group, Ci is the average tumor volume of the control group treated with solvent on a certain day, and C0 is the initial average tumor volume of the control group.

[0414] 3 Drug treatment scheme

[0415] The drug administration scheme and dose of each compound are shown in the following table

[0416] The in vivo anti-tumor effects of each drug administration group are summarized in the following table

[0417] 4. In vivo pharmacodynamic conclusion: The combination of compounds 31 and 35 described in the patent and PD-1 antibody RMP1-14 can significantly inhibit the in vivo proliferation of the T lymphoma xenotransplant mouse model, and other high-activity compounds also show good in vivo pharmacodynamic activity.

[0418] Test Example 3

[0419] The compounds with the test results of B or above on the enzyme activity of CD73 at the molecular level or the cell level are evaluated for cytotoxicity, and it is found that these compounds all have good safety and drugability.

[0420] The compounds 16, 31 and 33 do not exhibit significant cytotoxicity to human embryonic kidney cells 293 (HEK293) and normal human liver cells (L-02) at the level of 100 nM, indicating that the compounds in this series have good safety and drugability.

[0421] Therefore, after the activity test at the molecular level, the compounds of the present application are compounds capable of inhibiting CD73 well, which lays a foundation for the treatment of cancer mediated by CD73.

[0422] All the documents mentioned in the present application are cited as references in the present application, as if each document is cited as a reference individually. In addition, it should be understood that various modifications or changes can be made to the present application by those skilled in the art after reading the above teaching of the present application, and these equivalent forms also fall within the scope defined by the claims attached to the present application.

Claims

1. A compound of Formula I: ###0001### or a pharmaceutically acceptable salt thereof. wherein, A is an optionally substituted benzene ring, a nitrogen-containing, oxygen- and sulfur-containing 5- or 6-membered heterocycle; M is an optionally substituted C8-C12 aryl or heteroaryl or heterocyclyl; Z1is selected from the group consisting of O, S, CR1R2or NR3, wherein R1, R2and R3are independently selected from the group consisting of hydrogen, halogen, optionally substituted C1-C10alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C5-C6aryl, optionally substituted C5-C6heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O or S; Z2is selected from the group consisting of CR4or N, wherein R4is hydrogen, halogen, optionally substituted C1-C10alkyl, optionally C3-C8cycloalkyl, optionally substituted C5-C6aryl, optionally substituted C5-C6heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O or S; X is selected from CR5R6, NR7, O, S, carbonyl, sulfone or sulfoxide, wherein R5, R6and R7are independently selected from the group consisting of H, halogen, optionally substituted C1-C10alkyl, optionally substituted C3-C8cycloalkyl; Y is selected from CR8R9, NR 10 , O, S, carbonyl, sulfone or sulfoxide, wherein R8, R9and R 10 are independently selected from H, halogen, optionally substituted C1-C10alkyl, optionally substituted C3-C8cycloalkyl; CH2, NH, O, S, carbonyl, sulfone or sulfoxide; Q1and Q2are each independently selected from the group consisting of hydrogen, optionally substituted C1-C10alkyl (including but not limited to hydroxymethyl, hydroxyethyl, optionally substituted (e.g. deuterated) C1-C3alkoxymethyl, optionally substituted C1-C3alkoxyethyl), optionally substituted C3-C8cycloalkyl, optionally substituted C5-C6aryl, optionally substituted C5-C6heterocyclyl, optionally substituted phenyl C1-C5alkyl, optionally substituted C5-C6heterocyclyl C1-C5alkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, hydroxyl, optionally substituted C1-C3formyl (including but not limited to hydroxyformyl, C1-C3alkoxycarbonyl); W1and W2are independently selected from NH, O or S; P1is H, optionally substituted C8-C12aryl and optionally substituted C8-C12heteroaryl or heterocyclyl, optionally substituted C1-C10alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C1-C10alkylcarbonyloxymethyl; or, W1P1together forms an amino acid linked by a phosphoramidate bond, an esterified amino acid linked by a phosphoramidate bond, a phosphoric acid prodrug group; P2is H, optionally substituted C8-C12aryl and optionally substituted C8-C12heteroaryl or heterocyclyl, optionally substituted C1-C10alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C1-C10alkylcarbonyloxymethyl; W2P2together forms an amino acid linked by a phosphoramidate bond, an esterified amino acid linked by a phosphoramidate bond, a phosphoric acid prodrug group; or P1, P2may form an optionally substituted 5-8 membered cyclic ether, lactone, lactam.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein The compounds are represented by the general formula II: wherein, M, Z1, Z2, X, Y, Q1, Q2, W1, W2, P1, P2are as described in claim 1.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein The compound is shown as general formula III: wherein, M, Q1, Q2, W1, W2, P1, P2are as described in claim 2.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein The compound is shown as general formula IV: wherein, B is an optionally substituted C5-C6aromatic ring, an optionally substituted C5-C6heterocycle containing N, O or S; A1, A2, A3, A4, A5are each independently selected from CH or N; A1, A2, A3, A4, A5are each independently selected from CH or N; R3is selected from the group consisting of: H, halogen (F, CI or Br), nitro, cyano, optionally substituted C1-C10 alkyl (e.g. trifluoromethyl, hydroxymethyl), optionally substituted C3-C8 cycloalkyl, optionally substituted C5-C6 heterocyclyl C1-C5 alkyl (e.g. benzyl), optionally substituted C1-C5 alkoxy, optionally substituted C1-C5 alkoxycarbonyl, optionally substituted amino, optionally substituted C1-C5 alkylcarbonylamino; n is selected from an integer from 1 to 5, preferably from 1 to 3; Q1, Q2, W1, W2, P1, P2 are as described in claim 3.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein The compound is shown as general formula V: wherein A1, R3, Q1, Q2, W1, W2, P1, P2 and n are as described in claim 4.

6. A compound selected from the group consisting of: Preferably, the compound is selected from the following compounds:

7. A pharmaceutical composition comprising a compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

8. Use of a compound of any one of claims 1-6 for the manufacture of a CD73 inhibitor.

9. Use according to claim 8, characterized in that, The CD73 inhibitor is a drug for the treatment or prevention of a CD73 mediated disease, or for the inhibition of CD73.

10. Use according to claim 9, characterized in that, The CD73 mediated disease is a cancer.

11. Use according to claim 10, characterized in that, The cancer is selected from the group consisting of: the cancer includes but is not limited to breast cancer, multiple myeloma, bladder cancer as preferred, the cancer is selected from the group consisting of breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumor, cholangiocellular carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, schwannoma, lung squamous cell carcinoma, Darier's disease, synovial sarcoma, skin cancer, adenocarcinoma, testicular cancer or liposarcoma. The CD73 inhibitor is a drug for the treatment or prevention of a CD73 mediated disease, or for the inhibition of CD73. The CD73 mediated disease is a cancer. The cancer is selected from the group consisting of: the cancer includes but is not limited to breast cancer, multiple myeloma, bladder cancer as preferred, the cancer is selected from the group consisting of breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumor, cholangiocellular carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, schwannoma, lung squamous cell carcinoma, Darier's disease, synovial sarcoma, skin cancer, adenocarcinoma, testicular cancer or liposarcoma.

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