Heteroaromatic ring compound as well as preparation method and application thereof

Abstract

The invention discloses a heteroaromatic ring compound as well as a preparation method and application thereof. Specifically, the invention relates to compounds of formula (I), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope labeled analogues thereof. The invention also relates to a preparation method and application of the compound. # imgabs0 #

Description

Heteroaromatic ring compound and its preparation method and use Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a class of heteroaromatic ring compounds and their preparation methods and uses. Background Art

[0002] Cancer is one of the leading causes of death in humans. Excessive proliferation of cancer cells is often accompanied by chromosomal instability, as DNA fragments or even entire chromosomes may be duplicated, mutated, or completely lost as cancer cells divide rapidly. This instability is primarily related to cancer invasion. The more unstable the chromosomes, the more likely it is that DNA fragments from these chromosomes will end up in places where they do not originally exist, such as floating in the cytoplasm outside the cell nucleus. Cells recognize these free DNA fragments as evidence of viral invasion, thereby triggering an autoimmune response within the cell, inducing inflammation, and recruiting immune cells to the tumor site to launch an attack.

[0003] The cGAS-STING pathway is an intracellular early warning system involved in this process. When viral or cancer cell chromosomal DNA enters the cytoplasm, cGAS binds to it, forming the second messenger cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). This acts as a warning signal, activating the STING pathway within the cell, leading to the production of type I interferon (IFN) and other co-stimulatory molecules that trigger an immune response. This is a key anti-cancer innate immune pathway, initiating an immune attack against virally infected or cancerous cells. While cancer cells theoretically attract immune cell attacks due to DNA fragments scattered in the cytoplasm, in reality, they can effectively evade immune surveillance, metastasize, and spread. In 2020, scientists at Memorial Sloan Kettering Cancer Center discovered the mechanism that explains this phenomenon: a molecule on the outside of cancer cells destroys the cGAMP signal before it reaches immune cells. This scissor-like protein on the cancer cell surface is ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1), the primary known hydrolase of cGAMP. When cGAMP appears outside the cell, ENPP1 uses its ATPase activity to quickly hydrolyze cGAMP into AMP and GMP, preventing the signal from activating the STING pathway and thus immune cells. AMP also further releases adenosine, an immunosuppressive molecule. Therefore, ENPP1 inhibitors can achieve a "two birds with one stone" effect in immune regulation.

[0004] Several companies are currently developing small-molecule ENPP1 inhibitors for cancer treatment. Internationally, these include Mavupharma (acquired by AbbVie in 2019), Stingray Therapeutics, and Riboscience, LLC. Domestically, these include Nanjing Zhengxiang Pharmaceutical and Betta Pharmaceuticals. Riboscience, LLC's RBS2418 is the most advanced, with Phase I enrollment beginning in March 2022. The remaining companies' compounds are in preclinical development.

[0005] RBS2418 is a product under development by Riboscience, LLC. Its structure has not yet been disclosed, and no activity data for this compound have been found. The company currently has two patents published on ENPP1 small molecule inhibitors (WO2020210649 and WO2020140001). Its structure is a quinoline and phosphate compound (Scheme 1), and some compounds have an in vitro enzyme activity IC50 below 10nM. It is currently in Phase I clinical recruitment, and plans to first conduct a ramp-up study of monotherapy and combination with the PD-1 antibody Perbrolizumab, starting from 100mg BID to 800mg BID, for oral administration. After the dose is determined, the efficacy and safety of the monotherapy and combination will be evaluated. Phase I clinical trials are expected to be completed in 2024.

[0006] Stingray Therapeutics has published six patents on ENPP1 small molecule inhibition to date, covering two structural types. The main type is quinoline compounds, which differ from Riboscience's compounds mainly in the aminosulfonamide tail portion; the other type is thioether compounds, which have significant structural differences from other molecules under development, and most compounds have an in vitro enzyme activity IC50 of above 100nM.

[0007] MV-626 is an ENPP1 inhibitor developed by MavuPharma, whose structure has not yet been disclosed. In July 2019, AbbVie announced its acquisition of MavuPharma, acquiring its investigational ENPP1 inhibitor, MV-626. Analysis of the company's publicly available patents reveals that its structure primarily consists of variations of the quinoline ring, either bicyclic or tricyclic, with an aminosulfonamide tail. The compound also exhibits nanomolar inhibitory activity against ENPP1 and exhibits favorable PK properties, with 100% oral availability in rats and mice.

[0008] Although some ENPP1 inhibitor small molecules have been disclosed, no ENPP1 inhibitor has been developed and marketed yet. Therefore, there is still an urgent need to develop new compounds with potential for marketing and better efficacy and pharmacokinetic results.

[0009] Summary of the Invention

[0010] The present invention designs a series of compounds having novel structures represented by the general formula, and finds that compounds having such structures exhibit excellent effects and functions, which has positive significance for the development of ENPP1 inhibitors.

[0011] The object of the present invention is to provide a compound with a novel structure as an ENPP1 inhibitor, a preparation method thereof and use thereof in treating diseases mediated by ENPP1.

[0012] The present invention provides a compound of formula (I), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs thereof.

[0013] in

[0014] L is selected from -(NR L3 )SO2N(R L1 )(R L2 ),-SO2R L1 、-C(O)OR L1 、-C(O)N(R L1 )(R L2 ),-C(O)NHOR L1 、-P(O)(OR L1 )(OR L2 )、-P(O)(NHR L1 )(OR L2 )、-P(O)(OR L1 )(R L2 )、-P(O)(NHR L1 )(NHR L2 )、-P(O)(NHR L1 )(R L2 )、-P(O)(R L1 )(R L2 )、-P(O)(SR L1 )(SR L2 )、-P(O)(NHR L1 )(SR L2 )、-P(O)(SR L1 )(R L2 ) or -B(OH)2, where R L1 、R L2 and R L3R is independently selected from hydrogen, deuterium, halogen, amino, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted aryl; or R L1 and R L2 are linked to form an optionally substituted ring structure;

[0015] A is selected from optionally substituted alkylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylenealkylene, optionally substituted heterocyclylenealkylene, optionally substituted arylenealkylene, or optionally substituted heteroarylenealkylene;

[0016] Z is selected from -(chemical bond), -O-, -S-, -CO-, -SO-, -SO2-, -C(R Z1 )(R Z2 )-、-N(R Z1 )-、-CH2N(R Z1 )-、-N(R Z1 )CH2-、-CON(R Z1 )-、-N(R Z1 )CO-、-SON(R Z1 )-、-SO2N(R Z1 )-、-N(R Z1 )SO-、-N(R Z1 )SO2- or where R Z1 and R Z2 is independently selected from hydrogen, deuterium, halogen, hydroxy, thiol, amino, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl;

[0017] R 1 is selected from deuterium, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, -OR 3 、-SR 3 、-NR 3 R 4 、-COOR 3 、-CONR 3 R 4 、-NR 3 COR 4 、-COR 3 、-OCOR 3 、-SONR 3 R 4 、-SO2NR 3 R4 、-NR 3 SOR 4 、-NR 3 SO2R 4 or -Si(R 3 )(R 4 )(R 5 ), where R 3 、R 4 or R 5 independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0018] n = 0, 1, 2 or 3;

[0019] X 1 、X 2 、X 3 and X 4 independently selected from N or C(R X ), where R X are independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, -OR a 、-SR a 、-NR a R b 、-COOR a 、-CONR a R b 、-NR b COR a 、-COR a 、-OCOR a 、-SONR a R b 、-SO2NR a R b 、-NR b SOR a 、-NR b SO2R a or -Si(R a )(R b )(R c ), where R a 、R b and R c is independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or X 1 With X 2 are linked to form an optionally substituted ring structure; or X2 With X 3 are linked to form an optionally substituted ring structure; or X 3 With X 4 are linked to form an optionally substituted ring structure; or X 1 and Z are linked together to form an optionally substituted ring structure.

[0020] The present invention also provides a method for treating a disease mediated by ENPP1, comprising administering a compound of formula (I) to a patient in need thereof.

[0021] The present invention also provides use of the compound of formula (I) in preparing a medicament for treating a disease mediated by ENPP1. DETAILED DESCRIPTION

[0022] definition

[0023] As used herein, the term "alkyl", alone or in combination, refers to a straight or branched saturated hydrocarbon chain, including C 1-6 Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1,2,2-trimethylpropyl, and the like.

[0024] As used herein, the term "alkenyl", alone or in combination, refers to a straight or branched unsaturated hydrocarbon chain having at least one carbon-carbon double bond, for example, a C-1-1-2-6 carbon atom. 2-6 -alkenyl, such as vinyl, allyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, and the like.

[0025] As used herein, the term "alkynyl", alone or in combination, refers to a straight or branched unsaturated hydrocarbon chain having at least one carbon-carbon triple bond, for example a C-1-6 carbon atom. 2-6 -alkynyl, such as ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 2-hexynyl, 3-hexenyl, and the like.

[0026] As used herein, the term "cycloalkyl", alone or in combination, refers to a saturated non-aromatic cyclic hydrocarbon group, such as a C1-C12-C16-C18-C19-C19-C18 ... 3-6 - cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0027] As used herein, the term "heterocyclyl", alone or in combination, refers to a non-aromatic cyclic group containing one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from O, S, and N, such as a 4-6 membered heterocyclyl having 4 to 6 ring atoms or a 4-10 membered heterocyclyl having 4 to 10 ring atoms. Examples of heterocyclyl groups include pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, indolinyl, pyranyl, tetrahydropyran, thiomorpholinyl, tetrahydrothiophenyl, isoxazolidinyl, isothiazolidinyl, oxazolidinyl, thiazolidinyl, azepanyl, benzazepine, and the like.

[0028] As used herein, the term "aryl", alone or in combination, refers to a monocyclic or polycyclic aromatic ring, for example a C 6-10 Aryl groups such as phenyl, naphthyl, indenyl and the like.

[0029] As used herein, the term "heteroaryl", alone or in combination, refers to a monovalent aromatic heterocyclic monocyclic or polycyclic ring system containing one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, and S, the remaining ring atoms being carbon, e.g., a C 5-6 Heteroaryl, C 5-10 Heteroaryl and C having 5 to 12 ring atoms 5-12 Examples of heteroaryl groups include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, aza Base, diazepine benzothiophene, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, benzothiophenyl, benzoquinolyl and benzoisoquinolyl.

[0030] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0031] As used herein, the term "hydroxy" refers to an -OH group.

[0032] As used herein, the term "thiol" refers to a -SH group.

[0033] As used herein, the term "amino" refers to a -NH2 group.

[0034] As used herein, the term "cyano" refers to a -CN group.

[0035] As used herein, the term "carbonyl" refers to a -CHO group.

[0036] As used herein, the term "nitro" refers to a -NO2 group.

[0037] As used herein, the term "stereoisomer" refers to a compound composed of the same atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. "Stereoisomer" includes enantiomers, diastereomers, and other stereoisomeric forms defined by absolute stereochemistry. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms.

[0038] As used herein, the term "geometric isomers" refers to isomeric forms due to carbon-carbon double bonds or other centers of geometric asymmetry.

[0039] As used herein, the term "tautomer" refers to isomeric forms resulting from the interchange of a single bond with an adjacent double bond, along with the concomitant migration of a proton.

[0040] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid, and salts with organic carboxylic and sulfonic acids such as acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and naphthalenedisulfonic acid; or salts with conventional bases such as alkali metal salts (e.g., sodium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), ammonium salts derived from ammonia and organic amines (e.g., diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, methylpiperidine, L-arginine, creatine, choline, L-lysine, ethylenediamine, N,N-dibenzylethylenediamine (benzathine), ethanolamine, meglumine, and tromethamine).

[0041] As used herein, the term "prodrug" refers to a compound that undergoes biotransformation before exhibiting its pharmacological effect. Prodrugs can be prepared using well-known methods, such as those described in Burgers Medicinal Chemistry and Drug Development (1995) 172-178, 949-982 (Manfred E. Wolff).

[0042] As used herein, the term "solvate" refers to a complex formed by coordination with a solvent molecule. When the solvent molecule is water, the solvate is a hydrate.

[0043] The compounds described herein may be isotopically labeled, i.e., one or more atoms therein are replaced by atoms having a different atomic mass or mass number. Such isotopically labeled compounds are considered to be within the scope of the present invention. Examples of isotopes that may be incorporated into the compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, respectively 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I.

[0044] In one aspect, the present invention provides a compound of formula (I), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopically labeled analogs thereof,

[0045] in

[0046] L is selected from -(NR L3 )SO2N(R L1 )(R L2 ),-SO2R L1 、-C(O)OR L1 、-C(O)N(R L1 )(R L2 ),-C(O)NHOR L1 、-P(O)(OR L1 )(OR L2 )、-P(O)(NHR L1 )(OR L2 )、-P(O)(OR L1 )(R L2 ), -P(O)(NHR L1 )(NHR L2 )、-P(O)(NHR L1 )(R L2 )、-P(O)(R L1 )(RL2 )、-P(O)(SR L1 )(SR L2 )、-P(O)(NHR L1 )(SR L2 )、-P(O)(SR L1 )(R L2 ) or -B(OH)2, where R L1 、R L2 and R L3 R is independently selected from hydrogen, deuterium, halogen, amino, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted aryl; or R L1 and R L2 are linked to form an optionally substituted ring structure;

[0047] A is selected from optionally substituted alkylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylenealkylene, optionally substituted heterocyclylenealkylene, optionally substituted arylenealkylene, or optionally substituted heteroarylenealkylene;

[0048] Z is selected from -(chemical bond), -O-, -S-, -CO-, -SO-, -SO2-, -C(R Z1 )(R Z2 )-、-N(R Z1 )-、-CH2N(R Z1 )-、-N(R Z1 )CH2-、-CON(R Z1 )-、-N(R Z1 )CO-、-SON(R Z1 )-、-SO2N(R Z1 )-、-N(R Z1 )SO-、-N(R Z1 )SO2- or where R Z1 and R Z2 is independently selected from hydrogen, deuterium, halogen, hydroxy, thiol, amino, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl;

[0049] R 1 is selected from deuterium, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, -OR 3 、-SR 3 、-NR 3 R4 、-COOR 3 、-CONR 3 R 4 、-NR 3 COR 4 、-COR 3 、-OCOR 3 、-SONR 3 R 4 、-SO2NR 3 R 4 、-NR 3 SOR 4 、-NR 3 SO2R 4 or -Si(R 3 )(R 4 )(R 5 ), where R 3 、R 4 or R 5 independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0050] n = 0, 1, 2 or 3;

[0051] X 1 、X 2 、X 3 and X 4 independently selected from N or C(R X ), where R X are independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, -OR a 、-SR a 、-NR a R b 、-COOR a 、-CONR a R b 、-NR b COR a 、-COR a 、-OCOR a 、-SONR a R b 、-SO2NR a R b 、-NR b SOR a 、-NR b SO2R a or -Si(R a )(Rb )(R c ), where R a 、R b and R c is independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or X 1 With X 2 are linked to form an optionally substituted ring structure; or X 2 With X 3 are linked to form an optionally substituted ring structure; or X 3 With X 4 are linked to form an optionally substituted ring structure; or X 1 and Z are linked together to form an optionally substituted ring structure.

[0052] In some embodiments, R L1 、R L2 and R L3 are independently selected from hydrogen, deuterium, halogen, amino, cyano, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclic group or optionally substituted C 6-10 Aryl.

[0053] In some embodiments, R L1 、R L2 and R L3 independently selected from hydrogen, deuterium, halogen, amino, cyano; unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl; and alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, thiol, amino, cyano, alkyl (e.g., C 1-6 Alkyl), alkenyl (e.g. C 2-6 alkenyl), alkynyl (e.g. C 2-6 Alkynyl), cycloalkyl (e.g. C 3-6 Cycloalkyl), heterocyclyl (e.g., 4-6 membered heterocyclyl), -OC(O)-alkyl (e.g., -OC(O)-C 1-6 alkyl), -C(O)O-alkyl (e.g. -C(O)OC 1-6 alkyl), -OC(O)O-alkyl (e.g. -OC(O)OC 1-6 alkyl), phenyl or halogenated phenyl (e.g., chlorophenyl or fluorophenyl).

[0054] In some embodiments, L is selected from: -(NR L3 )SO2N(R L1 )(R L2 ),-SO2R L1 、-C(O)OR L1 、-C(O)NHOR L1 、-P(O)(OR L1 )(OR L2 )、-P(O)(NHR L1 )(OR L2 )、-P(O)(NHR L1 )(NHR L2 ) or -B(OH)2.

[0055] In some embodiments, R L1 、R L2 and R L3 are independently selected from hydrogen, amino, optionally substituted alkyl (e.g., C 1-6 alkyl) and optionally substituted aryl (e.g., C 6-10 aryl).

[0056] In some embodiments, R L1 、R L2 and R L3 independently selected from hydrogen, unsubstituted alkyl and phenyl, and alkyl substituted with one or more substituents independently selected from: -OC(O)-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, phenyl or halogenated phenyl.

[0057] In some embodiments, L is selected from: -P(O)(OH)2, -C(O)OH, -C(O)NHOH, -B(OH)2, -SO2NH2, -NHSO2NH2, -P(O)(OCH2OC(O)C(CH3)3)2, -P(O)(OCH2OC(O)OCH(CH3)2)2, -P(O)(NHCH(CH3)C(O)OCH(CH3)2)2, -P(O)(OC6H5)(NHCH(CH3)C(O)OCH(CH3)2).

[0058] In some embodiments, R L1 and R L2 They are linked to form an optionally substituted 5- or 6-membered ring structure.

[0059] In some embodiments, R L1 and R L2are connected to form a cyclic structure, which is substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, thiol, amino, cyano, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 4- to 6-membered heterocyclyl, optionally substituted phenyl (eg, halophenyl), or optionally substituted 5- to 6-membered heteroaryl.

[0060] In some embodiments, R L1 and R L2 connected to form a cyclic structure, the cyclic structure being substituted by one or more substituents independently selected from the group consisting of: deuterium; halogen; hydroxyl; thiol; amino; cyano; unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; or C substituted by substituents independently selected from deuterium, halogen, hydroxy, mercapto, amino, cyano, nitro, carboxyl, alkyl, cycloalkyl or alkoxy 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.

[0061] In some embodiments, L is -P(O)(OR L1 )(OR L2 ), R L1 and R L2 are independently optionally substituted alkyl (e.g., C 1-3 alkyl, such as methyl or ethyl), and R L1 and R L2 are linked to form an optionally substituted 5-membered or 6-membered ring structure. In a specific embodiment, L is -P(O)(OR L1 )(OR L2 ), R L1 is ethyl and R L2 is a methyl group substituted by a phenyl group or a halogenated phenyl group (eg, a chlorophenyl group or a fluorophenyl group), and R L1 and R L2 They are linked together to form a 6-membered ring structure substituted with a phenyl group or a halogenated phenyl group (eg, a chlorophenyl group or a fluorophenyl group).

[0062] In some embodiments, A is selected from optionally substituted C 1-6 Alkylene, optionally substituted C 3-6Cycloalkylene, optionally substituted 4-10 membered heterocyclylene, optionally substituted C 6-10 Arylene, optionally substituted 5-10 membered heteroarylene, optionally substituted C 3-6 Cycloalkylene C 1-3 Alkylene, optionally substituted 4-10 membered heterocyclylene C 1-3 Alkylene, optionally substituted C 6-10 Arylene C 1-3 Alkylene or optionally substituted 5-10 membered heteroarylene C 1-3 Alkylene.

[0063] In some embodiments, A is selected from unsubstituted alkylene, cycloalkylene, heterocyclylene, arylene, heteroarylene, cycloalkylenealkylene, heterocyclylenealkylene, arylenealkylene, or heteroarylenealkylene; and alkylene, cycloalkylene, heterocyclylene, arylene, heteroarylene, cycloalkylenealkylene, heterocyclylenealkylene, arylenealkylene, or heteroarylenealkylene substituted with one or more substituents independently selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, acetyl, alkyl (e.g., C 1-6 Alkyl), alkenyl (e.g. C 2-6 alkenyl), alkynyl (e.g. C 2-6 Alkynyl), cycloalkyl (e.g. C 3-6 Cycloalkyl), heterocyclic group (e.g. 4-6 membered heterocyclic group), -O-alkyl (e.g. -OC 1-6 Alkyl), -NH-alkyl (e.g. -NHC 1-6 Alkyl), -S-alkyl (e.g. -SC 1-6 Alkyl), -O-cycloalkyl (e.g. -OC 1-6 Cycloalkyl), -NH-cycloalkyl (e.g., -NHC 1-6 Cycloalkyl) or -S-cycloalkyl (e.g. -SC 1-6 cycloalkyl).

[0064] In some embodiments, the substituent is located on the alkylene, cycloalkylene, heterocyclylene, arylene, or heteroarylene portion of A. In some embodiments, the substituent is located on the cycloalkylene, heterocyclylene, arylene, or heteroarylene portion of a cycloalkylenealkylene, heterocyclylenealkylene, arylenealkylene, or heteroarylenealkylene group (e.g., ortho or meta relative to the alkylene portion).

[0065] In some embodiments, A is selected from optionally substituted C 1-4 Alkylene (e.g., methylene, ethylene, propylene, butylene), optionally substituted arylene (e.g., phenylene), optionally substituted cycloalkylene C 1-4 Alkylene, optionally substituted arylene C 1-4 Alkylene or optionally substituted heteroarylene C1-4 Alkylene.

[0066] In some embodiments, A is selected from methylene, ethylene, propylene, butylene, phenylene, phenylene, C 1-2 Alkylene (e.g., phenylenemethylene or phenyleneethylene), cyclohexylene C 1-2 Alkylene (e.g. cyclohexylenemethylene), pyridylene C 1-2 Alkylene (eg, pyridylenemethylene).

[0067] In some embodiments, A is selected from halogen (eg, fluorine or chlorine) or -O-alkyl (eg, -OC 1-6 Alkyl, such as methoxy) substituted phenylene C 1-2 Alkylene (eg, phenylenemethylene or phenyleneethylene). In some embodiments, A is selected from fluorophenylene-methylene, chlorophenylene-methylene, methoxyphenylene-methylene.

[0068] In some embodiments, R Z1 and R Z2 are independently selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, cyano, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 cycloalkyl or an optionally substituted 4- to 6-membered heterocyclic group.

[0069] In some embodiments, R Z1 and R Z2 independently selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, cyano; unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl; and alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl substituted with one or more substituents independently selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, alkyl (e.g., C 1-6 Alkyl), alkenyl (e.g. C 2-6 alkenyl), alkynyl (e.g. C 2-6 Alkynyl), cycloalkyl (e.g. C 3-6 cycloalkyl) or a heterocyclic group (e.g., a 4- to 6-membered heterocyclic group).

[0070] In some embodiments, Z is selected from -(chemical bond) or -C(R Z1 )(R Z2 )-.

[0071] In some embodiments, R Z1 and R Z2 are independently selected from hydrogen and optionally substituted alkyl (e.g., C 1-6 alkyl groups, such as methyl groups).

[0072] In some embodiments, Z is selected from -(chemical bond), -CH2-, or -CH(CH3)-.

[0073] In specific embodiments, Z is -CH(CH3)- having the (R) or (S) configuration.

[0074] In some embodiments, R 1 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclic group, optionally substituted C 6-10 Aryl, -OR 3 、-SR 3 、-NR 3 R 4 、-COOR 3 、-CONR 3 R 4 、-NR 3 COR 4 、-COR 3 、-OCOR 3 、-SONR 3 R 4 、-SO2NR 3 R 4 、-NR 3 SOR 4 、-NR 3 SO2R 4 or -Si(R 3 )(R 4 )(R 5 ).

[0075] In some embodiments, R 1 is selected from unsubstituted alkyl, alkenyl, cycloalkyl, heterocyclyl or aryl; and alkyl, alkenyl, cycloalkyl, heterocyclyl or aryl substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, thiol, amino, cyano, nitro, carboxyl, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted alkoxy.

[0076] In some embodiments, R 1 selected from alkyl, alkenyl, cycloalkyl, heterocyclyl or aryl substituted with one or more substituents independently selected from the group consisting of deuterium; halogen; hydroxyl; mercapto; amino; cyano; nitro; carboxyl; and alkyl, cycloalkyl or alkoxy substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, carboxyl, alkyl, cycloalkyl or alkoxy.

[0077] In some embodiments, R 1 Selected from alkyl, alkenyl, cycloalkyl, heterocyclyl or aryl substituted with one or more substituents independently selected from the group consisting of deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, cyano, nitro, alkyl, cycloalkyl, alkoxy, alkylamino, carboxyl, haloalkyl, haloalkoxy.

[0078] In some embodiments, R 3 、R 4 and R 5 are independently selected from hydrogen, deuterium, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclic group, optionally substituted C 6-10 aryl or optionally substituted 5-6 membered heteroaryl.

[0079] In some embodiments, R 3 、R 4 and R 5 independently selected from hydrogen; deuterium; unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; and alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, thiol, amino, cyano, nitro, carboxyl, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted alkoxy.

[0080] In some embodiments, R 3 、R 4 and R 5 independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituted with one or more substituents independently selected from the group consisting of deuterium; halogen; hydroxyl; thiol; amino; cyano; nitro; carboxyl; and alkyl, cycloalkyl or alkoxy substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, carboxyl, alkyl, cycloalkyl or alkoxy.

[0081] In some embodiments, R 3 、R 4 and R 5 independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituted with one or more substituents independently selected from the group consisting of deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, cyano, nitro, alkyl, cycloalkyl, alkoxy, alkylamino, carboxyl, haloalkyl, haloalkoxy.

[0082] In some embodiments, R 1 is selected from deuterium, halogen, hydroxy, amino, cyano; unsubstituted or halogen-substituted alkyl, alkenyl, cycloalkyl or aryl (e.g. phenyl); or -OR 3 In some embodiments, R 3 are independently selected from unsubstituted or halogen-substituted alkyl (e.g., C 1-6 alkyl).

[0083] In some embodiments, R 1 Selected from fluorine, chlorine, bromine, iodine, cyano, methyl, tert-butyl, methoxy.

[0084] In some embodiments, n is 0, 1, or 2.

[0085] In some embodiments, R X independently selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, -OR a 、-SR a 、-NR a R b 、-COOR a 、-CONR a R b 、-NR b COR a 、-COR a 、-OCOR a 、-SONR a R b 、-SO2NR a R b 、-NR b SOR a 、-NR b SO2R a or -Si(R a )(R b )(R c ), where R a 、R b and R c are independently selected from hydrogen, deuterium, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclic group, optionally substituted C 6-10 aryl or optionally substituted 5-6 membered heteroaryl; and R XThe substituents in the optional substitution are selected from one or more of the following: hydrogen, deuterium, halogen, hydroxyl, thiol, amino, cyano, alkyl (e.g., C 1-6 Alkyl), alkenyl (e.g. C 2-6 alkenyl), alkynyl (e.g. C 2-6 Alkynyl), cycloalkyl (e.g. C 3-6 Cycloalkyl), heterocyclic group (e.g. 4-6 membered heterocyclic group), aryl group (e.g. C 6-10 aryl) or heteroaryl (e.g., 5-6 membered heteroaryl).

[0086] In some embodiments, R X are independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, -OR a 、-SR a and -NR a R b , where R a and R b are independently selected from hydrogen, deuterium, and optionally substituted alkyl.

[0087] In some embodiments, R X are independently selected from unsubstituted alkyl groups (e.g., C 1-6 Alkyl) or alkyl substituted by deuterium or halogen (e.g. C 1-6 alkyl).

[0088] In some embodiments, R a and R b are independently selected from unsubstituted alkyl groups (e.g., C 1-6 Alkyl) or alkyl substituted by deuterium or halogen (e.g. C 1-6 alkyl).

[0089] In some embodiments, R X are independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl (e.g., C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, tert-butyl), haloalkyl, deuterated alkyl, -OR a 、-SR a or -NR a R b , where R a and R b are independently selected from hydrogen, deuterium, alkyl (e.g., C 1-4 alkyl, such as methyl or ethyl), deuterated alkyl, or haloalkyl.

[0090] In some embodiments, R Xare independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, deuterated alkyl (e.g., 1D-methyl, 2D-methyl, and 3D-methyl), methoxy, ethoxy, methylthio, methylamino, or dimethylamino.

[0091] In some embodiments, X 1 、X 2 、X 3 and X 4 are independently C(R X ).

[0092] In some embodiments, X 1 、X 2 、X 3 and X 4 For CH.

[0093] In some embodiments, X 1 、X 2 、X 3 and X 4 One of the 1 、X 2 、X 3 or X 4 ) or two (e.g. X 1 and X 3 ) are independently C(R X ), where R X As defined above (excluding hydrogen), and the remainder is CH.

[0094] In some embodiments, X 1 、X 2 、X 3 and X 4 One of the 1 、X 2 、X 3 or X 4 ) or two (e.g. X 1 and X 3 ;X 2 and X 4 ) are independently N, and the rest are independently C(R X ), where R X As defined above.

[0095] In some embodiments, X 1 、X 2 、X 3 and X 4 One of them is N and the rest are CH.

[0096] In some embodiments, X 1 With X2 are linked to form an optionally substituted 5-membered or 6-membered ring structure; or X 2 With X 3 are linked to form an optionally substituted 5-membered or 6-membered ring structure; or X 3 With X 4 are linked to form an optionally substituted 5-membered or 6-membered ring structure; or X 1 and Z are linked together to form an optionally substituted 5-membered or 6-membered ring structure.

[0097] In some embodiments, the ring structure is substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, thiol, amino, cyano, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 4- to 6-membered heterocyclyl, optionally substituted aryl, or optionally substituted 5- to 6-membered heteroaryl.

[0098] In some embodiments, the ring structure is substituted with one or more substituents independently selected from the group consisting of: deuterium; halogen; hydroxyl; thiol; amino; cyano; unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, aryl or 5-6 membered heteroaryl; or C substituted by substituents independently selected from deuterium, halogen, hydroxy, mercapto, amino, cyano, nitro, carboxyl, alkyl, cycloalkyl or alkoxy 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, aryl or 5-6 membered heteroaryl.

[0099] In some embodiments, the compound of formula (I), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically labeled analogs thereof are selected from the following compounds:

[0100] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) of the present invention and its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotope-labeled analogs as an active ingredient. The pharmaceutical composition can be used to prevent and / or treat diseases mediated by ENPP1.

[0101] In some embodiments, the pharmaceutical composition of the present invention may also include additional drugs (such as small molecules, polypeptides, nucleic acids, antibodies, antibody-drug conjugates) for preventing and / or treating cancer or tumors. When the compound of formula (I) of the present invention and its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs are administered in combination with additional drugs for preventing and / or treating cancer or tumors, the compound of the present invention or its pharmaceutically acceptable salts, etc. can provide enhanced anti-cancer effects.

[0102] In some embodiments, representative examples of drugs used to treat cancer or tumors include, but are not limited to, cell signaling inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, Tamoxifen, flutamide, gonadorelin analogs, megestrol acetate, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alfa, leucovorin, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danuceritid, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, la Patinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracutinib, saridegib, sorafenib, sunitinib, telatinib, tivan tinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, berentuzumab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, PI3K inhibitors, CSF1R inhibitors, A2A and / or A2B receptor antagonists, IDO inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, TIGIT antibodies, CD47 antibodies, CLAUDIN 18.2 antibodies, anti-CTLA-4 antibodies, or any combination thereof.

[0103] In some embodiments, the pharmaceutical composition of the present invention may further comprise an additional antibody-drug conjugate (ADC) for preventing and / or treating cancer or tumors. When the compound of formula (I) of the present invention and its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs are administered in combination with another antibody-drug conjugate for preventing and / or treating cancer or tumors, the compound of the present invention or its pharmaceutically acceptable salt may provide an enhanced anti-cancer effect.

[0104] In some embodiments, representative examples of antibody-drug conjugates for preventing and / or treating cancer or tumors may include, but are not limited to, emtansine trastuzumab, vedicizumab, osartuzumab, vedicizumab, gosartan, delutec-trastuzumab, or any combination thereof.

[0105] In some embodiments, the pharmaceutical composition of the present invention may also include additional therapeutic agents for treating inflammatory diseases, autoimmune diseases and immune-mediated diseases. When the compound of formula (I) of the present invention and its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs are administered in combination with additional therapeutic agents for treating inflammatory diseases, autoimmune diseases and immune-mediated diseases, the compound of the present invention or its pharmaceutically acceptable salt, etc. can provide enhanced therapeutic effects.

[0106] In some embodiments, representative examples of therapeutic agents for treating inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, steroidal drugs (e.g., prednisone, hydroprednisolone, methylhydroprednisolone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFα agents (e.g., etanercept, infliximab, adalimumab, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.), antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), or any combination thereof.

[0107] In yet another aspect, the present invention provides a method for preventing and / or treating a disease mediated by ENPP1, comprising administering the compound of formula (I) or the pharmaceutical composition of the present invention to a patient in need thereof.

[0108] In yet another aspect, the present invention provides use of the compound of formula (I) or pharmaceutical composition of the present invention in the preparation of a medicament for preventing and / or treating a disease mediated by ENPP1.

[0109] In some embodiments, the disease mediated by ENPP1 includes cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease, or immune-mediated disease.

[0110] In some embodiments, the disease mediated by ENPP1 comprises cancer, tumor, inflammatory disease, autoimmune disease, or immune-mediated disease.

[0111] In some embodiments, the disease mediated by ENPP1 is selected from cancer or tumor. Representative examples of cancer and tumor include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis carcinoma, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, Hodgkin's disease, Kim lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, leukemia, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchogenic carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myeloid leukemia, liposarcoma, fibrosarcoma, Ewing sarcoma and plasmacytoma.

[0112] In some embodiments, the disease mediated by ENPP1 is selected from inflammatory diseases, autoimmune diseases and immune-mediated diseases, representative examples of which include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, atopic dermatitis, pain, lung disease, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic inflammatory lung disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjögren's syndrome, Autoimmune thyroid disease, urticaria (hives), multiple sclerosis, scleroderma, organ transplant rejection, xenotransplantation, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, and allergic sinusitis.

[0113] Example

[0114] The invention is hereinafter illustrated by the following non-limiting examples.

[0115] The starting materials in the examples of this application are known and can be obtained from commercial suppliers, or can be synthesized according to methods known in the art.

[0116] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or liquid chromatography (HPLC). NMR measurements were performed using a Bruker AVANCE NEO 400 MHz; LC-MS measurements were performed using a LCMS WATERS ACQUITY UPLC H-Class PLUS and / or SQD2; and HPLC measurements were performed using a WATERS ACQUITY UPLC and / or Agilent 1260.

[0117] Example 1: Preparation of (4-((3,6-dichloro-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0118] Step 1: Preparation of di-tert-butyl (4-methylbenzyl)phosphonate:

[0119] Di-tert-butyl phosphonate (20.0 g, 108 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (200 mL). Sodium hydride (0.516 g, 129 mmol, 1.2 equivalent) was added at 0°C and stirred for half an hour. 1-bromomethyl-4-methylbenzene (16.4 g, 119 mmol, 1.1 equivalent) was then added and the temperature was raised to 70°C for 16 hours. Water (100 mL) was added to the reaction solution to quench the reaction and the mixture was extracted three times with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V=1 / 1)) to give the title compound (20.0 g, yield: 62.1%) as a brown solid. LCMS (ESI): [2M+H] + =597.8.

[0120] Step 2: Preparation of di-tert-butyl (4-bromomethyl)benzyl)phosphonate:

[0121] Di-tert-butyl (4-methylbenzyl)phosphonate (20.0 g, 67.0 mmol, 1.0 equiv) was dissolved in carbon tetrachloride (200 mL). N-bromosuccinimide (NBS) (13.1 g, 73.7 mmol, 1.1 equiv) and dibenzoyl peroxide (BPO) (800 mg, 3.40 mmol, 0.05 equiv) were then added to the mixture, and the mixture was stirred at 78°C for 3 hours. The reaction mixture was concentrated under reduced pressure, rediluted with ethyl acetate, quenched with water (100 mL), and extracted three times with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (v / v = 1 / 1)) to afford the title compound (20.0 g (crude), 79.1% yield) as a yellow liquid. 1 HNMR (400MHz, DMSO-d6) δ7.38 (d, J = 8.0 Hz, 2H), 7.26 (dd, J = 8.0, 2.0 Hz, 2H), 4.67 (s, 2H), 3.26 (d, J = 21.6 Hz, 2H), 1.21 (s, 18H).

[0122] Step 3: Preparation of di-tert-butyl (4-((3,6-dichloro-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0123] 3,6-Dichlorocarbazole (100 mg, 0.42 mmol, 1 equivalent) was added to N,N-dimethylformamide (2 mL), followed by sodium hydride (60% by mass, 34 mg, 0.84 mmol, 2 equivalents). After stirring at 0°C for half an hour, di-tert-butyl (4-(bromomethyl)benzyl)phosphonate (175 mg, 0.42 mmol, 1 equivalent) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was extracted three times with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 100% to 1 / 1) to obtain the title compound (53 mg, 23.5% yield) as a white solid. LCMS (ESI) [M+1] + =532.1.

[0124] Step 4: Preparation of (4-((3,6-dichloro-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0125] Di-tert-butyl (4-((3,6-dichloro-9H-carbazol-9-yl)methyl)benzyl)phosphonate (53 mg, 0.1 mmol, 1 eq) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (2.28 mg, 0.02 mmol, 0.2 eq) was added, and the reaction mixture was stirred at room temperature for 1 hour. Filtration afforded a white solid, (4-((3,6-dichloro-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid (32 mg, 0.08 mmol, 76.5%). LCMS (ESI) [M+1] + =420.1; 1 H NMR(400MHz,DMSO-d6)δ10.5(br,1H),8.37(d,J=2.0Hz,2H),7.70(d,J=8.8Hz,2H), 7.49(dd,J=8.8,2.1Hz,2H),7.21-6.98(m,4H),5.64(s,2H),2.86(d,J=21.4Hz,2H).

[0126] Example 2

[0127] Similarly, using commercially available 3,6-dimethoxycarbazole and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate as starting materials, Example 2 was prepared according to Steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =412.2; 1H NMR (400MHz, CD3OD) δ7.59(d,J=2.4Hz,2H),7.32(d,J=7.2Hz,2H),7.27(d,J=8 .0Hz,2H),7.01-6.98(m,4H),5.43(s,2H),3.89(s,6H),2.80(d,J=20.0Hz,2H).

[0128] Example 3

[0129] Similarly, using commercially available 3,6-dimethylcarbazole and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate as starting materials, Example 3 was prepared according to Steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =380.2; 1 H NMR (400MHz, DMSO-d6) δ7.89(s,2H),7.45(d,J=8.3Hz,2H),7.21(d,J=8.2Hz,2H),7.05(dd,J=33.6,7.1Hz,4H),5.52(s,2H),2.83(s,2H),2.45(s,6H).

[0130] Example 4

[0131] Similarly, using commercially available 3,6-dibromocarbazole and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate as starting materials, Example 4 was prepared according to Steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =506.9; 1 H NMR (400MHz, DMSO-d6) δ8.51(d,J=2.1Hz,2H),7.66(dd,J=8.7,2.9Hz,2H),7.60(ddd,J=8.7,3 .2,1.9Hz,2H),7.13(dd,J=8.2,2.5Hz,2H),7.08-7.01(m,2H),5.64(s,2H),2.93-2.78(m,2H).

[0132] Example 5

[0133] Similarly, using commercially available 3,6-diiodocarbazole and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate as starting materials, Example 5 was prepared according to steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =603.1; 1H NMR (400MHz, DMSO-d6) δ8.64(d,J=1.7Hz,2H),7.73(dd,J=8.6,1.8Hz,2H),7.53(d,J=8.6Hz, 2H), 7.12 (dd, J = 8.2, 2.4Hz, 2H), 7.04 (d, J = 7.9Hz, 2H), 5.61 (s, 2H), 2.86 (d, J = 21.4Hz, 2H).

[0134] Example 6

[0135] Similarly, using commercially available 2,7-dimethylcarbazole and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate as starting materials, Example 6 was prepared according to Steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =380.2; 1 H NMR(400MHz,DMSO-d6)δ7.97(d,J=7.6Hz,2H),7.36(s,2H),7.15-7.08(m,2 H), 7.01 (t, J = 8.4Hz, 4H), 5.53 (s, 2H), 2.84 (d, J = 21.2Hz, 2H), 2.45 (s, 6H).

[0136] Example 7

[0137] Similarly, using commercially available 3-chlorocarbazole and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate as starting materials, Example 7 was prepared according to Steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =386.1; 1 H NMR (400MHz, DMSO-d6) δ8.38-8.15(m,2H),7.66(t,J=7.6Hz,2H),7.52-7.38(m,2 H),7.23(t,J=7.2Hz,1H),7.14-7.04(m,4H),5.63(s,2H),2.85(d,J=21.2Hz,2H).

[0138] Example 8

[0139] Similarly, using commercially available 3-methoxycarbazole and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate as starting materials, Example 8 was prepared according to Steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =382.1; 1H NMR (400MHz, DMSO-d6) δ8.15(d,J=7.6Hz,1H),7.75(d,J=2.4Hz,1H),7.59(d,J=8.4Hz,1H),7.54(d,J=8.8H z, 1H), 7.40 (t, J = 7.2Hz, 1H), 7.21-7.00 (m, 6H), 5.58 (d, J = 2.0Hz, 2H), 3.86 (s, 3H), 2.86 (d, J = 21.2Hz, 2H).

[0140] Example 9

[0141] Similarly, using commercially available 2,7-dimethoxycarbazole and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate as starting materials, Example 9 was prepared according to Steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =412.1; 1 H NMR(400MHz,DMSO-d6)δ7.73(d,J=2.6Hz,2H),7.48(dd,J=8.9,2.4Hz,2H),7 .18-6.93(m,6H),5.50(s,2H),3.83(d,J=2.4Hz,6H),2.85(d,J=21.2Hz,2H).

[0142] Example 10

[0143] Similarly, using commercially available 3,6-di-tert-butylcarbazole and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate as starting materials, Example 10 was prepared according to Steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =463.3; 1 HNMR (400MHz, DMSO-d6) δ8.19(s,2H),7.47(d,J=2.8Hz,4H),7.08(q,J=8.2Hz,4H),5.51(s,2H),2.82(d,J=21.3Hz,2H),1.39(s,18H).

[0144] Example 11

[0145] Similarly, using commercially available 3,6-dicyanocarbazole and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate as starting materials, Example 11 was prepared according to Steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =402.3; 1H NMR (400MHz, DMSO-d6) δ8.87 (s, 2H), 7.95 (t, J = 1.9Hz, 4H), 7.12 (q, J = 7.8Hz, 4H), 5.77 (s, 2H), 2.87 (d, J = 21.4Hz, 2H).

[0146] Example 12

[0147] Similarly, using commercially available 2-fluorocarbazole and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate as starting materials, Example 12 was prepared according to Steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =370.1; 1 H NMR (400MHz, CD3OD) δ8.07-8.03(m,2H),7.46(d,J=8.4Hz,1H),7.39-7.36(m,1H),7.24-7 .16(m,4H),7.05(d,J=7.6Hz,2H),6.95-6.91(m,1H),5.51(s,2H),2.91(d,J=20.8Hz,2H).

[0148] Example 13

[0149] Similarly, using commercially available 3-fluorocarbazole and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate as starting materials, Example 13 was prepared according to Steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =370.1; 1 H NMR (400MHz, CD3OD) δ8.07(d,J=7.6Hz,1H),7.79(dd,J=9.2,2.4Hz,1H),7.48-7.30( m,3H),7.22-7.13(m,4H),7.03(d,J=8.0Hz,2H),5.53(s,2H),2.89(d,J=20.8Hz,2H).

[0150] Example 14

[0151] Similarly, using commercially available 9H-pyrido[2,3-b]indole and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate as starting materials, Example 14 was prepared according to Steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =353.1; 1H NMR (400MHz, CD3OD) δ8.49(dd,J=7.6,2.0Hz,1H),8.43(dd,J=5.2,2.0Hz,1H),8.13(d,J=8.0Hz,1H),7.47(d,J=8.0Hz,1 H),7.46-7.42(m,1H),7.27-7.25(m,2H),7.24-7.22(m,2H),7.11(d,J=7.6Hz,2H),5.67(s,2H),2.87(d,J=20.6Hz,2H).

[0152] Example 15

[0153] Similarly, using commercially available 9H-pyrido[3,4-b]indole and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate as starting materials, Example 15 was prepared according to Steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =353.1; 1 H NMR (400MHz, CD3OD) δ8.85(s,1H),8.32(d,J=5.6Hz,1H),8.23(d,J=8.0Hz,1H),8.13(d,J=5.6Hz,1H),7.65(d,J=8.0Hz,1H ),7.60(t,J=8.0Hz,1H),7.32-7.31(m,1H),7.31-7.29(m,2H),7.04(d,J=8.0Hz,2H),5.64(s,2H),2.81(d,J=20.0Hz,2H).

[0154] Example 16

[0155] Similarly, using commercially available 5H-pyrido[4,3-b]indole and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate as starting materials, Example 16 was prepared according to Steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =353.1; 1 H NMR (400MHz, CD3OD) δ9.68(s,1H),8.59(dd,J=7.2,1.6Hz,1H),8.29(d,J=8.0Hz,1H),7.85(d,J=6.8Hz,1H),7.72-7. 66(m,2H),7.50-7.46(m,1H),7.42(dd,J=8.0,2.0Hz,2H),7.37(d,J=8.0Hz,2H),5.72(s,2H),2.97(d,J=20.8Hz,2H).

[0156] Example 17

[0157] Similarly, using commercially available 5H-pyrido[3,2-b]indole and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate as starting materials, Example 17 was prepared according to Steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =353.1; 1 H NMR (400MHz, CD3OD) δ8.43(dd,J=4.8,1.2Hz,1H),8.33(d,J=8.0Hz,1H),7.99(dd,J=8.4,1.2Hz,1H),7.62(d,J=8.4Hz,1H),7.59-7.54(m,1H ),7.45(dd,J=8.4,4.8Hz,1H),7.31(t,J=7.2Hz,1H),7.23(dd,J=8.0,2.4Hz,2H),7.07(d,J=8.0Hz,2H),5.60(s,2H),2.90(d,J=21.2Hz,2H).

[0158] Example 18

[0159] Similarly, using commercially available 3-bromocarbazole and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate as starting materials, Example 18 was prepared according to Steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =428.1; 1 H NMR (400MHz, CD3OD) δ8.22(d,J=1.7Hz,1H),8.08(d,J=7.8Hz,1H),7.55-7.33(m,4H),7.28(dd,J= 8.2, 1.9Hz, 2H), 7.20 (t, J = 7.0Hz, 1H), 7.00 (d, J = 8.0Hz, 2H), 5.51 (s, 2H), 2.81 (d, J = 19.8Hz, 1H).

[0160] Example 19: Preparation of (4-((3-(trifluoromethyl)-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0161] Step 1: Preparation of diethyl (4-(bromomethyl)benzyl)phosphonate:

[0162] 1,4-Bis(bromomethyl)benzene (6 g, 22.73 mmol, 1 equivalent) was dissolved in a 1,4-dioxane solution (10 mL), followed by the addition of triethyl phosphite (15.11 g, 90.92 mmol, 4 equivalents). The reaction mixture was microwaved at 100°C for 1 hour. The reaction mixture was concentrated at 60°C using an oil pump, and the crude product was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 10 / 1)) to afford the title compound (2.3 g, yield: 31.51%) as a colorless oil. LCMS (ESI): [M+H] + =321.2.

[0163] Step 2: Preparation of diethyl 4-(3-bromo-9H-carbazole-9-methyl)benzylphosphonate:

[0164] 3-Bromocarbazole (350 mg, 1.42 mmol, 1 equivalent) was dissolved in ultra-dry tetrahydrofuran (10 mL), and diethyl (4-(bromomethyl)benzyl)phosphonate (913 mg, 2.84 mmol, 2 equivalents) and sodium hydride (454 mg, 11.38 mmol, 8 equivalents) were added. Under argon protection, the reaction solution was stirred at room temperature for 1 hour, and the reaction was monitored for completion by LCMS. Saturated aqueous ammonium chloride solution (10 mL) was added to the reactants, and the mixture was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by flash chromatography (silica gel, 100% ethyl acetate) to obtain the title compound (350 mg, yield: 50.6%) as a yellow solid. LCMS (ESI): [M+H] + =486.0.

[0165] Step 3: Preparation of diethyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole-9-methyl)benzyl)phosphonate:

[0166] Diethyl 4-(3-bromo-9H-carbazole-9-methyl)benzylphosphonate (340 mg, 0.7 mmol, 1 equiv) was dissolved in 1,4-dioxane (8 mL), followed by the addition of pinacol diboron (266 mg, 1.05 mmol, 1.5 equiv) and potassium acetate (137 mg, 1.4 mmol, 2 equiv). Finally, 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (103 mg, 0.14 mmol, 0.2 equiv) was added. Under argon protection, the reaction solution was microwaved at 110°C for 1 hour. LCMS monitored the reaction completion. Saturated aqueous ammonium chloride (10 mL) was added, and the mixture was extracted three times with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 1 / 1)) to give the title compound (340 mg, yield: 91%) as a light yellow solid. LCMS: (ESI) [M+H] + =533.4.

[0167] Step 4: Preparation of diethyl (4-((3-trifluoromethyl-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0168] Diethyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole-9-methyl)benzyl)phosphonate (40 mg, 0.07 mmol, 1 equiv) was dissolved in N,N-dimethylformamide (DMF) (4 mL), and cesium carbonate (49 mg, 0.15 mmol, 2 equiv) and trifluoromethyl(1,10-phenanthroline)copper(I) (35 mg, 0.11 mmol, 1.5 equiv) were added. Under argon protection, the reaction solution was stirred at 50°C for 2 hours, and the reaction was monitored for completion by LCMS. Saturated aqueous ammonium chloride (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude title compound (20 mg, yield: 56.1%) as a yellow solid. LCMS (ESI): [M+Na] + =498.2.

[0169] Step 5: Preparation of (4-((3-(trifluoromethyl)-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0170] Diethyl (4-((3-trifluoromethyl-9H-carbazol-9-yl)methyl)benzyl)phosphonate (20 mg, 0.04 mmol, 1 equiv) was dissolved in anhydrous dichloromethane (2 mL) and trimethylsilyl bromide (0.21 mL, 1.37 mmol, 32.6 equiv) was added. The reaction was heated to 50 ° C and stirred for 1 hour. The reaction was monitored by LCMS. Water (2 mL) was added to the reaction and the organic and aqueous phases were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, dried, dissolved in tetrahydrofuran, and prepared by reverse phase HPLC (C18, 10 mmol / L ammonia, acetonitrile) to give the title compound (1.55 mg) as a white solid.

[0171] Example 20: Preparation of (4-((2-(trifluoromethyl)-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid

[0172] Step 1: Preparation of diethyl (4-((2-bromo-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0173] 2-Bromo-9H-carbazole (300 mg, 1.22 mmol, 1 equivalent) was dissolved in anhydrous tetrahydrofuran (2 mL). Sodium hydride (495 mg, 4.88 mmol, 4 equivalents) was added and stirred at room temperature under nitrogen for 0.5 hours. Diethyl (4-(bromomethyl)benzyl)phosphonate (783 mg, 2.44 mmol, 2 equivalents) was then added and the mixture was allowed to react at room temperature under nitrogen for 1 hour. Saturated aqueous ammonium chloride (10 mL) was added to the reaction, and the mixture was extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified on a preparative plate (PE:EA (V / V = 3 / 1)) to give the title compound (200 mg, yield: 33.7%) as a yellow solid. LCMS (ESI): [M+H] + =508.1.

[0174] Step 2: Preparation of diethyl (4-((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0175] Diethyl (4-((2-bromo-9H-carbazol-9-yl)methyl)benzyl)phosphonate (150 mg, 0.31 mmol, 1 equiv) was dissolved in 1,4-dioxane (2 mL). Diboronic acid pinacol bis(pyrazolyl)boronate (117 mg, 0.46 mmol, 1.5 equiv) and potassium acetate (61 mg, 0.62 mmol, 2 equiv) were added, followed by 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (45 mg, 0.06 mmol, 0.2 equiv). The reaction mixture was microwaved at 110°C for 1 hour under nitrogen protection. After cooling to room temperature, saturated aqueous ammonium chloride (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified on a silica gel prep plate (100% ethyl acetate) to afford the title compound (120 mg, 54.7% yield) as a pale yellow solid. LCMS (ESI): [M+H] + =534.2.

[0176] Step 3: Diethyl (4-((2-(trifluoromethyl)-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0177] Diethyl (4-((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazol-9-yl)methyl)benzyl)phosphonate (80 mg, 0.15 mmol, 1 equiv) was dissolved in N,N-dimethylformamide (1 mL), and cesium carbonate (98 mg, 0.3 mmol, 2 equiv) and trifluoromethyl(1,10-phenanthroline)copper(I) (70 mg, 0.22 mmol, 1.5 equiv) were added. The mixture was reacted at 50°C under argon for 16 hours. Saturated aqueous ammonium chloride (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude title compound (45 mg, 50.5% yield) as a yellow solid. LCMS (ESI): [M+H] + =476.1.

[0178] Step 4: Preparation of (4-((2-(trifluoromethyl)-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid

[0179] Diethyl (4-((2-(trifluoromethyl)-9H-carbazol-9-yl)methyl)benzyl)phosphonate (35 mg, 0.07 mmol, 1 eq) was dissolved in anhydrous dichloromethane (1 mL), and trimethylsilyl bromide (56.35 mg, 0.37 mmol, 5 eq) was added. The reaction mixture was heated to 50°C and stirred for 2 hours. The reaction mixture was concentrated at low temperature, and the crude product was isolated and purified by reverse-phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to obtain the title compound (2.62 mg, 8.5% yield) as a white solid. LCMS (ESI): [MH] - =418.2; 1 H NMR (400MHz, CD3OD) δ8.27(d,J=8.0Hz,1H),8.19(d,J=8.0Hz,1H),7.79(s,1H),7.55(d,J=8.0Hz,1H),7.51-7 .46(m,2H),7.29-7.27(m,1H),7.25-7.22(m,2H),7.05(d,J=8.0Hz,2H),5.63(s,2H),2.94(d,J=20.9Hz,2H).

[0180] Example 21: Preparation of (4-((4-(trifluoromethyl)-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0181] Step 1: Preparation of diethyl (4-((4-bromo-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0182] 4-Bromo-9H-carbazole (500 mg, 2.04 mmol, 1 equiv) was dissolved in ultra-dry tetrahydrofuran (10 mL), followed by the addition of diethyl (4-(bromomethyl)benzyl)phosphonate (653 mg, 4.08 mmol, 2 equiv) and sodium hydride (653 mg, 16.3 mmol, 8 equiv). Under argon, the reaction mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride (10 mL) was then added, and the mixture was extracted three times with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 100% ethyl acetate) to afford the title compound (500 mg, 50.6% yield) as a yellow solid. LCMS (ESI): [M+H] + =486.0.

[0183] Step 2: Preparation of diethyl (4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0184] Diethyl (4-((4-bromo-9H-carbazol-9-yl)methyl)benzyl)phosphonate (500 mg, 1.03 mmol, 1 equiv) was dissolved in 1,4-dioxane (10 mL). Diboron (pinacol diboron) (392 mg, 1.55 mmol, 1.5 equiv) and potassium acetate (202 mg, 2.06 mmol, 2 equiv) were added, followed by 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (150 mg, 0.21 mmol, 0.2 equiv). Under argon, the reaction mixture was stirred at 110°C for 1 hour. Saturated aqueous ammonium chloride (10 mL) was added, and the mixture was extracted three times with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 1 / 1)) to give the title compound (500 mg, yield: 91.1%) as a light yellow solid. LCMS (ESI): [M+H] + =534.2.

[0185] Step 3: Preparation of diethyl (4-((4-(trifluoromethyl)-9H-carbazol-9-yl)methyl)benzyl)phosphonate

[0186] Diethyl (4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazol-9-yl)methyl)benzyl)phosphonate (160 mg, 0.28 mmol, 1 equiv) was dissolved in N,N-dimethylformamide (4 mL), and cesium carbonate (195 mg, 0.60 mmol, 2 equiv) and trifluoromethyl(1,10-phenanthroline)copper(I) (141 mg, 0.44 mmol, 1.5 equiv) were added. Under argon protection, the reaction solution was stirred at 50°C for 16 hours. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction, and the mixture was extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude title compound (50 mg, yield: 37.6%) as a yellow solid. LCMS (ESI): [M+H] + =476.2.

[0187] Step 4: Preparation of (4-((4-(trifluoromethyl)-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0188] Diethyl (4-((4-(trifluoromethyl)-9H-carbazol-9-yl)methyl)benzyl)phosphonate (35 mg, 0.07 mmol, 1 eq) was dissolved in dichloromethane (1 mL), and trimethylsilyl bromide (54 mg, 0.35 mmol, 5 eq) was added. The reaction mixture was heated to 50°C and stirred for 2 hours. The reaction mixture was concentrated at low temperature, and the crude product was isolated and purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (6.24 mg, yield: 21.3%) as a white solid. LCMS (ESI): [MH] - =418.2; 1 H NMR (400MHz, CD3OD) δ8.27(d,J=8.0Hz,1H),7.79(d,J=6.8Hz,1H),7.59(d,J=8.4Hz,1H),7.5 4-7.48(m,3H),7.28-7.21(m,3H),7.04(d,J=8.0Hz,2H),5.65(s,2H),2.93(d,J=21.2Hz,2H).

[0189] Example 22: Preparation of (4-((2,4,6-trifluoro-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0190] Step 1: Preparation of 2-bromo-N-(3,5-difluorophenyl)-4-fluoroaniline:

[0191] 1,3,5-trifluorobenzene (2.00 g, 15.1 mmol, 1 equivalent) was dissolved in dimethyl sulfoxide (10 mL), and 2-bromo-4-fluoroaniline (3.45 g, 18.2 mmol, 1.2 equivalent) and potassium tert-butoxide (1.70 g, 15.1 mmol, 1 equivalent) were added. The mixture was reacted at room temperature for 2 hours under argon protection. The reaction solution was quenched with saturated ammonium chloride (10 mL) and extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude product, which was purified by flash chromatography (silica gel, 100% petroleum ether) to obtain the title compound (700 mg, yield: 15.3%). LCMS (ESI): [MH] - =299.9.

[0192] Step 2: Preparation of 2,4,6-trifluoro-9H-carbazole:

[0193] 2-Bromo-N-(3,5-difluorophenyl)-4-fluoroaniline (500 mg, 1.66 mmol, 1 equiv) was dissolved in N-methylpyrrolidone (10 mL), and tert-butanol (477 mg, 4.97 mmol, 3 equiv), cuprous iodide (63 mg, 0.33 mmol, 0.2 equiv), and palladium acetate (37 mg, 0.17 mmol, 0.1 equiv) were added. Under argon protection, the reaction system was microwaved at 150°C for 2 hours. The reaction solution was quenched with saturated ammonium chloride (10 mL) and extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product, which was purified on a silica gel prep plate (dichloromethane:petroleum ether (V / V = 2 / 1)) to obtain the title compound (300 mg, yield: 81.9%). LCMS (ESI): [MH] - =220.0.

[0194] Step 3: Preparation of diethyl (4-((2,4,6-trifluoro-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0195] 2,4,6-trifluoro-9H-carbazole (20 mg, 0.09 mmol, 1 equivalent) was dissolved in tetrahydrofuran (2 mL), and then sodium hydride (14 mg, 0.36 mmol, 4 equivalents) was added. The mixture was stirred at room temperature for 0.5 hours under nitrogen protection, and then diethyl (4-(bromomethyl)benzyl)phosphonate (57 mg, 0.18 mmol, 2 equivalents) was added. The reaction was stirred for 1 hour. The reaction solution was quenched with saturated ammonium chloride (5 mL), extracted three times with ethyl acetate (5 mL × 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (10 mg, yield 24.1%). LCMS (ESI): [M+H] + =462.1.

[0196] Step 4: Preparation of (4-((2,4,6-trifluoro-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0197] (4-((2,4,6-Trifluoro-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid (10 mg, 0.02 mmol, 1 equiv) was dissolved in dichloromethane (1 mL), followed by the addition of trimethylsilyl bromide (16 mg, 0.11 mmol, 5 equiv). The reaction was stirred at 50°C for 2 hours. The reaction solution was purified by reverse-phase HPLC (C18, 10 mmol / L aqueous ammonia, acetonitrile) to afford the title compound (2.11 mg, 24.0% yield). 1H NMR (400MHz, CD3OD) δ7.74(dd,J=7.2,1.6Hz,1H),7.50(dd,J=8.8,4.0Hz,1H),7.25(dd,J=8.0,4.0Hz,2H),7.20(td,J=9.2,2. 4Hz,1H),7.11(dd,J=9.6,2.0Hz,1H),7.03(d,J=7.6Hz,2H),6.76(td,J=10.0,2.0Hz,1H),5.52(s,2H),2.89(d,J=20.8Hz,2H).

[0198] Example 23

[0199] Similarly, using commercially available 2-bromoaniline as a starting material, Example 23 was prepared according to Steps 1-4 of the preparation method of Example 22. LCMS (ESI) [M+1] + =388.1; 1 H NMR (400MHz, CD3OD) δ8.08(d,J=7.8Hz,1H),7.51(d,J=8.4Hz,1H),7.45-7.40(m,1H),7.31-7.28(m,1H),7.27-7.21(m,2 H), 7.08 (dd, J = 8.4, 2.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 2H), 6.74 (td, J = 10.0, 2.0 Hz, 1H), 5.52 (s, 2H), 2.90 (d, J = 19.2 Hz, 2H).

[0200] Example 24

[0201] Similarly, using commercially available 2-bromo-5-fluoroaniline as a starting material, Example 24 was prepared according to Steps 1-4 of the preparation method of Example 22. LCMS (ESI) [M+1] + =406.1; 1 H NMR (400MHz, CD3OD) δ8.04 (dd, J=8.4, 6.6Hz, 1H), 7.28-7.20 (m, 3H), 7.12 (dd, J=9.6, 2.8Hz, 1H), 7.05-6.99 (m, 3H), 6.81-6.50 (m, 1H), 5.50 (s, 2H), 2.90 (d, J = 20.8Hz, 2H).

[0202] Example 25. Preparation of (4-((1-amino-3,6-dichloro-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0203] Step 1: Preparation of 1-nitro-3,6-dichloro-9H-carbazole

[0204] 3,6-Dichloro-9H-carbazole (300 mg, 1.27 mmol, 1 equivalent) was dissolved in a mixture of 1,4-dioxane (3 mL) and acetic acid (3 mL). Sodium nitrite (175 mg, 2.54 mmol, 2 equivalents) was slowly added to the mixture. The reaction mixture was stirred at 110°C for 4 hours. The reaction mixture was cooled and poured into ice water, slowly stirred for 10 minutes, and filtered. The filter cake was rinsed with water, collected, and dried to obtain the title compound (320 mg, 90% yield).

[0205] Step 2: Preparation of di-tert-butyl (4-((1-nitro-3,6-dichloro-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0206] 1-Nitro-3,6-dichloro-9H-carbazole (100 mg, 0.36 mmol, 1 equivalent) was dissolved in N,N-dimethylformamide (5 mL). Potassium carbonate (200 mg, 1.42 mmol, 4 equivalents) and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate (134 mg, 0.36 mmol, 1.0 equivalent) were added. The reaction mixture was allowed to react at room temperature for 16 hours. The reaction solution was extracted three times with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 100% to 1 / 1) to obtain the title compound (70 mg, 34% yield) as a yellow oily liquid. LCMS (ESI) [M+1-56-56] + =465.0.

[0207] Step 3: Preparation of di-tert-butyl (4-((1-amino-3,6-dichloro-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0208] Di-tert-butyl (4-((1-nitro-3,6-dichloro-9H-carbazol-9-yl)methyl)benzyl)phosphonate (70 mg, 0.12 mmol, 1 eq) was dissolved in tetrahydrofuran (5 mL), and zinc powder (39 mg, 0.6 mmol, 5 eq) and acetic acid (5 mL) were added, respectively. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to give the title compound (64 mg, 96% yield). LCMS (ESI) [M+1-56-56] + =435.0.

[0209] Step 4: Preparation of (4-((1-amino-3,6-dichloro-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0210] Di-tert-butyl (4-((1-amino-3,6-dichloro-9H-carbazol-9-yl)methyl)benzyl)phosphonate (64 mg, 0.12 mmol, 1 equivalent) was dissolved in DCM (5 mL) and trifluoroacetic acid (0.5 mL) was added. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated, and the crude product was purified by reverse-phase HPLC (C18, 10 mmol / L aqueous ammonia solution, acetonitrile) to afford the title compound (8 mg, 15.6% yield) as a white solid. LCMS (ESI) [M+1] + =435.1; 1 H NMR (400MHz, DMSO-d6) δ8.18(d,J=2.0Hz,1H),7.68-7.55(m,2H),7.36(dd,J=8.8,2.0Hz,1H),7.04(d,J=7 .2Hz,2H),6.90(d,J=7.6Hz,2H),6.81(d,J=2.0Hz,1H),5.75(s,2H),5.30(s,2H),2.72(d,J=21.2Hz,2H).

[0211] Example 26: Preparation of (3-(3,6-dichloro-9H-carbazol-9-yl)propyl)phosphonic acid:

[0212] Step 1: Preparation of diethyl (3-(3,6-dichloro-9H-carbazol-9-yl)propyl)phosphonate:

[0213] 3,6-Dichloro-9H-carbazole (150 mg, 0.64 mmol, 1 eq) was dissolved in N,N-dimethylformamide (4 mL), cooled to 0°C, and sodium hydride (60% by mass, 27.9 mg, 0.7 mmol, 1.1 eq) was added. The mixture was stirred at 0°C for 30 minutes, and diethyl (3-bromopropyl)phosphonate (181 mg, 0.7 mmol, 1.1 eq) was added dropwise. After the addition was complete, stirring was continued at 0°C for 1 hour. The mixture was quenched by addition of water (2 mL) and extracted three times with ethyl acetate (5 mL x 3). The organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, methanol:dichloromethane (v / v = 60 / 1)) to afford the title compound (240 mg, 90.52% yield) as an off-white solid. LCMS (ESI) [M+1] + =414.1.

[0214] Step 2: Preparation of (3-(3,6-dichloro-9H-carbazol-9-yl)propyl)phosphonic acid:

[0215] Diethyl (3-(3,6-dichloro-9H-carbazol-9-yl)propyl)phosphonate (240 mg, 0.58 mmol, 1 eq) was dissolved in acetonitrile (8 mL), and trimethylsilyl bromide (444 mg, 2.9 mmol, 5.0 eq) was added. The mixture was stirred at 50°C for 16 hours. The reaction mixture was concentrated, and the crude product was purified by reverse-phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to afford the title compound (130.0 mg, 62.58% yield) as a white solid. LCMS (ESI) [M+1] + =358.0; 1 H NMR (400MHz, DMSO-d6) δ8.34(d,J=2.1Hz,2H),7.72(d,J=8.8Hz,2H),7.50(dd, J=8.7, 2.1Hz, 2H), 4.49 (t, J=7.0Hz, 2H), 2.02-1.86 (m, 2H), 1.59-1.42 (m, 2H).

[0216] Example 27: Preparation of (4-(3,6-dichloro-9H-carbazol-9-yl)butyl)phosphonic acid:

[0217] Step 1: Preparation of diethyl (4-(3,6-dichloro-9H-carbazol-9-yl)butyl)phosphonate:

[0218] 3,6-Dichloro-9H-carbazole (50 mg, 0.21 mmol, 1 equiv) was dissolved in N,N-dimethylformamide (2 mL), cooled to 0°C, and sodium hydride (60% by mass, 9 mg, 0.23 mmol, 1.1 equiv) was added. The mixture was stirred at 0°C for 30 minutes, and diethyl (4-bromobutyl)phosphonate (64 mg, 0.23 mmol, 1.1 equiv) was added dropwise. After the addition was complete, the mixture was slowly warmed to room temperature and stirred for 1 hour. Water (2 mL) was added to quench the mixture, and the mixture was extracted three times with ethyl acetate (5 mL x 3). The organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, methanol:dichloromethane (V / V = 60 / 1)) to afford the title compound (86.0 mg, 94.82% yield) as a light yellow oil. LCMS (ESI) [M+1] + =428.10.

[0219] Step 2: Preparation of (4-(3,6-dichloro-9H-carbazol-9-yl)butyl)phosphonic acid:

[0220] Diethyl (4-(3,6-dichloro-9H-carbazol-9-yl)butyl)phosphonate (80 mg, 0.19 mmol, 1 eq) was dissolved in acetonitrile (2 mL), and trimethylsilyl bromide (143 mg, 0.93 mmol, 5 eq) was added. The mixture was stirred at 50°C for 16 hours. The reaction mixture was concentrated, and the crude product was slurried with acetonitrile and acetonitrile / methanol, filtered, and dried to obtain the title compound (41.0 mg, 58.98% yield) as a white solid. LCMS (ESI) [M+1] + =372.0; 1 H NMR (400MHz, DMSO-d6) δ8.33(d,J=2.1Hz,2H),7.69(d,J=8.8Hz,2H),7.49(dd, J=8.7,2.2Hz,2H),4.41(t,J=7.1Hz,2H),1.87-1.76(m,2H),1.58-1.42(m,4H).

[0221] Example 28: Preparation of ((4-((3,6-dichloro-9H-carbazol-9-yl)methyl)cyclohexyl)methyl)phosphonic acid:

[0222] Step 1: Preparation of diethyl ((4-(bromomethyl)cyclohexyl)methyl)phosphonate:

[0223] 1,4-Bis(bromomethyl)cyclohexane (600 mg, 2.22 mmol, 1 equiv) and triethyl phosphite (184 mg, 1.11 mmol, 0.5 equiv) were dissolved in N,N-dimethylformamide (2.5 mL), heated to 150°C, and reacted under microwave conditions for 3 minutes. The mixture was cooled to 0°C and quenched with water. The reaction solution was extracted three times with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 100% to 1 / 3)) to afford the title compound (100.0 mg, 13.75% yield) as a light yellow oil. LCMS (ESI) [M+1] + =327.1.

[0224] Step 2: Preparation of diethyl ((4-((3,6-dichloro-9H-carbazol-9-yl)methyl)cyclohexyl)methyl)phosphonate:

[0225] 3,6-Dichloro-9H-carbazole (72.16 mg, 0.31 mmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL) and cooled to 0°C. Sodium hydride (60% by mass, 8.07 mg, 0.34 mmol, 1.1 eq) was added and stirred for 30 minutes. Diethyl ((4-(bromomethyl)cyclohexyl)methyl)phosphonate (100 mg, 0.31 mmol, 1 eq) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water and extracted three times with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, dichloromethane:methanol (v / v = 0% to 1 / 10)) to obtain the title compound (35.0 mg, 23.41% yield) as a light yellow oil. LCMS (ESI) [M+1] + =482.1.

[0226] Step 3: Preparation of ((4-((3,6-dichloro-9H-carbazol-9-yl)methyl)cyclohexyl)methyl)phosphonic acid:

[0227] Diethyl ((4-((3,6-dichloro-9H-carbazol-9-yl)methyl)cyclohexyl)methyl)phosphonate (35 mg, 0.07 mmol, 1 eq) was dissolved in acetonitrile (2 mL) and trimethylsilyl bromide (53.58 mg, 0.35 mmol, 5 eq) was added. The mixture was stirred at 50°C for 16 hours and then at 80°C for another 16 hours. The reaction mixture was concentrated, and the crude product was purified by reverse phase HPLC (C18, 10 mmol / L formic acid solution, acetonitrile) to afford the title compound (1.9 mg, 6.37% yield) as a white solid. LCMS (ESI) [M+1] + =426.2; 1 H NMR (400MHz, DMSO-d6) δ8.33(d,J=2.1Hz,2H),7.68(d,J=8.8Hz,2H),7.48(dd,J=8.8,2.2Hz,2H),4.24(d,J=7.3Hz,2 H), 3.36 (d, J = 6.1Hz, 2H), 1.95-1.64 (m, 3H), 1.60-1.44 (m, 3H), 1.22-1.05 (m, 2H), 0.89 (qd, J = 11.1, 9.4, 2.5Hz, 2H).

[0228] Example 29: Preparation of 3-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0229] Step 1: Preparation of di-tert-butyl (3-methylbenzyl)phosphonate:

[0230] Di-tert-butyl phosphonite (4.6 g, 23.8 mmol, 1.1 equivalents) was dissolved in tetrahydrofuran (40 mL). Sodium hydride (60% by mass, 951 mg, 23.8 mmol, 1.1 equivalents) was added at 0°C and stirred for half an hour. 1-Bromomethyl-3-methylbenzene (4.0 g, 21.6 mmol, 1.0 equivalents) was added and the mixture was heated to 70°C and allowed to react overnight. LCMS monitoring of the reaction was completed. Water (30 mL) was added to the reaction solution to quench the reaction and the mixture was extracted three times with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then added to silica gel for spin drying. Flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V=1 / 1)) was used to obtain the title compound (4.0 g, yield: 62.0%) as a brown solid. 1 H NMR (400MHz, DMSO-d6) δ7.16 (t, J = 7.6 Hz, 1H), 7.06-7.00 (m, 3H), 2.95 (d, J = 21.2 Hz, 2H), 2.27 (s, 3H), 1.36 (s, 18H).

[0231] Step 2: Preparation of di-tert-butyl (3-bromomethyl)benzyl)phosphonate:

[0232] Di-tert-butyl (3-methylbenzyl)phosphonate (2.0 g, 6.70 mmol, 1.0 equiv) was dissolved in carbon tetrachloride (20 mL). N-bromosuccinimide (1.3 g, 7.37 mmol, 1.1 equiv) and dibenzoyl peroxide (BPO) (80 mg, 0.340 mmol, 0.05 equiv) were added to the mixture and stirred at 78°C for 3 hours. LCMS monitored the reaction completion. Water (50 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then added to silica gel for spin drying. The crude product was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (v / v = 1 / 1)) to obtain the title compound (1.0 g, yield: 39.5%) as a brown oily liquid. 1 H NMR (400MHz, DMSO-d6) δ7.42-7.27(m,3H),7.20-7.16(m,1H),4.68(s,2H),3.01(d,J=21.2Hz,2H),1.37(s,18H).

[0233] Step 3: Preparation of di-tert-butyl (3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0234] 3,6-dimethoxy-9H-carbazole (181 mg, 0.800 mmol, 1.5 equivalents) was dissolved in tetrahydrofuran (2 mL) and sodium hydride (mass fraction 60%, 32 mg, 0.800 mmol, 1.5 equivalents) was added at 0 ° C. After half an hour of reaction, di-tert-butyl (3-bromomethyl) benzyl) phosphonate (200 mg, 0.530 mmol, 1.0 equivalents) was added and returned to room temperature and stirred for 2 hours. Water (10 mL) was added to the reaction solution to quench the reaction and extracted three times with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and added to silica gel for spin drying. Flash chromatography separation and purification (silica gel, petroleum ether: ethyl acetate (V / V = 3 / 1)) gave the title compound (200 mg, yield: 72.0%) as a yellow solid. LCMS (ESI): [M-2 t Bu+3H] + =412.2.

[0235] Step 4: Preparation of 3-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0236] Di-tert-butyl (3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphonate (180 mg, 0.340 mmol, 1.0 equiv) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (2 mL) was added to the mixture and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude brown oil. The crude product was purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to obtain the title compound (86.05 mg, yield: 60.8%) as a white solid. LCMS (ESI): [M+H] + =412.2; 1 H NMR (400MHz, DMSO-d6) δ7.72(d,J=2.8Hz,2H),7.39(d,J=8.8Hz,2H),7.22(s,1H),7.08(d,J=7.2H z,1H),7.01-6.97(m,3H),6.56(d,J=7.9Hz,1H),5.44(s,2H),3.83(s,6H),2.66(d,J=20.0Hz,2H).

[0237] Example 30: Preparation of 4-(3,6-dimethoxy-9H-aminooxazol-9-yl)benzyl)phosphonic acid:

[0238] Step 1: Preparation of ethyl (4-(3,6-dimethoxy-9H-carbazol-9-yl)benzyl)phosphonate:

[0239] 3,6-Dimethoxy-9H-carbazole (200 mg, 0.88 mmol, 1.0 equiv) and diethyl (4-iodobenzyl)phosphonate (468 mg, 1.3 mmol, 1.5 equiv) were dissolved in dimethyl sulfoxide (3 mL), and 1,10-phenanthroline (16 mg, 0.09 mmol, 0.1 equiv), cesium carbonate (574 mg, 1.8 mmol, 2.0 equiv) and cuprous iodide (17 mg, 0.09 mmol, 0.1 equiv) were added. The reaction mixture was continued at 150°C under inert gas for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a brown oily crude product. The crude product was prepared by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to obtain the title compound (120 mg, yield: 32.1%) as a white solid. LCMS (ESI): [M+2MeCN+H] + =408.3.

[0240] Step 2: Preparation of 4-(3,6-dimethoxy-9H-aminoazol-9-yl)benzyl)phosphonic acid:

[0241] Ethyl (4-(3,6-dimethoxy-9H-carbazol-9-yl)benzyl)phosphonate (120 mg, 0.28 mmol, 1.0 equiv) was dissolved in acetonitrile (2 mL), and trimethylsilyl bromide (648 mg, 4.2 mmol, 15 equiv) was added to the mixture and stirred at 50°C for 1 hour. The reaction solution was quenched with methanol and concentrated under reduced pressure to obtain a brown oily crude product. The title compound (76.54 mg, yield: 68.3%) was obtained by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) as a white solid. LCMS (ESI): [M+H] + =398.0;1H NMR (400MHz, DMSO-d6) δ7.77(d,J=2.4Hz,2H),7.46(d,J=8.0Hz,2H),7.37(d,J=8.0Hz,2H ), 7.16 (d, J = 8.8Hz, 2H), 6.93 (dd, J = 8.8, 2.4Hz, 2H), 3.85 (s, 6H), 2.87 (d, J = 20.0Hz, 2H).

[0242] Example 31: Preparation of 4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenylboronic acid:

[0243] Step 1: Preparation of 9-(4-bromobenzyl)-3,6-dimethoxy-9H-carbazole:

[0244] 3,6-Dimethoxy-9H-carbazole (500 mg, 2.2 mmol, 1.0 equiv) was added to N,N-dimethylformamide (6 mL). Sodium hydride (60% by mass, 132 mg, 5.5 mmol, 2.5 equiv) was slowly added at 0°C. The reaction was allowed to proceed for 30 minutes. 4-Bromobenzyl bromide (1.1 g, 4.4 mmol, 2.0 equiv) was added and the reaction was continued at room temperature for 3 hours. The reaction was quenched with water (15 mL) and extracted three times with ethyl acetate (25 mL x 3). The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and then added to silica gel for spin drying. Flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 5 / 1)) afforded the title compound (760 mg, 87.2% yield) as a white solid. LCMS (ESI): [M+H] + =395.1.

[0245] Step 2: Preparation of 3,6-dimethoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolin-2-yl)benzyl)-9H-carbazole:

[0246] 9-(4-Bromobenzyl)-3,6-dimethoxy-9H-carbazole (200 mg, 0.5 mmol, 1.0 equiv) was dissolved in dioxane (2 mL). Diboronic acid pinacol bis(pyrazolyl)boronate (192 mg, 0.8 mmol, 1.5 equiv), potassium acetate (149 mg, 1.5 mmol, 3.0 equiv), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (39 mg, 0.1 mmol, 0.1 equiv) were added and stirred at 80°C for 2 hours. The reaction mixture was quenched with water (15 mL) and extracted three times with ethyl acetate (25 mL x 3). The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and added to silica gel for spin drying. Flash chromatography (silica gel, petroleum ether:ethyl acetate (v / v = 5 / 1)) afforded the title compound (200 mg, 89.3% yield) as a white solid. LCMS(ESI):[M+H] + =443.3.

[0247] Step 3: Preparation of 4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenylboronic acid:

[0248] 3,6-Dimethoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolin-2-yl)benzyl)-9H-carbazole (90 mg, 0.2 mmol, 1.0 equiv) was dissolved in water and tetrahydrofuran (1 mL). Sodium periodate (129 mg, 0.6 mmol, 3.0 equiv) was added and the reaction was stirred at room temperature for 1 hour. Aqueous hydrochloric acid (1 M, 0.4 mL, 0.4 mmol, 2.0 equiv) was then added to the reaction mixture. The reaction was monitored for completion by LCMS. The reaction mixture was quenched with water (15 mL) and extracted three times with ethyl acetate (25 mL x 3). The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by reverse-phase HPLC (C18, 10 mmol / L ammonia, acetonitrile) to afford the title compound (46.1 mg, 63.8% yield) as a pink solid. LCMS(ESI):[M+H] + =362.2; 1HNMR(400MHz, DMSO-d6)δ7.93(s,2H),7.73(d,J=8.4Hz,2H),7.64(d,J =8.0Hz,2H),7.44(d,J=8.8Hz,2H),7.11-6.98(m,4H),5.56(s,2H),3.83(s,6H).

[0249] Example 32: Preparation of (4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenethyl)phosphonic acid:

[0250] Step 1: Preparation of diethyl (E)-(4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenyl)phosphonate:

[0251] 9-(4-Bromobenzyl)-3,6-dimethoxy-9H-carbazole (350 mg, 0.88 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (5 mL). Diethyl vinylphosphonate (725 mg, 4.4 mmol, 5.0 equiv), potassium carbonate (244 mg, 1.7 mmol, 2.0 equiv), palladium acetate (20 mg, 0.09 mmol, 0.1 equiv), and triphenylphosphine (93 mg, 0.35 mmol, 0.4 equiv) were added. The reaction mixture was allowed to react at 100°C under inert gas for 16 hours. The reaction was monitored by LCMS. Saturated aqueous sodium chloride solution (30 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (30 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then added to silica gel for spin drying. Flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V=5 / 1)) gave the title compound (120 mg, yield: 28.4%) as a yellow oily liquid. LCMS (ESI): [M+H+MeCN] + =521.4.

[0252] Step 2: Preparation of diethyl (4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenethyl)phosphonate:

[0253] Diethyl (E)-(4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenylvinyl)phosphonate (120 mg, 0.25 mmol, 1.0 equivalent) was dissolved in methanol (2 mL). Palladium on carbon (50 mg) was then added to the mixture. The atmosphere was replaced with hydrogen three times and stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and dried to give the title compound (100 mg, 83.3% yield) as a colorless oil. LCMS (ESI): [M+H] + =481.7.

[0254] Step 3: Preparation of (4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenethyl)phosphonic acid:

[0255] Diethyl (4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenethyl)phosphonate (100 mg, 0.21 mmol, 1.0 equiv) was dissolved in acetonitrile (2 mL), and trimethylsilyl bromide (477 mg, 3.1 mmol, 15 equiv) was added and stirred at 50 ° C for 16 hours. The reaction solution was quenched with methanol and concentrated under reduced pressure to obtain a brown oily crude product. The crude product was prepared by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (47.5 mg, yield: 53.9%) as a white solid. LCMS (ESI): [M+H] + =426.2; 1 H NMR(400MHz,DMSO-d6)δ7.73(d,J=2.4Hz,2H),7.45(d,J=8.8Hz,2H),7.06-6 .97(m,6H),5.49(s,2H),3.84(s,6H),2.67-2.61(m,2H),1.68-1.54(m,2H).

[0256] Example 33: Preparation of 4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenyl)phosphonic acid:

[0257] Step 1: Preparation of diethyl p-tolylphosphonate:

[0258] 1-Iodo-4-methylbenzene (5.0 g, 22.9 mmol, 1.0 equiv) and tetrakis(triphenylphosphine)palladium (270 mg, 2.29 mmol, 0.1 equiv) were dissolved in toluene (50 mL), and triethylphosphite (5.7 g, 34.4 mmol, 1.5 equiv) and triethylamine (7.0 g, 68.8 mmol, 3.0 equiv) were added. The reaction mixture was stirred at 85°C for 16 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and added to silica gel for spin drying. Flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V=1 / 1)) gave the title compound (1.5 g, yield: 28.7%) as a brown solid. LCMS (ESI): [M+H] + =229.1.

[0259] Step 2: Preparation of diethyl (4-(dibromomethyl)phenyl)phosphonate

[0260] Diethyl p-tolylphosphonate (1.5 g, 6.57 mmol, 1.0 equiv) was dissolved in carbon tetrachloride (20 mL), and N-bromosuccinimide (2.3 g, 13.1 mmol, 2.0 equiv) and dibenzoyl peroxide (80 mg, 0.329 mmol, 0.05 equiv) were added. The reaction mixture was stirred at 78°C for 3 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Reverse phase HPLC (C18, 10 mmol / L formic acid in water, acetonitrile) afforded the title compound (270 mg, yield: 10.6%) as a brown oily liquid. LCMS (ESI): [M+H] + =386.9.

[0261] Step 3: Preparation of diethyl ((4-bromomethyl)phenyl)phosphonate:

[0262] Diethyl (4-(dibromomethyl)phenyl)phosphonate (270 mg, 0.699 mmol, 1.0 equiv) was dissolved in acetonitrile (3 mL), and diethyl phosphite (97 mg, 0.699 mmol, 1.0 equiv) and N,N-diisopropylethylamine (181 mg, 1.40 mmol, 2.0 equiv) were added sequentially. The reaction mixture was stirred at 0°C for 2 hours. Aqueous sodium bicarbonate solution (10 mL) was added to quench the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 3 / 1)) to obtain the title compound (170 mg, yield: 79.1%) as a colorless oily liquid. LCMS (ESI): [M+H] + =307.0.

[0263] Step 4: Preparation of diethyl (4-((3,6-dimethoxy-9H-carbazole-9-methyl)phenyl)phosphonate:

[0264] 3,6-Dimethoxy-9H-carbazole (126 mg, 0.553 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (2 mL). Sodium hydride (60% by mass, 44 mg, 1.11 mmol, 2.0 equiv) was added at 0°C and stirred for half an hour. Diethyl ((4-bromomethyl)phenyl)phosphonate (170 mg, 0.553 mmol, 1.0 equiv) was added and the mixture was warmed to room temperature and stirred for 2 hours. Aqueous ammonium chloride (10 mL) was added to the reaction mixture to quench the reaction. The mixture was then extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Flash chromatography (silica gel, petroleum ether:ethyl acetate (v / v = 3 / 1)) afforded the title compound (100 mg, 39.8% yield) as a colorless oil. LCMS (ESI): [M+H] + =454.2.

[0265] Step 5: Preparation of 4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenyl)phosphonic acid:

[0266] Diethyl (4-((3,6-dimethoxy-9H-carbazole-9-methyl)phenyl)phosphonate (100 mg, 0.220 mmol, 1.0 equiv) was dissolved in acetonitrile (1 mL), and trimethylsilyl bromide (0.51 mL, 3.31 mmol, 15 equiv) was added to the mixture, and the mixture was stirred at 50°C for 1 hour. The reaction solution was quenched with methanol and concentrated under reduced pressure to obtain a brown oily crude product. Reverse phase HPLC (C18, 10 mmol / L aqueous ammonia, acetonitrile) gave the title compound (45.68 mg, yield: 52.3%) as a white solid. LCMS (ESI): [M+H] + =398.0; 1 H NMR (400MHz, DMSO-d6) δ7.73 (d, J = 2.4Hz, 2H), 7.46-7.42 (m, 4H), 7.03-6.94 (m, 4H), 5.51 (s, 2H), 3.84 (s, 6H).

[0267] Example 34: Preparation of 2-(4-(3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenyl)acetic acid:

[0268] Step 1: Preparation of methyl 2-(4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenyl)acetate:

[0269] 9-(4-Bromobenzyl)-3,6-dimethoxy-9H-carbazole (500 mg, 1.26 mmol, 1.0 equiv) was dissolved in ultra-dry toluene (5 mL). Methyl acetoacetate (220 mg, 1.9 mmol, 1.5 equiv), potassium phosphate (803 mg, 3.8 mmol, 3.0 equiv), and palladium acetate (28.4 mg, 0.13 mmol, 0.1 equiv) were then added. Finally, t-Buxphos (2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl) (107 mg, 0.25 mmol, 0.2 equiv) was added. The reaction mixture was stirred at 120°C for 16 hours. The reaction mixture was concentrated, and the crude product was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (v / v = 7 / 3)) to afford the title compound (480 mg, 97.8% yield) as a yellow solid. LCMS(ESI):[M+H] + =390.3.

[0270] Step 2: Preparation of 2-(4-(3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenyl)acetic acid:

[0271] Methyl 2-(4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenyl)acetate (250 mg, 0.64 mmol, 1.0 equiv) was dissolved in water and methanol (1:1, 3 mL). Lithium hydroxide (46 mg, 1.9 mmol, 3.0 equiv) was then added to the mixture and stirred at room temperature for 2 hours. The reaction was monitored by LCMS and the reaction solution was concentrated under reduced pressure. The title compound (160 mg, yield: 66.6%) was purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give a white solid. LCMS (ESI): [M+H] + =376.2; 1H NMR (400MHz, CD3OD) δ7.61 (d, J = 2.4Hz, 2H), 7.30 (d, J = 8.8Hz, 2H), 7.17 (d, J = 8.0Hz, 2H), 7.06-6.95 (m, 4H),5.47(s,2H),3.89(s,6H),3.45(s,2H).

[0272] Example 35: Preparation of (2-(4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenyl)ethylboronic acid

[0273] Step 1: Preparation of 9-((4-vinylphenyl)methyl)-3,6-dimethoxy-9H-carbazole:

[0274] 3,6-Dimethoxy-9H-carbazole (100 mg, 0.44 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (2 mL), and sodium hydride (35 mg, 0.88 mmol, 2.0 equiv) was added. The reaction mixture was allowed to react at 0°C for 0.5 hours. 4-Chloromethylstyrene (153 mg, 0.88 mmol, 2.0 equiv) was then added, and the reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was quenched with water (50 mL) and then extracted three times with ethyl acetate (50 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and added to silica gel for spin drying. The crude product was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 5 / 1)) to obtain the title compound (120 mg, yield: 79.4%). LCMS (ESI): [M+H] + =344.2.

[0275] Step 2: Preparation of 3,6-dimethoxy-9-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)phenyl)methyl)-9H-carbazole:

[0276] 9-((4-vinylphenyl)methyl)-3,6-dimethoxy-9H-carbazole (120 mg, 0.35 mmol, 1.0 equiv) was dissolved in chloroform (2 mL), and pinacol borane (90 mg, 0.7 mmol, 2.0 equiv) and calcium chloride (117 mg, 1.1 mmol, 3.0 equiv) were added to the mixture. The reaction mixture was stirred at 110°C for 16 hours. The reaction mixture was filtered, and a saturated aqueous sodium chloride solution (50 mL) was added to the filtrate, and the mixture was extracted three times with ethyl acetate (50 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and added to silica gel for spin drying. The crude product was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 5 / 1)) to obtain the title compound (80 mg, yield: 48.7%). LCMS (ESI): [M+H] + =472.3.

[0277] Step 3: Preparation of (2-(4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenyl)ethylboronic acid:

[0278] 3,6-Dimethoxy-9-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)phenyl)methyl)-9H-carbazole (80 mg, 0.17 mmol, 1.0 eq) was dissolved in tetrahydrofuran / H2O (V / V=5 / 1, 2 mL). Lithium hydroxide (8 mg, 0.34 mmol, 2 eq) was then added to the mixture and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to give a crude white solid. The crude product was purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (37.42 mg, yield: 56.7%). LCMS (ESI): [M+H] + =390.2; 1 H NMR(400MHz,DMSO-d6)δ7.73(d,J=2.4Hz,2H),7.52-7.40(m,4H),7.11-6.94 (m,6H),5.50(s,2H),3.85(s,6H),2.55-2.51(m,2H),0.82(t,J=8.4Hz,2H).

[0279] Example 36: Preparation of 3-(4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenyl)propanoic acid

[0280] Step 1: Preparation of (E)-3-(4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenylacrylate:

[0281] 9-((4-Bromophenyl)methyl)-3,6-dimethoxy-9H-carbazole (350 mg, 0.88 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (5 mL). Methyl acrylate (380 mg, 4.4 mmol, 5.0 equiv), potassium carbonate (244 mg, 1.7 mmol, 2.0 equiv), palladium acetate (20 mg, 0.09 mmol, 0.1 equiv), and triphenylphosphine (93 mg, 0.35 mmol, 0.4 equiv) were added. The reaction mixture was allowed to react at 100°C under an argon atmosphere for 16 hours. Saturated aqueous sodium chloride solution (30 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (30 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V=5 / 1)) to give the title compound (120 mg, yield: 33.9%) as a yellow oily liquid. LCMS (ESI): [M+H] + =402.1.

[0282] Step 2: Preparation of methyl 3-((3,6-dimethoxy-9H-carbazole-9-methyl)phenyl)propanoate:

[0283] Methyl (E)-3-(4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenylacrylate (120 mg, 0.30 mmol, 1.0 equivalent) was dissolved in methanol (2 mL). Palladium on carbon (50 mg) was then added to the mixture. The atmosphere was replaced with hydrogen three times, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (100 mg, yield: 83.3%) as a yellow oil. LCMS (ESI): [M+H] + =403.5.

[0284] Step 3: Preparation of 3-(4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)phenyl)propanoic acid:

[0285] Methyl 3-((3,6-dimethoxy-9H-carbazole-9-methyl)phenyl)propanoate (100 mg, 0.25 mmol, 1.0 equiv) was dissolved in tetrahydrofuran / H₂O (V / V = 5 / 1, 2 mL). Lithium hydroxide (32 mg, 0.75 mmol, 3 equiv) was then added to the mixture, and the reaction was stirred at room temperature for 16 hours. The reaction solution was neutralized with dilute hydrochloric acid solution and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (C₁₈, 10 mmol / L aqueous ammonia, acetonitrile) to give the title compound (10.69 mg, yield: 11.1%) as a white solid. LCMS (ESI): [M+H] + =390.2; 1 H NMR (400MHz, DMSO-d6) δ7.73(d,J=1.2Hz,2H),7.47(d,J=8.8Hz,2H),7.09(d,J=8.0Hz,2H) ,7.06-6.96(m,4H),5.51(s,2H),3.85(s,6H),2.70(t,J=7.6Hz,2H),2.36(t,J=7.6Hz,2H).

[0286] Example 37: Preparation of (4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)boronic acid

[0287] Step 1: Preparation of 9-(4-(bromomethyl)benzyl)-3,6-dimethoxy-9H-carbazole:

[0288] 3,6-Dimethoxy-9H-carbazole (200 mg, 2.2 mmol, 1.0 equiv) was added to N,N-dimethylformamide (6 mL). Sodium hydride (220 mg, 5.5 mmol, 2.5 equiv) was slowly added at 0°C and stirred for 30 minutes. 1,4-Bis(bromomethyl)benzene (464 mg, 1.76 mmol, 2.0 equiv) was then added, and the reaction mixture was allowed to react at room temperature for 3 hours. Water (15 mL) was added to quench the reaction mixture, and the mixture was extracted three times with ethyl acetate (25 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 4 / 1)) to obtain the title compound as a white solid.

[0289] Step 2: Preparation of 3,6-dimethoxy-9-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)benzyl)-9H-carbazole:

[0290] 9-(4-(Bromomethyl)benzyl)-3,6-dimethoxy-9H-carbazole (150 mg, 0.37 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (3 mL). Diboronic acid pinacol ester (186 mg, 1.7 mmol, 2.0 equiv), cuprous iodide (7 mg, 0.04 mmol, 0.1 equiv), and lithium methoxide (42 mg, 1.1 mmol, 3.0 equiv) were then added. Finally, triphenylphosphine (12 mg, 0.04 mmol, 0.12 equiv) was added and stirred at 35°C for 18 hours. The reaction mixture was quenched with water (15 mL) and extracted three times with ethyl acetate (25 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then added to silica gel for spin drying. The crude product was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V=3 / 1)) to give the title compound (130 mg, yield: 79.1%) as a white solid.

[0291] Step 3: Preparation of (4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)boronic acid:

[0292] 3,6-Dimethoxy-9-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)benzyl)-9H-carbazole (120 mg, 0.26 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (2 mL). Lithium hydroxide (19 mg, 0.78 mmol, 3.0 equiv) was then added to the mixture, and the reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (23.06 mg, yield: 23.6%) as a white solid. LCMS (ESI): [M+H] + =376.2; 1 H NMR (400MHz, DMSO-d6) δ7.73 (d, J = 2.0 Hz, 2H), 7.59 (s, 2H), 7.47 (d, J = 8.8 Hz, 2H), 7.03-6.93 (m, 6H), 5.48 (s, 2H), 3.84 (s, 6H), 1.99 (s, 2H).

[0293] Example 38: Preparation of (6-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)pyridin-3-yl)methyl)phosphonic acid

[0294] Step 1: Preparation of methyl 5-((diethoxyphosphonoyl)methyl)picolinate:

[0295] 5-Bromomethylpyridine-2-carboxylic acid methyl ester (3.5 g, 15.2 mmol, 1.0 equivalent) was dissolved in 1,4-dichlorohexacyclopentane (35 mL), triethyl phosphite (2.5 g, 15.2 mmol, 1.0 equivalent) was added to the mixture and stirred at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure and dried. The crude product was separated and purified by flash chromatography (silica gel, dichloromethane: methanol (V / V = 20 / 1)) to give the title compound (3.0 g, yield: 68.6%) as a yellow oil. LCMS (ESI): [M+H] + =288.1.

[0296] Step 2: Preparation of diethyl (6-(hydroxymethyl)pyridin-3-yl)methyl)phosphonate:

[0297] At 0 ° C, 5-((diethoxyphosphonic acid acyl) methyl) picolinate (2.7 g, 9.40 mmol, 1.0 equivalent) was added to tetrahydrofuran (27 mL), and lithium borohydride (204 mg, 9.40 mmol, 1.0 equivalent) was slowly added. The reaction solution continued to react for three hours at room temperature. Water (50 mL) was added to the reaction solution and extracted three times with ethyl acetate (50 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and then added to silica gel and spin-dried. The crude product was separated and purified by flash chromatography (silica gel, dichloromethane: methanol (V / V = 10 / 1)) to give the title compound (1.5 g, yield: 61.6%), the product being a yellow oil. LCMS (ESI): [M+H] + =260.1.

[0298] Step 3: Preparation of diethyl (6-(chloromethyl)pyridin-3-ylmethyl)phosphonate:

[0299] Diethyl (6-(hydroxymethyl)pyridin-3-yl)methyl)phosphonate (1.3 g, 5.01 mmol, 1.0 equiv) was added to dichloromethane (13 mL) at 0°C, and thionyl chloride (894 mg, 7.51 mmol, 1.5 equiv) was slowly added. The reaction mixture was allowed to react at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by flash chromatography (silica gel, dichloromethane:methanol (V / V=10 / 1)) to obtain the title compound (1.0 g, yield: 71.9%) as a yellow oil. LCMS (ESI): [M+H] + =278.1.

[0300] Step 4: Preparation of diethyl (6-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)pyridin-3-yl)methyl)phosphonate:

[0301] 3,6-Dimethoxy-9H-carbazole (200 mg, 0.88 mmol, 1.0 equiv) was added to N,N-dimethylformamide (2 mL). The reaction solution was cooled to zero degrees Celsius, and sodium hydride (53 mg, 1.32 mmol, 1.5 equiv) was slowly added. After half an hour of reaction, diethyl (6-(chloromethyl)pyridin-3-ylmethyl)phosphonate (367 mg, 1.32 mmol, 0.1 equiv) was added. The reaction solution was allowed to react at room temperature for another hour. LCMS monitored the reaction completion. Water (50 mL) was added to the reaction solution, and the solution was extracted three times with ethyl acetate (50 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and added to silica gel for spin drying. The crude product was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (v / v = 1 / 2)) to obtain the title compound (150 mg, 36.5% yield) as a yellow solid. LCMS(ESI):[M+H] + =469.1.

[0302] Step 5: Preparation of (6-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)pyridin-3-yl)methyl)phosphonic acid:

[0303] Diethyl (6-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)pyridin-3-yl)methyl)phosphonate (100 mg, 0.21 mmol, 1.0 equiv) was dissolved in dichloromethane (2 mL). Silane bromide (490 mg, 3.15 mmol, 15 equiv) was then added to the mixture and stirred at 50°C for 0.5 h. The reaction solution was filtered, quenched with methanol, and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (27.82 mg, yield: 31.6%) as a white solid. LCMS (ESI): [M+H] + =413.2; 1 H NMR(400MHz,DMSO-d6)δ8.27(s,1H),7.72(d,J=2.4Hz,2H),7.43-7.38(m,3H),6.99(dd,J =8.8, 2.4Hz, 2H), 6.65 (d, J = 7.6Hz, 1H), 5.52 (s, 2H), 3.84 (s, 6H), 2.60 (d, J = 20.4Hz, 2H).

[0304] Example 39: Preparation of ((5-(3,6-dimethoxy-9H-carbazol-9-yl)methyl)pyridin-2-yl)methyl)phosphonic acid:

[0305] Step 1: Preparation of methyl 6-(chloromethyl)nicotinate:

[0306] 6-(Hydroxymethyl)nicotinate (4.0 g, 23.9 mmol, 1.0 equivalent) was added to dichloromethane (40 mL). The reaction solution was cooled to 0°C and thionyl chloride (4.27 g, 35.9 mmol, 1.5 equivalent) was slowly added. The reaction solution was allowed to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried. The crude product was purified by flash chromatography (silica gel, dichloromethane:methanol (V / V=20 / 1)) to give the title compound (3.5 g, yield: 77.7%) as a yellow oil. LCMS (ESI): [M+H] + =186.0.

[0307] Step 2: Preparation of methyl 6-((diethoxyphosphono)methyl)nicotinate:

[0308] Diethyl phosphite (2.6 g, 18.9 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (35 mL). The reaction solution was cooled to 0°C and sodium hydride (1.14 g, 28.4 mmol, 1.5 equivalent) was slowly added. After half an hour of reaction, methyl 6-(chloromethyl)nicotinate (3.5 g, 18.9 mmol, 1.5 equivalent) was added and stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure and dried, and the crude product was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V=1 / 3)) to obtain the title compound (3.0 g, yield: 55.3%) as a yellow oil. LCMS (ESI): [M+H] + =288.1.

[0309] Step 3: Preparation of diethyl (5-(hydroxymethyl)pyridin-2-yl)methyl)phosphonate:

[0310] 6-((diethoxyphosphono)methyl)nicotinate (800 mg, 2.79 mmol, 1.0 equivalent) was added to tetrahydrofuran (8 mL), the reaction solution was cooled to zero degrees, and lithium aluminum tetrahydride (127 mg, 3.35 mmol, 1.2 equivalents) was slowly added. The reaction solution was allowed to react for two hours at room temperature. Water (50 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (50 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and then added to silica gel and dried. The crude product was separated and purified by flash chromatography (silica gel, dichloromethane: methanol (V / V = 10 / 1)) to give the title compound (180 mg, yield: 24.5%) as a yellow oil. LCMS (ESI): [M+H] + =260.1.

[0311] Step 4: Preparation of diethyl (5-(chloromethyl)pyridin-2-yl)methyl)phosphonate:

[0312] Under zero temperature conditions, diethyl (6-(hydroxymethyl)pyridin-3-yl)methyl)phosphonate (150 mg, 0.58 mmol, 1.0 equivalent) was added to dichloromethane (13 mL), and dichlorothionyl (103 mg, 0.87 mmol, 1.5 equivalents) was slowly added. The reaction solution was allowed to react for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure and dried. The crude product was separated and purified by flash chromatography (silica gel, dichloromethane:methanol (V / V=10 / 1)) to give the title compound (110 mg, yield: 68.5%) as a yellow oil. LCMS (ESI): [M+H] + =278.1.

[0313] Step 5: Preparation of diethyl (5-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)pyridin-2-yl)methyl)phosphonate:

[0314] 3,6-Dimethoxy-9H-carbazole (90 mg, 0.39 mmol, 1.0 equiv) was added to N,N-dimethylformamide (2 mL). The reaction solution was cooled to 0°C and sodium hydride (24 mg, 0.59 mmol, 1.5 equiv) was slowly added. After half an hour of reaction, diethyl (5-(chloromethyl)pyridin-2-yl)methyl)phosphonate (110 mg, 0.39 mmol, 1.0 equiv) was added and the reaction solution was continued to react at room temperature for 1 hour. Water (10 mL) was added to the reaction solution and extracted three times with ethyl acetate (10 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 1 / 2)) to obtain the title compound (80 mg, yield: 43.1%) as a yellow solid. LCMS (ESI): [M+H] + =469.2.

[0315] Step 6: Preparation of ((5-(3,6-dimethoxy-9H-carbazol-9-yl)methyl)pyridin-2-yl)methyl)phosphonic acid:

[0316] Diethyl (5-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)pyridin-2-yl)methyl)phosphonate (80 mg, 0.17 mmol, 1.0 equiv) was dissolved in dichloromethane (1 mL). Trimethylsilyl bromide (390 mg, 2.55 mmol, 15 equiv) was then added to the mixture and stirred at 50°C for 0.5 h. The reaction solution was filtered, quenched with methanol, and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the product (39.15 mg, yield: 55.8%) as an off-white solid. LCMS (ESI): [M+H] + =413.2; 1 H NMR (400MHz, DMSO-d6) δ8.22(s,1H),7.72(d,J=2.4Hz,2H),7.50(d,J=9.2Hz,2H),7.29(dd,J=8.0,2.0Hz, 1H), 7.19 (d, J = 8.0Hz, 1H), 7.02 (dd, J = 8.8, 2.4Hz, 2H), 5.51 (s, 2H), 3.84 (s, 6H), 2.85 (d, J = 20.8Hz, 2H).

[0317] Example 40: Preparation of ((4-((3-ethyl-9H-carbazol-9-yl)methyl)phenyl)methyl)phosphonic acid:

[0318] Step 1: Preparation of di-tert-butyl ((4-((3-bromo-9H-carbazol-9-yl)methyl)phenyl)methyl)phosphonate:

[0319] 3-Bromocarbazole (300 mg, 1.22 mmol, 1 equivalent) was dissolved in tetrahydrofuran (25 mL), followed by the addition of sodium hydride (244 mg, 6.1 mmol, 5 equivalents). To this mixture was added di-tert-butyl ((4-(bromomethyl)phenyl)methyl)phosphonate (1.38 g, 3.66 mmol, 3 equivalents), and the mixture was stirred at room temperature under argon for 1 hour. Methanol (5 mL) was added to the reaction solution to quench the reaction, which was then diluted with saturated ammonium chloride solution (5 mL) and extracted three times with ethyl acetate (20 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound (400 mg, 60.5% yield). LCMS (ESI): [M-2tBu+3H] + =430.0.

[0320] Step 2: Preparation of di-tert-butyl ((4-((3-vinyl-9H-carbazol-9-yl)methyl)phenyl)methyl)phosphonate:

[0321] Di-tert-butyl ((4-((3-bromo-9H-carbazol-9-yl)methyl)phenyl)methyl)phosphonate (200 mg, 0.37 mmol, 1 equiv) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). Potassium ethylene trifluoroborate (148 mg, 1.11 mmol, 3 equiv), potassium carbonate (153 mg, 1.11 mmol, 3 equiv), and Pd(dppf)Cl2 ((1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride) (54 mg, 0.07 mmol, 0.2 equiv) were added and reacted at 110°C for 1 hour. The reaction solution was diluted with ethyl acetate (20 mL) and washed with saturated ammonium chloride (30 mL × 3). The organic phase was dried, filtered, and concentrated under reduced pressure to give the title compound (150 mg, yield: 83.1%). LCMS (ESI): [M-2tBu+3H] + =378.0.

[0322] Step 3: Preparation of di-tert-butyl ((4-((3-ethyl-9H-carbazol-9-yl)methyl)phenyl)methyl)phosphonate:

[0323] Di-tert-butyl ((4-((3-vinyl-9H-carbazol-9-yl)methyl)phenyl)methyl)phosphonate (70 mg, 0.14 mmol, 1 equivalent) was dissolved in anhydrous methanol (5 mL), and palladium on carbon (30 mg, 43 wt%) was added. The mixture was reacted at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered and concentrated to give the title compound (70 mg, yield: 99.6%). LCMS (ESI): [M-2tBu+3H] + =380.2.

[0324] Step 4: Preparation of ((4-((3-ethyl-9H-carbazol-9-yl)methyl)phenyl)methyl)phosphonic acid:

[0325] Di-tert-butyl ((4-((3-ethyl-9H-carbazol-9-yl)methyl)phenyl)methyl)phosphonate (70 mg, 0.14 mmol, 1 eq) was dissolved in dichloromethane (5 ml), and trifluoroacetic acid (1 mL, 8.77 mmol, 62.6 eq) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with water, and the crude product was purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (2.58 mg, yield: 7.1%). LCMS (ESI): [M+H] + =380.1; 1H NMR (400MHz, CD3OD) δ8.05(d,J=8.0Hz,1H),7.89(s,1H),7.42(d,J=8.0Hz,1H),7.37-7.33(m,2H),7.28-7.23 (m,3H),7.17-7.13(m,1H),7.02(d,J=8.0Hz,2H),5.67-5.63(m,2H),2.82-2.77(m,4H),1.32(t,J=7.6Hz,3H).

[0326] Example 41: Preparation of (4-((3-isopropyl-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0327] Step 1: Preparation of diethyl (4-((3-(propyl-1-en-2-yl)-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0328] Isopropenylboronic acid pinacol ester (173 mg, 1.03 mmol, 2 equivalents) and diethyl (4-((3-bromo-9H-carbazol-9-yl)methyl)benzyl)phosphonate (250 mg, 0.51 mmol, 1 equivalent) were dissolved in water (1 mL) and 1,4-dioxane (5 mL). Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride) (75 mg, 0.1 mmol, 0.2 equivalents) and potassium carbonate (213 mg, 1.54 mmol, 3 equivalents) were added. The mixture was stirred at 100°C for 1 hour. The reaction solution was diluted with saturated ammonium chloride (10 mL) and extracted with ethyl acetate (30 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (280 mg, yield: 82.9%). LCMS (ESI): [M+H] + =448.1.

[0329] Step 2: Preparation of diethyl (4-((3-isopropyl-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0330] Diethyl (4-((3-(propyl-1-en-2-yl)-9H-carbazol-9-yl)methyl)benzyl)phosphonate (50 mg, 0.11 mmol, 1 equivalent) was dissolved in methanol (5 mL). Palladium on carbon (25 mg, 50 wt%) was then added to the mixture. The mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (40 mg, 80.1% yield). LCMS (ESI): [M+Na] + =472.1.

[0331] Step 3: Preparation of (4-((3-isopropyl-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0332] Diethyl (4-((3-isopropyl-9H-carbazol-9-yl)methyl)benzyl)phosphonate (50 mg, 0.11 mmol, 1 equivalent) was dissolved in dichloromethane (3 mL). Trimethylsilyl bromide (0.17 mL, 1.1 mmol, 10 equivalents) was then added to the mixture, and the reaction was stirred at 50°C for 0.5 hours. The reaction solution was filtered, quenched with methanol, and concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC (C18, 10 mmol / L aqueous ammonia, acetonitrile) to give the title compound (6.05 mg, 14.0% yield) as a white solid. LCMS (ESI): [MH] - =392.1; 1 H NMR (400MHz, CD3OD) δ8.07(d,J=7.6Hz,1H),7.93(d,J=1.2Hz,1H),7.43(d,J=8.4Hz,1H),7.38-7.35(m,2H),7.31-7.26(m,3H ),7.17(t,J=6.8Hz,1H),7.01(d,J=8.0Hz,2H),5.50(s,2H),3.11-3.04(m,1H),2.81(d,J=19.6Hz,2H),1.34(d,J=6.8Hz,6H).

[0333] Example 42: Preparation of (4-((2-(methoxy-d3)-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0334] Step 1: Preparation of 2-(methoxy-d3)-9H-carbazole:

[0335] Sodium (420 mg, 18.3 mmol, 10 equiv) was dissolved in 2 mL of deuterated methanol and stirred at room temperature for 0.5 h. A solution of 2-bromo-9H-carbazole (450 mg, 1.83 mmol, 1 equiv) and cuprous iodide (100 mg, 0.53 mmol, 0.29 equiv) in N,N-dimethylformamide (3 mL) was then added. The reaction mixture was stirred at 120°C under argon for 12 h. The mixture was quenched with saturated ammonium chloride and extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the title compound (257 mg, 70.19% yield) as a yellow solid. LCMS (ESI): [M+H] + =201.1.

[0336] Step 2: Preparation of diethyl (4-((2-(methoxy-d3)-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0337] 2-(Methoxy-d3)-9H-carbazole (257 mg, 1.28 mmol, 1 equivalent) was dissolved in tetrahydrofuran (10 mL), and diethyl (4-(bromomethyl)benzyl)phosphonate (822 mg, 2.56 mmol, 2 equivalents) and sodium hydride (256 mg, 6.4 mmol, 5 equivalents) were added. After stirring at room temperature for 1 hour, the reaction solution was quenched with saturated ammonium chloride and extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (137 mg, yield: 24.3%) as a yellow oil. LCMS (ESI): [M+H] + =441.2.

[0338] Step 3: Preparation of (4-((2-(methoxy-d3)-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0339] Diethyl (4-((2-(methoxy-d3)-9H-carbazol-9-yl)methyl)benzyl)phosphonate (137 mg, 0.31 mmol, 1 equivalent) was dissolved in dichloromethane (5 mL), and trimethylsilyl bromide (1 mL, 6.5 mmol, 21 equivalents) was added. The reaction solution was stirred at 50°C under argon protection for 1 hour. The reaction solution was purified by reverse phase preparative purification (C18, 10 mmol / aqueous ammonia, acetonitrile) to obtain the title compound (23.22 mg, yield: 19.42%) as a white solid. LCMS (ESI): [M+H] + =385.1; 1 H NMR (400MHz, CD3OD) δ7.95(dd,J=11.8,8.0Hz,2H),7.39(d,J=8.0Hz,1H),7.29(t,J=7.2Hz,1H),7.23-7.21(m,2H),7.14(t, J=7.2Hz,1H),7.04(d,J=8.0Hz,2H),6.95(d,J=2.0Hz,1H),6.80(dd,J=8.4,2.4Hz,1H),5.49(s,2H),2.89(d,J=20.8Hz,2H).

[0340] Example 43: Preparation of (4-((2,3-difluoro-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0341] Step 1: Preparation of 2,3-difluoro-9H-carbazole:

[0342] Nitrosobenzene (200 mg, 1.87 mmol, 1 equivalent) was dissolved in anhydrous acetonitrile (5 mL), and cesium fluoride (1.4 g, 9.35 mmol, 5 equivalents) was added. After stirring under argon for 10 minutes, 4,5-difluoro-2-(trimethylsilyl)phenol trifluoromethanesulfonate (624 mg, 1.87 mmol, 1 equivalent) was added. Under argon protection, the reaction was allowed to proceed at room temperature for 72 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified on a silica gel preparation plate (petroleum ether: dichloromethane (V / V = 1 / 2)) to obtain the title compound (80 mg, yield: 21.1%). LCMS (ESI): [MH] - =202.0.

[0343] Step 2: Preparation of diethyl (4-((2,3-difluoro-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0344] 2,3-Difluoro-9H-carbazole (40 mg, 0.2 mmol, 1 eq) was dissolved in tetrahydrofuran (1 mL), and sodium hydride (32 mg, 0.79 mmol, 4 eq) was added. Under nitrogen protection, the mixture was stirred at room temperature for 0.5 h, and diethyl (4-(bromomethyl)benzyl)phosphonate (126 mg, 0.39 mmol, 2 eq) was added. Stirring was continued for 1 h. The reaction solution was quenched with saturated ammonium chloride and extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title compound (65 mg, yield: 73.3%). LCMS (ESI): [M+H] + =444.1.

[0345] Step 3: Preparation of (4-((2,3-difluoro-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0346] Diethyl (4-((2,3-difluoro-9H-carbazol-9-yl)methyl)benzyl)phosphonate (60 mg, 0.14 mmol, 1 eq) was dissolved in dichloromethane (1 mL), and trimethylsilyl bromide (104 mg, 0.68 mmol, 5 eq) was added. The mixture was reacted at 50°C for 2 hours, and the reaction solution was concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC (C18, 10 mmol / L aqueous ammonia, acetonitrile) to give the title compound (4.70 mg, 9.0% yield) as a white solid. LCMS (ESI): [MH] - =386.1; 1H NMR (400MHz, CD3OD) δ8.05(d,J=7.6Hz,1H),7.96(dd,J=10.8,8.0Hz,1H),7.49(d,J=8.0Hz,1H),7.43-7.39(m,1 H),7.36(dd,J=11.6,2.8Hz,1H),7.23-7.19(m,3H),7.04(d,J=7.6Hz,2H),5.51(s,2H),2.92(d,J=20.8Hz,2H).

[0347] Example 44: Preparation of (4-((3-(methylthio)-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid

[0348] Step 1: Preparation of 3-(methylthio)-9H-carbazole:

[0349] 3-Bromo-9H-carbazole (500 mg, 2.0 mmol, 1 equivalent) was dissolved in DMSO (10 mL), and then sodium thiosulfate pentahydrate (1 g, 4.1 mmol, 2 equivalents), dimethyl carbonate (915 mg, 10.2 mmol, 5 equivalents), P(t-Bu)3.HBF4 (tri-tert-butylphosphine tetrafluoroborate) (118 mg, 0.4 mmol, 0.2 equivalents), potassium tert-butoxide (456 mg, 4.1 mmol, 2 equivalents), tetrabutylammonium bromide (2 g, 6.1 mmol, 3 equivalents), and Pd(acac)2 (bis(acetylacetonato)palladium(II)) (6 mg, 0.02 mmol, 0.01 equivalents) were added to the mixture. The mixture was stirred at 120°C under argon protection for 16 hours. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction, and the mixture was extracted three times with ethyl acetate (10 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (320 mg, yield: 73.8%). LCMS (ESI): [MH] - =212.0.

[0350] Step 2: Preparation of diethyl (4-((3-(methylthio)-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0351] 3-(Methylthio)-9H-carbazole (300 mg, 1.41 mmol, 1 equivalent) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (450 mg, 11.25 mmol, 8 equivalents) was added. Under argon protection, the mixture was stirred at room temperature for 0.5 hours. Then, diethyl (4-(bromomethyl)benzyl)phosphonate (2.3 g, 7.03 mmol, 5 equivalents) was added. Under argon protection, the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction, and the mixture was extracted three times with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (500 mg, yield: 78.4%). LCMS (ESI): [M+H] + =454.1.

[0352] Step 3: Preparation of (4-((3-(methylthio)-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0353] Diethyl (4-((3-(methylthio)-9H-carbazol-9-yl)methyl)benzyl)phosphonate (110 mg, 0.24 mmol, 1 equivalent) was dissolved in dichloromethane (2 mL), and trimethylsilyl bromide (0.4 mL, 2.61 mmol, 10 equivalents) was added. The mixture was reacted at 50°C for 1 hour. The reaction solution was concentrated at low temperature, dissolved in 2 mL of methanol, and purified by reverse phase HPLC (C18, 10 mmol / L aqueous ammonia, acetonitrile) to give the title compound (11 mg, yield: 12.2%). LCMS (ESI): [M+H] - =396.1; 1 H NMR(400MHz,CD3OD)δ8.11-8.08(m,2H),7.47-7.38(m,4H),7.23-7.17(m,3 H), 7.03 (d, J = 8.0Hz, 2H), 5.52 (s, 2H), 2.88 (d, J = 20.8Hz, 1H), 2.53 (s, 3H).

[0354] Example 45: Preparation of ((6-((5H-pyrido[3,2-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonic acid:

[0355] Step 1: Preparation of diethyl ((6-((5H-pyrido[3,2-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonate

[0356] 5H-pyrido[3,2-b]indole (200 mg, 1.19 mmol, 1.0 equiv) was added to tetrahydrofuran (5 mL). The reaction solution was cooled to 0°C, and sodium hydride (72 mg, 1.78 mmol, 1.5 equiv) was slowly added. After reacting at 0°C for half an hour, diethyl ((6-(chloromethyl)pyridin-3-yl)methyl)phosphonate (364 mg, 1.31 mmol, 1.1 equiv) was added, and the reaction was continued at room temperature for 1 hour. Water (50 mL) was added to the reaction solution to quench the reaction, and the solution was extracted three times with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and added to silica gel for centrifugation. The crude product was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (v / v = 1 / 2)) to obtain the title compound (200 mg, 41.1% yield) as a yellow solid. LCMS(ESI):[M+H] + =410.2.

[0357] Step 2: Preparation of ((6-((5H-pyrido[3,2-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonic acid:

[0358] Diethyl ((6-((5H-pyrido[3,2-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonate (200 mg, 0.49 mmol, 1.0 equiv) was dissolved in dichloromethane (2 mL), and trimethylsilyl bromide (1.12 g, 7.33 mmol, 15 equiv) was added. The mixture was stirred at 50°C for 1 hour. The reaction solution was filtered, quenched with methanol, and concentrated under reduced pressure. The crude product was prepared by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (125.3 mg, yield: 72.4%) as an off-white solid. LCMS (ESI): [M+H] + =354.0; 1 H NMR(400MHz, DMSO-d6,)δ8.46(dd,J=4.4,1.2Hz,1H),8.25(s,1H),8.21(d,J=7.6Hz,1H),8.02(dd,J=8.4,1.2Hz,1H),7.66(d,J=8.4Hz ,1H),7.53-7.43(m,2H),7.38(dd,J=8.4,4.4Hz,1H),7.26(t,J=7.2Hz,1H),6.93(d,J=8.0Hz,1H),5.65(s,2H),2.63(d,J=20.8Hz,2H).

[0359] Example 46: Preparation of (4-((3-amino-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0360] Step 1: Preparation of diethyl (4-((3-nitro-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0361] 3-Nitro-9H-carbazole (500 mg, 2.36 mmol, 1 equivalent) was dissolved in tetrahydrofuran (10 mL) and sodium hydride (756 mg, 18.9 mmol, 8 equivalents) was added. The reaction mixture was stirred at room temperature under argon for 0.5 hours. Diethyl (4-(bromomethyl)benzyl)phosphonate (3.8 g, 11.8 mmol, 5 equivalents) was added and reacted at room temperature for 1 hour. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (900 mg, yield: 84.3%). LCMS (ESI): [M+H] + =453.2.

[0362] Step 2: Preparation of diethyl (4-((3-amino-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0363] Diethyl (4-((3-nitro-9H-carbazol-9-yl)methyl)benzyl)phosphonate (500 mg, 1.11 mmol, 1 equivalent) was dissolved in anhydrous methanol (10 mL), and palladium on carbon (50 mg, 10 wt%) was added. The mixture was stirred under hydrogen protection at room temperature for 1 hour. The reaction solution was filtered and concentrated under reduced pressure to give the title compound (400 mg, yield: 85.7%). LCMS (ESI): [M+H] + =423.2.

[0364] Step 3: Preparation of (4-((3-amino-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid:

[0365] Diethyl (4-((3-amino-9H-carbazol-9-yl)methyl)benzyl)phosphonate (100 mg, 0.24 mmol, 1 equivalent) was dissolved in dichloromethane (2 mL), and trimethylsilyl bromide (0.5 mL, 3.27 mmol, 14 equivalents) was added. The mixture was reacted at 50°C for 1 hour. The reaction solution was quenched with 2 mL of methanol and purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (13.5 mg, yield: 15.6%). LCMS (ESI): [M+H] + =367.0; 1H NMR (400MHz, CD3OD) δ7.97(d,J=8.0Hz,1H),7.51(d,J=2.0Hz,1H),7.37-7.33(m,2H),7.31-7.23(m,3H),7. 09(t,J=6.8Hz,1H),7.00(d,J=8.0Hz,2H),6.94(dd,J=8.8,2.4Hz,1H),5.89(s,2H),2.81(d,J=20.4Hz,2H).

[0366] Example 47: Preparation of (((4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphino)bis(oxo))bis(methylene)bis(2,2-dimethylpropionate)

[0367] Step 1: Preparation of (((4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphino)bis(oxo))bis(methylene)bis(2,2-dimethylpropionate)

[0368] (4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid (95 mg, 0.23 mmol, 1.0 equiv) was dissolved in acetonitrile (2 mL), and then iodomethyl 2,2-dimethylpropionate (278 mg, 1.15 mmol, 5 equiv) and N,N-diisopropylethylamine (149 mg, 1.15 mmol, 5 equiv) were added to the mixture, and the mixture was stirred at 60°C for 16 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (46.8 mg, yield: 31.8%) as a white solid. LCMS (ESI): [M+NH4] + =657.7; 1 H NMR(400MHz,DMSO-d6)δ7.73(d,J=2.4Hz,2H),7.45(d,J=8.8Hz,2H),7.17-7.09(m,2H), 7.06-6.97(m,4H),5.64-5.40(m,6H),3.85(s,6H),3.26(d,J=20.4Hz,2H),1.07(s,18H).

[0369] Example 48: Preparation of (((4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphino)bis(oxo))bis(methylene)diisopropyl bis(carbonate):

[0370] Step 1: Preparation of (((4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphino)bis(oxo))bis(methylene)diisopropyl bis(carbonate):

[0371] (4-((3,6-Dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid (200 mg, 0.49 mmol, 1.0 equiv) was dissolved in acetonitrile (2 mL). To this mixture was added iodomethylpropan-2-yl carbonate (598 mg, 2.45 mmol, 5.0 equiv) and N,N-diisopropylethylamine (317 mg, 2.45 mmol, 5.0 equiv). The mixture was stirred at 60°C for 16 hours. The reaction solution was concentrated under reduced pressure. The crude product was subjected to reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (100 mg, yield: 31.7%) as a brown oil. LCMS (ESI): [M+NH4] + =661.2; 1 H NMR (400MHz, DMSO-d6) δ7.74(d,J=2.4Hz,2H),7.46(d,J=8.8Hz,2H),7.11(dd,J=8.4,2.4Hz,2H),7.04-7. 00(m,4H),5.54-5.45(m,6H),4.80-4.74(m,2H),3.85(s,6H),3.28(d,J=22.0Hz,2H),1.21-1.19(m,12H).

[0372] Example 49: Preparation of diisopropyl 2,2'-(((4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphino)bis(azanediyl))(2S,2'S)-dipropionate:

[0373] Step 1: Preparation of (4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphonyl chloride:

[0374] (4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphonic acid (1.3 g, 3.16 mmol, 1.0 equiv) was dissolved in dichloromethane (15 mL), followed by the addition of oxalyl chloride (802 mg, 6.32 mmol, 2.0 equiv) and N,N-dimethylformamide (23.1 mg, 0.32 mmol, 0.1 equiv). The mixture was stirred at room temperature for 2 hours. The reaction solution was directly concentrated under reduced pressure to dryness to afford the title compound (1.3 g, 92.9% yield) as an off-white solid. LCMS (ESI): [M+H] +=440.2.

[0375] Step 2: Preparation of diisopropyl 2,2'-(((4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphino)bis(azanediyl))(2S,2'S)-dipropionate:

[0376] (4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphonoyl chloride (100 mg, 0.22 mmol, 1.0 equiv) was dissolved in dichloromethane (2 mL), and L-alanine isopropyl ester (87.8 mg, 7.33 mmol, 3 equiv) and N,N-diisopropylethylamine (114 mg, 1.12 mmol, 5 equiv) were added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (9.8 mg, yield: 6.89%) as a white solid. LCMS (ESI): [M+H] + =638.4; 1 H NMR (400MHz, DMSO-d6, ppm) δ7.73(d,J=2.4Hz,2H),7.46(d,J=8.8Hz,2H),7.13(dd,J=8.0,2.0 Hz,2H),7.02(d,J=8.8Hz,2H),7.00(d,J=8.8Hz,2H),5.52(s,2H),4.90-4.72(m,2H),4.43-4.33(m,1H),4.30-4.19( m,1H),3.84(s,6H),3.70-3.56(m,1H),3.54-3.51(m,1H),2.99-2.84(m,2H),1.16-1.12(m,15H),1.02-1.00(m,3H).

[0377] Example 50: Preparation of 4-(3-chlorophenyl)-2-(4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)-1,3,2-dioxaphosphorinane 2-oxide:

[0378] Step 1: Preparation of 1-(3-chlorophenyl)propane-1,3-diol:

[0379] Ethyl 3-(3-chlorophenyl)-3-oxopropanoate (2.0 g, 8.8 mmol, 1.0 equivalent) was added to methanol (20 mL), followed by the slow addition of sodium borohydride (1.7 g, 44.0 mmol, 5.0 equivalents). The reaction mixture was allowed to react at 65° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to yield a clear, oily crude product. The crude product was prepared by reverse-phase HPLC (C18, 10 mmol / L formic acid, acetonitrile) to yield the title compound (1.4 g, 85.4% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6, ppm) δ7.36-7.25(m,4H),5.28(brs,1H),4.69-4.66(m,1H),4.58-4.39(brs,1H),3.54-3.39(m,2H),1.76-1.67(m,2H).

[0380] Step 2: Preparation of 4-(3-chlorophenyl)-2-(4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)-1,3,2-dioxaphosphorinane 2-oxide:

[0381] (4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphonoyl chloride (80 mg, 0.18 mmol, 1.0 equiv) was dissolved in dichloromethane (2 mL). 1-(3-chlorophenyl)propane-1,3-diol (66.6 mg, 0.36 mmol, 2 equiv) and N,N-diisopropylethylamine (115 mg, 0.89 mmol, 5 equiv) were then added to the mixture. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure and the product was purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (3.56 mg, 3.52% yield) as a white solid. LCMS (ESI): [M+H] + =562.2; 1 H NMR(400MHz,DMSO-d6,ppm)δ7.73(d,J=2.4Hz,2H),7.44(d,J=8.8Hz,2H),7.36-7.07(m,6H),7.01-6 .97(m,4H),5.50(s,2H),4.63-4.50(m,1H),3.86-3.82(m,8H),3.68-3.52(m,2H),2.83-2.75(m,2H).

[0382] Example 51: Preparation of ((4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)(phenoxy)phosphoryl)-L-alanine isopropyl ester:

[0383] Step 1: Preparation of diphenyl (4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0384] (4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphonic dichloride (1.00 g, 2.23 mmol, 1.0 equiv) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (1.44 g, 11.2 mmol, 5.0 equiv) and phenol (1.05 g, 11.2 mmol, 5.0 equiv) were added sequentially. The reaction solution was continued to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V=1 / 1)) to give the title compound (500 mg, yield: 39.8%) as a white solid. LCMS (ESI): [M+H] + =564.4.

[0385] Step 2: Preparation of phenyl (4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphonate:

[0386] Diphenyl (4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphonate (500 mg, 0.887 mmol, 1.0 equiv) was dissolved in methanol (5 mL) and water (5 mL). Sodium hydroxide (710 mg, 17.7 mmol, 20.0 equiv) was added, and the reaction mixture was allowed to react at 50°C for 16 hours. The reaction mixture was concentrated under reduced pressure and dried. The crude product was purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (150 mg, 34.7% yield) as a white oil. LCMS (ESI): [M+H] + =488.3.

[0387] Step 3: Preparation of phenyl (4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)chlorophosphonate:

[0388] Phenyl (4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)phosphonate (150 mg, 0.308 mmol, 1.0 equiv) was added to dichloromethane (2 mL), followed by oxalyl chloride (391 mg, 3.08 mmol, 10.0 equiv), and finally three drops of N,N-dimethylformamide. The reaction mixture was allowed to react at room temperature for 1 hour. After quenching with methanol, the reaction was monitored by LCMS to completion. The reaction mixture was concentrated under reduced pressure to give the title compound (100 mg, yield: 64.1%) as a white solid. LCMS (ESI): [M-Cl+MeO+H] + =502.2.

[0389] Step 4: Preparation of ((4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)(phenoxy)phosphoryl)-L-alanine isopropyl ester:

[0390] Phenyl (4-((3,6-dimethoxy-9H-carbazol-9-yl)methyl)benzyl)chlorophosphonate (100 mg, 0.20 mmol, 1.0 equiv) was dissolved in dichloromethane (2 mL), followed by the addition of N,N-diisopropylethylamine (128 g, 0.99 mmol, 5.0 equiv), and finally L-alanine isopropyl ester (130 mg, 0.99 mmol, 5.0 equiv). The reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product. Reverse-phase HPLC (C18, 10 mmol / L formic acid, acetonitrile) afforded the title compound (4.99 mg, 4.15% yield) as a white solid. LCMS (ESI): [M+H] + =601.2; 1 H NMR (400MHz, CDCl3, ppm) δ7.55 (d, J = 2.2Hz, 2H), 7.32-7.27 (m, 1H), 7.26-7.21 (m, 5H), 7.13-7.01 (m,7H),5.44(s,2H),4.95-4.84(m,1H),4.01-3.86(m,7H),3.33-3.01(m,3H),1.20-1.03(m,9H).

[0391] Example 52: Preparation of (4-(4-(dimethylamino)-7,9-difluoro-2-(trifluoromethyl)-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0392] Step 1: Preparation of 4,6-difluoro-3-nitro-1H-indole-2-carboxylic acid:

[0393] Under ice-cooling, concentrated nitric acid (1 mL) was added to acetic anhydride (9 mL), followed by 4,6-difluoro-1H-indole-2-carboxylic acid (5 g, 25.4 mmol, 1 equivalent). The reaction was allowed to proceed under ice-cooling for two hours until a solid formed. After completion of the reaction, the reaction solution was filtered to obtain the title compound (5.8 g, yield: 94.4%). LCMS (ESI): [MH] - =241.2.

[0394] Step 2: Preparation of methyl 4,6-difluoro-3-nitro-1H-indole-2-carboxylate:

[0395] 4,6-Difluoro-3-nitro-1H-indole-2-carboxylic acid (2 g, 8.26 mmol, 1 equivalent) was added to methanol (50 mL), followed by the addition of thionyl chloride (2 mL, 16.8 mmol, 2.04 equivalents). The reaction was heated to 80°C and continued for 1 hour. LCMS monitoring revealed the completion of the reaction. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, neutralized with saturated aqueous sodium bicarbonate solution, and extracted three times with ethyl acetate (20 mL x 3). The mixture was concentrated under reduced pressure to obtain the title compound (600 mg, yield: 28.3%). LCMS (ESI): [MH] - =255.2.

[0396] Step 3: Preparation of 4,6-difluoro-3-nitro-1H-indole-2-carboxamide:

[0397] Methyl 4,6-difluoro-3-nitro-1H-indole-2-carboxylate (2 g, 7.81 mmol, 1 equivalent) was added to 1,4-dioxane (24 mL), followed by aqueous ammonia (24 mL, 0.68 mol, 87.7 equivalents). The reaction was stirred at 100°C for 16 hours. LCMS monitored the completion of the reaction, and the mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed three times with aqueous ammonium chloride. The organic phase was concentrated to obtain the title compound (1.4 g, yield: 74.3%). LCMS (ESI): [MH] - =240.1.

[0398] Step 4: Preparation of 3-amino-4,6-difluoro-1H-indole-2-carboxamide:

[0399] 4,6-difluoro-3-nitro-1H-indole-2-carboxamide (250 mg, 1.04 mmol, 1 equivalent) was dissolved in water (5 mL) and ethanol (5 mL), and iron powder (289 mg, 5.18 mmol, 5 equivalents) and solid ammonium chloride (554 mg, 10.4 mmol, 10 equivalents) were added. The reaction was heated to 80°C and stirred for 1 hour. LCMS monitored the reaction completion. The reaction solution was cooled and concentrated under reduced pressure. Dichloromethane was added and sonicated for 10 minutes, then filtered. The filtrate was extracted three times with dichloromethane and concentrated to give the title compound (150 mg, yield: 68.5%). LCMS (ESI): [M+H] + =212.1.

[0400] Step 5: Preparation of 7,9-difluoro-2-(trifluoromethyl)-5H-pyrimido[5,4-b]indole-4-ol:

[0401] 3-Amino-4,6-difluoro-1H-indole-2-carboxamide (400 mg, 1.89 mmol, 1 equivalent) was dissolved in dichloromethane (7 mL), and triethylamine (575 mg, 5.68 mmol, 3 equivalents) and trifluoroacetic anhydride (1.19 g, 5.68 mmol, 3 equivalents) were added. The reaction was allowed to react at room temperature for 2 hours. The reaction solution was diluted with saturated aqueous sodium bicarbonate (30 mL), and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by preparative thin-layer chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 3 / 1)) to give the title compound (200 mg, 36.6% yield) as a brown solid. LCMS (ESI): [MH] - =288.0.

[0402] Step 6: Preparation of 4-chloro-7,9-difluoro-2-(trifluoromethyl)-5H-pyrimido[5,4-b]indole:

[0403] 7,9-Difluoro-2-(trifluoromethyl)-5H-pyrimido[5,4-b]indole-4-ol (200 mg, 0.69 mmol, 1 eq) was dissolved in acetonitrile (3 mL). N,N-diisopropylethylamine (447 mg, 3.46 mmol, 5 eq) and phosphorus oxychloride (530 mg, 3.46 mmol, 5 eq) were added sequentially. The mixture was reacted at 120°C for 2 hours. After completion of the reaction, the reaction solution was diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted three times with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude title compound (100 mg, 47.0% yield) as a brown solid. LCMS (ESI): [MH] - =306.0.

[0404] Step 7: Preparation of 7,9-difluoro-N,N-dimethyl-2-(trifluoromethyl)-5H-pyrimido[5,4-b]indol-4-amine

[0405] 4-Chloro-7,9-difluoro-2-(trifluoromethyl)-5H-pyrimido[5,4-b]indole (100 mg, 0.33 mmol, 1 equivalent) was dissolved in acetonitrile (3 mL), and dimethylamine (1 mL) and N,N-diisopropylethylamine (0.5 mL) were added sequentially. Under argon protection, the reaction solution was heated to 100°C and stirred for 1 hour. LCMS monitored the reaction completion. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the title compound (50 mg, yield: 48.6%) as a yellow liquid. LCMS (ESI): [M+H] + =317.0.

[0406] Step 8: Preparation of diethyl (4-((4-(dimethylamino)-7,9-difluoro-2-(trifluoromethyl)-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate

[0407] 7,9-Difluoro-N,N-dimethyl-2-(trifluoromethyl)-5H-pyrimido[5,4-b]indol-4-amine (20 mg, 0.06 mmol, 1 eq) was dissolved in tetrahydrofuran (2 mL), and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate (24 mg, 0.06 mmol, 1 eq) and sodium hydride (15.2 mg, 0.38 mmol, 6 eq) were added. Under argon protection, the reaction solution was stirred at 25 degrees for 1 hour, and the reaction was monitored for completion by LCMS. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction, and the mixture was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the title compound (20 mg, yield: 51.6%) as a yellow liquid. LCMS (ESI): [M+H] + =613.1.

[0408] Step 9: Preparation of (4-(4-(dimethylamino)-7,9-difluoro-2-(trifluoromethyl)-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0409] Di-tert-butyl (4-(4-(dimethylamino)-7,9-difluoro-2-(trifluoromethyl)-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (61 mg, 0.1 mmol, 1 equivalent) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (49 mg, 0.5 mmol, 5 equivalents) was added. The reaction solution was stirred at room temperature for 0.5 hours under argon protection. LCMS monitored the completion of the reaction. Water (2 mL) was added to the reactants, and the aqueous phase was separated and purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (1.8 mg, 0.01 mmol, 3.64% yield) as a white solid. LCMS (ESI): [M+H] + =501.1; 1 H NMR(400MHz,CD3OD)δ7.30(d,J=6.4Hz,2H),7.07(d,J=7.6Hz,2H),7.03-7.01 (m,1H),6.67-6.62(m,1H),5.32(s,2H),3.10(s,6H),2.94(d,J=20.4Hz,2H).

[0410] Example 53: Preparation of (4-((7,9-difluoro-4-hydroxy-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0411] Step 1: Preparation of diethyl (4-((4-chloro-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate

[0412] 1-Chloro-5,7-difluoro-9H-pyrimido[3,4-b]indole (110 mg, 0.46 mmol, 1 eq) was dissolved in N,N-dimethylformamide (15 mL), and diethyl (4-(bromomethyl)benzyl)phosphonate (221 mg, 0.69 mmol, 1.5 eq) and potassium carbonate (64 mg, 0.46 mmol, 1 eq) were added. After stirring at 70°C for 1 hour, the reaction solution was quenched with saturated ammonium chloride and extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (130 mg, yield: 59.0%) as a yellow oil. LCMS (ESI): [M+H] + =480.0.

[0413] Step 2: Preparation of (4-((7,9-difluoro-4-hydroxy-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0414] Diethyl (4-((4-chloro-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (110 mg, 0.23 mmol, 1 equivalent) was dissolved in dichloromethane (5 mL), and trimethylsilyl bromide (1 ml, 6.5 mmol, 28 equivalents) was added. The reaction solution was stirred at 50°C under argon for 1 hour. The reaction solution was concentrated, and the crude product was purified by reverse phase HPLC (C18, 10 mmol / aqueous ammonia, acetonitrile) to give the title compound (50.87 mg, yield: 56.5%) as a white solid. LCMS (ESI): [M+H] + =406.1; 1 H NMR (400MHz, CD3OD) δ8.16 (s, 1H), 7.28-7.26 (m, 2H), 7.08 (d, J = 8.0Hz, 2H), 7.0 0 (d, J = 10.0 Hz, 1H), 6.65 (t, J = 8.0 Hz, 1H), 5.94 (s, 2H), 2.80 (d, J = 19.6 Hz, 2H).

[0415] Example 54: Preparation of 4-(4-chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0416] Step 1: Preparation of 7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-4-ol

[0417] 3-Amino-4,6-difluoro-1H-indole-2-carboxamide (1.5 g, 7.1 mmol, 1 equivalent) was dissolved in acetonitrile (15 mL), and hydrochloric acid (15 mL, 4 mol / L 1,4-dioxane solution) was added. The reaction was microwaved at 120°C for 1 hour. LCMS indicated that the reaction was complete. The reaction solution was diluted with ethyl acetate and neutralized with sodium bicarbonate. The solution was extracted three times with ethyl acetate (50 mL x 3) and concentrated to afford the title compound (1.3 g, yield: 77.8%). LCMS (ESI): [M+H] + =236.0.

[0418] Step 2: Preparation of 4-chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indole

[0419] 7,9-Difluoro-2-methyl-5H-pyrimido[5,4-b]indol-4-ol (200 mg, 0.85 mmol, 1 equivalent) was added to phenylphosphoryl dichloride (15 mL). The reaction system was heated to 180°C and stirred for 1 hour. The reaction solution was diluted with ethyl acetate (20 mL) and neutralized with sodium bicarbonate. The solution was extracted three times with ethyl acetate (30 mL × 3) and concentrated to obtain the title compound (150 mg, yield: 69.5%). LCMS (ESI): [M+H] + =254.0.

[0420] Step 3: Preparation of di-tert-butyl (4-chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate:

[0421] 4-Chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indole (180 mg, 0.71 mmol, 1.0 equiv) was added to N,N-dimethylformamide (3 mL), followed by di-tert-butyl (4-bromomethyl)benzylphosphonate (402 mg, 1.06 mmol, 1.5 equiv) and potassium carbonate (393 mg, 2.84 mmol, 4.0 equiv). The reaction mixture was allowed to react at 80°C for 1 hour. The reaction mixture was quenched with water (10 mL) and extracted three times with ethyl acetate (20 mL x 3). The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 1 / 1)) to afford the title compound (155 mg, 39.7% yield) as a white solid. LCMS (ESI): [M+Na] + =572.1.

[0422] Step 4: Preparation of 4-(4-chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0423] Di-tert-butyl (4-chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (50 mg, 0.09 mmol, 1.0 equiv) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL, 5.1 mmol, 56 equiv) was added. The mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to obtain the title compound (39.4 mg, yield: 71.0%) as a white solid. LCMS (ESI): [M+H] + =437.9; 1 H NMR (400MHz, DMSO-d6) δ7.56(d,J=10.0Hz,1H),7.21(t,J=8.4Hz,1H),7.08(d,J=7 .6Hz, 2H), 6.94 (d, J = 7.6Hz, 2H), 5.84 (s, 2H), 2.73 (s, 3H), 2.69 (d, J = 19.2Hz, 2H).

[0424] Example 55: Preparation of ((4-((7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)phenyl)methyl)phosphonic acid

[0425] Step 1: Preparation of 7,9-difluoro-5H-pyrimido[5,4-b]indole:

[0426] Dissolve 4-chloro-7,9-difluoro-5H-pyrimido[5,4-b]indole (800 mg, 3.34 mmol, 1 equivalent) in methanol (10 mL), add palladium on carbon (36 mg, 4.5 wt%), and stir at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture is filtered and concentrated under reduced pressure to give the title compound (300 mg, yield: 43.8%). LCMS (ESI): [M+H] + =206.1.

[0427] Step 2: Preparation of diethyl ((4-((7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)phenyl)methyl)phosphonate:

[0428] 7,9-Difluoro-5H-pyrimido[5,4-b]indole (200 mg, 0.97 mmol, 1 eq) was dissolved in N,N-dimethylformamide (15 mL), and diethyl ((4-(bromomethyl)phenyl)methyl)phosphonate (626 mg, 1.95 mmol, 2 eq) and potassium carbonate (404 mg, 2.92 mmol, 3 eq) were added. The mixture was reacted at 80°C for 1 hour, diluted with saturated ammonium chloride, and extracted three times with ethyl acetate (30 mL x 3). The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (250 mg, yield: 57.6%). LCMS (ESI): [M+H] + =446.1.

[0429] Step 3: Preparation of ((4-((7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)phenyl)methyl)phosphonic acid:

[0430] Diethyl ((4-((7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)phenyl)methyl)phosphonate (100 mg, 0.22 mmol, 1 eq) was dissolved in dichloromethane (6 mL), and trimethylsilyl bromide (2 mL, 13.06 mmol, 29.68 eq) was added, and the mixture was stirred at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by reverse phase preparative purification (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (22.23 mg, 0.06 mmol, 25.96%). LCMS (ESI): [M+H] + =390.0; 1H NMR (400MHz, D2O) δ8.81-8.73(m,2H),7.08-7.05(m,2H),6.96-6.90(m,2H),6.78-6.70(m,2H),5.41-5.13(m,2H),2.66-2.56(m,2H).

[0431] Example 56: Preparation of 4-((4,8-dichloro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0432] Step 1: Preparation of 5-chloro-3-nitro-1H-indole-2-carboxylic acid methyl ester:

[0433] At 0°C, concentrated nitric acid (3 mL) was added to acetic anhydride (27 mL), followed by the addition of methyl 5-chloro-1H-indole-2-carboxylate (20 g, 102.3 mmol, 1 equivalent). The reaction mixture was allowed to react at room temperature for two hours. The reaction mixture was filtered, the solid phase was washed with water, and then dried to obtain the title compound (20 g, yield: 81.3%). LCMS (ESI): [MH] - =239.1.

[0434] Step 2: Preparation of 5-chloro-3-nitro-1H-indole-2-carboxamide:

[0435] Methyl 5-chloro-3-nitro-1H-indole-2-carboxylate (2.8 g, 10.42 mmol, 1 equivalent) was dissolved in 1,4-dioxane (8 mL), and aqueous ammonia (8 mL, 228 mmol, 22 equivalents) was added. The mixture was microwaved at 100°C for 1 hour. Saturated aqueous ammonium chloride (20 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude title compound (2 g, yield: 80.1%) as a yellow solid. LCMS (ESI): [MH] - =238.0.

[0436] Step 3: Preparation of 3-amino-5-chloro-1H-indole-2-carboxamide:

[0437] 5-Chloro-3-nitro-1H-indole-2-carboxamide (2 g, 8.35 mmol, 1 equivalent) was dissolved in ethanol (20 mL) and water (2 mL), and iron powder (2.33 g, 41.8 mmol, 5 equivalents) and ammonium chloride (2.23 g, 41.8 mmol, 5 equivalents) were added. The reaction was stirred at 90 ° C under a hydrogen atmosphere for 16 hours. Filter, concentrate under reduced pressure, add saturated sodium bicarbonate aqueous solution (30 mL), and extract with ethyl acetate (20 mL × 3). The organic phase was collected, dried and concentrated to obtain the crude title compound (1.8 g, crude yield: 90%) as a brown solid. LCMS (ESI): [M+H] + =210.1.

[0438] Step 4: Preparation of 8-chloro-5H-pyrimido[5,4-b]indol-4-ol:

[0439] 3-Amino-5-chloro-1H-indole-2-carboxamide (500 mg, 2.39 mmol, 1 eq) and formamidine acetate (99.95 mg, 0.96 mmol, 2 eq) were dissolved in anhydrous ethanol (3 mL) and the reaction mixture was refluxed for 16 hours. The reaction mixture was cooled to room temperature and filtered to obtain the title compound (300 mg, 1.37 mmol, 57.27%) as a gray solid. LCMS (ESI): [M+H] + =220.0.

[0440] Step 5: Preparation of 4,8-dichloro-5H-pyrimido[5,4-b]indole:

[0441] 8-Chloro-5H-pyrimido[5,4-b]indol-4-ol (400 mg, 1.28 mmol, 1.0 equiv) was added to phenylphosphonic dichloride (4 mL) and reacted at 180°C for 1 hour. The reaction solution was quenched with water (10 mL) and extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel was added and spin-dried. The product was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 3 / 1)) to obtain the title compound (150 mg, yield: 34.6%) as a white solid. LCMS (ESI): [M+H] + =238.0.

[0442] Step 6: Preparation of di-tert-butyl ((4,8-dichloro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate:

[0443] 4,8-Dichloro-5H-pyrimido[5,4-b]indole (150 mg, 0.630 mmol, 1.0 equiv) was added to N,N-dimethylformamide (2 mL), followed by di-tert-butyl ((4-bromomethyl)benzyl)phosphonate (238 mg, 0.630 mmol, 1.0 equiv) and potassium carbonate (261 mg, 1.89 mmol, 3.0 equiv). The mixture was allowed to react at 80°C for 1 hour. The reaction mixture was quenched with water (10 mL) and extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography (silica gel, petroleum ether:ethyl acetate (v / v = 3 / 1)) afforded the title compound (200 mg, 59.4% yield) as a white solid. LCMS (ESI): [M+Na] + =556.1.

[0444] Step 7: Preparation of 4-((4,8-dichloro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0445] Di-tert-butyl (4,8-dichloro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (100 mg, 0.190 mmol, 1.0 equiv) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (0.5 mL, 5.1 mmol, 56 equiv) was then added to the mixture. The reaction was stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (32.48 mg, 42.1% yield) as a white solid. LCMS (ESI): [M+H] + =422.0; 1 HNMR(400MHz,DMSO-d6)δ8.95(s,1H),8.34(s,1H),7.81-7.72(m,2H),7.11( d, J=8.4Hz, 2H), 6.98 (d, J=8.0Hz, 2H), 5.92 (s, 2H), 2.65 (d, J=20.4Hz, 2H).

[0446] Example 57: Preparation of (4-((7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0447] Step 1: Preparation of diethyl (4-((4-chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate:

[0448] 4-Chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indole (300 mg, 1.18 mmol, 1 equivalent) was dissolved in N,N-dimethylformamide (10 mL), and anhydrous potassium carbonate (490 mg, 3.54 mmol, 3 equivalents) was added. The mixture was reacted at 70°C for 2 hours. The reaction solution was diluted with saturated ammonium chloride solution and extracted three times with ethyl acetate (30 mL x 3), filtered, and concentrated to give the title compound (500 mg, yield: 85.8%). LCMS (ESI): [M+H] + =494.2.

[0449] Step 2: Preparation of diethyl (4-((7,9-difluoro-2-methyl-3,4-dihydro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate:

[0450] Diethyl (4-((4-chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (350 mg, 0.71 mmol, 1 equivalent) was dissolved in anhydrous methanol (10 mL). Palladium on carbon (200 mg, 57 wt%) was added, and the atmosphere was replaced with hydrogen three times. The reaction was allowed to proceed at room temperature for 2 hours. The reaction solution was filtered and concentrated to give the crude title compound (300 mg, yield: 91.6%). LCMS (ESI): [M+H] + =462.1.

[0451] Step 3: Preparation of diethyl (4-((7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate:

[0452] Diethyl (4-((7,9-difluoro-2-methyl-3,4-dihydro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (300 mg, 0.65 mmol, 1 eq) was dissolved in dichloromethane (5 mL), and manganese dioxide (113 mg, 1.3 mmol, 2 eq) was added. The mixture was allowed to react at room temperature for 2 hours. The reaction mixture was filtered and concentrated to give the crude title compound (200 mg, yield: 67.0%). LCMS (ESI): [M+H] + =460.0.

[0453] Step 4: Preparation of (4-((7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0454] Diethyl (4-((7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (200 mg, 0.44 mmol, 1 equivalent) was dissolved in dichloromethane (6 mL), and trimethylsilyl bromide (1 mL, 6.53 mmol, 14.8 equivalents) was added. The mixture was reacted at 50°C for 1 hour. The reaction solution was concentrated, and the crude product was purified by reverse phase HPLC (C18, 10 mmol / L aqueous ammonia, acetonitrile) to give the title compound (27.3 mg, yield: 15.9%). LCMS (ESI): [M+H] + =404.0; 1 H NMR (400MHz, D2O) δ8.69(s,1H),7.14-7.09(m,2H),6.99-6.94(m,3H),6.78-6.73(m,1H),5.33(s,2H),2.71-2.64(m,5H).

[0455] Example 58: Preparation of (4-((8-methoxy-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0456] Step 1: Preparation of (5-methoxy-2-(4-methoxybenzyl)amino)benzonitrile:

[0457] 2-Fluoro-5-methoxybenzonitrile (16 g, 0.105 mol, 1.0 equiv) was dissolved in dimethyl sulfoxide (150 mL), followed by the addition of 4-methoxybenzylamine (15.9 g, 0.116 mol, 1.2 equiv) and potassium carbonate (16.0 g, 0.116 mol, 1.2 equiv). Under argon protection, the mixture was heated to 100°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled and filtered, and the filtrate was diluted with water (300 mL). The mixture was extracted three times with ethyl acetate (300 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude title compound (22 g, 0.82 mol, 77.7% yield) as a yellow solid. LCMS (ESI) [M+H] + =269.1.

[0458] Step 2: Preparation of ethyl 3-amino-5-methoxy-1-(4-methoxybenzyl)-1H-indole-2-carboxylate:

[0459] (5-Methoxy-2-(4-methoxybenzyl)amino)benzonitrile (4 g, 0.011 mol, 1.0 equiv) and ethyl bromoacetate (14.7 g, 0.088 mol, 8.0 equiv) were dissolved in anhydrous N,N-dimethylformamide (80 mL). Potassium tert-butoxide (4.9 g, 0.044 mol, 4 equiv) was then added. The reaction mixture was stirred at room temperature for 1 hour under argon. Potassium tert-butoxide (4.9 g, 0.044 mol, 4 equiv) was then added over one hour, leaving the reaction mixture light brown. The mixture was stirred at room temperature for 16 hours. The filtrate was diluted with saturated aqueous ammonium chloride (100 mL) and extracted three times with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 6 / 1)) to afford the title compound (1.0 g, 0.0025 mol, 25.1% yield) as a yellow oily liquid. LCMS (ESI) [M+H] + =355.0.

[0460] Step 3: Preparation of ethyl 5-methoxy-1-(4-methoxybenzyl)-3-(3-(2,2,2-trichloroacetyl)ureido)-1H-indole-2-carboxylate:

[0461] Ethyl 3-amino-5-methoxy-1-(4-methoxybenzyl)-1H-indole-2-carboxylate (4.5 g, 0.013 mol, 1.0 equivalent) was dissolved in anhydrous tetrahydrofuran (40 mL). Trichloroacetyl isocyanate (2.4 g, 0.013 mol, 1 equivalent) was added, and the reaction mixture was stirred at room temperature under argon for 10 minutes. The reaction mixture was directly concentrated under reduced pressure to obtain the crude title compound (5.8 g, 0.011 mol, 82.4% yield) as a yellow solid. LCMS (ESI) [MH] - =540.2.

[0462] Step 4: Preparation of 8-methoxy-5-(4-methoxybenzyl)-5H-pyrimido[5,4-b]indole-2,4-diol:

[0463] 5-Methoxy-1-(4-methoxybenzyl)-3-(3-(2,2,2-trichloroacetyl)ureido)-1H-indole-2-carboxylic acid ethyl ester (5.8 g, 0.011 mol, 1.0 equivalent) was dissolved in methanol (60 mL), and then sodium hydroxide (2.6 g, 0.066 mol, 6 equivalents) was added. The reaction solution was heated to 90 ° C and stirred for 1 hour under argon protection. The reaction was monitored by LCMS. The reaction solution was cooled to room temperature, and the mixture was adjusted to pH 2 with 1 mol / L hydrochloric acid aqueous solution to obtain a suspension. The suspension was filtered and the solid was dried to obtain the title compound (2.0 g, 0.008 mol, yield 48.5%) as a yellow solid. LCMS (ESI) [M+H] + =352.2.

[0464] Step 5: Preparation of 2,4-dichloro-8-methoxy-5H-pyrimido[5,4-b]indole

[0465] 8-Methoxy-5-(4-methoxybenzyl)-5H-pyrimido[5,4-b]indole-2,4-diol (500 mg, 1.42 mmol, 1 equivalent) was dissolved in phenylphosphonic dichloride (10 mL). The reaction was heated to 180°C under argon and stirred for 2 hours. The reaction solution was cooled to room temperature and placed in an ice bath. Saturated aqueous sodium bicarbonate solution was slowly added dropwise to quench the reaction and adjust the pH to 6-7. The mixture was extracted three times with ethyl acetate (300 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 4 / 1)) to obtain the title compound (250 mg, yield: 65.5%) as a light yellow solid. LCMS (ESI): [M+H] + =268.0.

[0466] Step 6: Preparation of 8-methoxy-4,5-dihydro-3H-pyrimido[5,4-b]indole

[0467] 2,4-Dichloro-8-methoxy-5H-pyrimido[5,4-b]indole (100 mg, 0.37 mmol, 1 equivalent) was dissolved in methanol (2 mL). Palladium on carbon (50% by weight, 50 mg) was then added to the mixture. The mixture was purged with hydrogen three times and allowed to react at 25°C for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain the title compound (74 mg, yield: 99.4%) as a yellow solid. LCMS (ESI): [M+H] + =202.1.

[0468] Step 7: Preparation of 8-methoxy-5H-pyrimido[5,4-b]indole

[0469] 8-Methoxy-4,5-dihydro-3H-pyrimido[5,4-b]indole (74 mg, 0.37 mmol, 1 equivalent) was dissolved in dichloromethane (2 mL). Manganese dioxide (64 mg, 0.74 mmol, 2 equivalents) was then added to the mixture. The mixture was purged with nitrogen three times and allowed to react at 25°C for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain the title compound (70 mg, yield: 95.0%) as a yellow solid. LCMS (ESI): [M+H] + =200.0.

[0470] Step 8: Preparation of diethyl (4-((8-methoxy-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate

[0471] 8-Methoxy-5H-pyrimido[5,4-b]indole (70 mg, 0.35 mmol, 1 equiv) was dissolved in tetrahydrofuran (2 mL). Sodium hydride (56.4 mg, 1.41 mmol, 4.0 equiv) was then added to the mixture, and the reaction was stirred for 0.5 h. Diethyl (4-(bromomethyl)benzyl)phosphonate (169 mg, 0.53 mmol, 1.5 equiv) was then added to the mixture, and the reaction was allowed to proceed at 25°C for 2 h. The reaction solution was diluted with saturated aqueous ammonium chloride (20 mL), and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by preparative thin-layer chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 1 / 1)) to afford the title compound (90 mg, 58.5% yield) as a yellow solid. LCMS (ESI): [M+H] + =440.1.

[0472] Step 9: Preparation of (4-((8-methoxy-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0473] Diethyl (4-((8-methoxy-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (85 mg, 0.19 mmol, 1 equivalent) was dissolved in acetonitrile (1 mL) and trimethylsilyl bromide (291 mg, 1.90 mmol, 10 equivalents) was added. The reaction solution was heated to 50°C and stirred for 2 hours. After the reaction was completed, water (1 mL) was added to the reaction solution, and the aqueous phase was separated and purified using reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to obtain the title compound (35 mg, yield: 51.8%) as a yellow solid. LCMS (ESI): [M+H] + =384.0; 1 H NMR (400MHz, CD3OD) δ9.09 (s, 1H), 8.98 (s, 1H), 7.85 (d, J = 2.4Hz, 1H), 7.66 (d, J = 11.2Hz, 1H), 7.37 (dd, J = 8.8, 2.4Hz, 1H), 7.28 (d, J = 8.0, 2.0Hz, 2H), 7.09 (d, J = 8.0Hz, 2H), 5.65 (s, 2H), 3.93 (s, 3H), 2.88 (d, J = 20.4Hz, 2H).

[0474] Example 59: Preparation of (4-((4-(dimethylamino)-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0475] Step 1: Preparation of 7,9-difluoro-N,N,2-trimethyl-5H-pyrimido[5,4-b]indol-4-amine:

[0476] 4-Chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indole (400 mg, 1.6 mmol, 1.0 equiv) was added to ultra-dry acetonitrile (5 mL), and N,N-diisopropylethylamine (611 mg, 4.7 mmol, 3.0 equiv) and dimethylamine (142 mg, 3.2 mmol, 2.0 equiv) were slowly added. The reaction mixture was continued at 90°C for 1 hour. The reaction mixture was quenched with water (15 mL) and extracted three times with ethyl acetate (25 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, dichloromethane:methanol (V / V = 19 / 1)) to give the title compound (195 mg, yield: 46.0%) as a yellow solid. LCMS (ESI): [M+H] + =263.1.

[0477] Step 2: Preparation of di-tert-butyl (4-((4-(dimethylamino)-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate:

[0478] 7,9-Difluoro-N,N,2-trimethyl-5H-pyrimido[5,4-b]indol-4-amine (195 mg, 0.74 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (3 mL). Sodium hydride (35.6 mg, 0.89 mmol, 1.2 equiv) was added at 0°C and the mixture was allowed to warm to room temperature for 30 minutes. Di-tert-butyl (4-(bromomethyl)benzyl)phosphonate (561 mg, 1.5 mmol, 2.0 equiv) was added and stirred at room temperature for 2 hours. The reaction was quenched with water (15 mL) and extracted three times with ethyl acetate (25 mL x 3). The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (v / v = 1 / 1)) to afford the title compound (144 mg, 37.0% yield) as a white solid. LCMS(ESI):[M+H] + =559.4.

[0479] Step 3: Preparation of (4-((4-(dimethylamino)-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0480] Di-tert-butyl (4-((4-(dimethylamino)-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (250 mg, 0.45 mmol, 1.0 equiv) was dissolved in methanol (3 mL). A solution of hydrogen chloride in dioxane (0.33 mL, 4 mol / L) was added and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by reverse-phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (57.71 mg, 28.7% yield) as a white solid. LCMS (ESI): [M+H] + =447.2; 1 H NMR(400MHz,DMSO-d6)δ7.43(d,J=9.6Hz,1H),7.01-6.95(m,3H),6.79(d,J =7.6Hz,2H),5.50(s,2H),2.96(s,6H),2.59(s,3H),2.53(d,J=12.4Hz,2H).

[0481] Example 60: Preparation of (4-((4-(dimethylamino)-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0482] Step 1: Preparation of 7,9-difluoro-N,N-dimethyl-5H-pyrimido[5,4-b]indol-4-amine:

[0483] 4-Chloro-7,9-difluoro-5H-pyrimido[5,4-b]indole (300 mg, 1.3 mmol, 1.0 equiv) was added to ultra-dry acetonitrile (5 mL), and N,N-diisopropylethylamine (485 mg, 3.8 mmol, 3.0 equiv) and dimethylamine (113 mg, 2.5 mmol, 2.0 equiv) were slowly added. The reaction was continued at 90°C for 16 hours. The reaction solution was quenched with water (15 mL) and extracted three times with ethyl acetate (25 mL x 3). The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and added to silica gel for spin drying. The crude product was separated and purified by flash chromatography (silica gel, dichloromethane:methanol (V / V = 10 / 1)) to give the title compound (300 mg, yield: 96.7%) as a yellow solid. LCMS (ESI): [M+H] + =249.1.

[0484] Step 2: Preparation of di-tert-butyl (4-((4-(dimethylamino)-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate:

[0485] 7,9-Difluoro-N,N-dimethyl-5H-pyrimido[5,4-b]indol-4-amine (300 mg, 1.2 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (5 mL). Sodium hydride (96 mg, 2.4 mmol, 2.0 equiv) was then added at 0°C and allowed to react for 30 minutes. Di-tert-butyl (4-(bromomethyl)benzyl)phosphonate (684 mg, 1.8 mmol, 2.0 equiv) was added and stirred at room temperature for 2 hours. The reaction was quenched with water (15 mL) and extracted three times with ethyl acetate (25 mL x 3). The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography (silica gel, dichloromethane:methanol (v / v = 10 / 1)) to afford the title compound (300 mg, 45.5% yield) as a white solid. LCMS(ESI):[M+H] + =545.5.

[0486] Step 3: Preparation of (4-((4-(dimethylamino)-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0487] Di-tert-butyl (4-((4-(dimethylamino)-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (200 mg, 0.4 mmol, 1.0 equiv) was dissolved in methanol (3 mL). To this mixture was added a solution of hydrogen chloride in dioxane (0.3 mL, 4 mol / L), and the mixture was stirred at room temperature for 16 hours. The reaction solution was quenched with methanol and concentrated under reduced pressure to obtain a white crude product. The title compound (86.14 mg, 53.9% yield) was obtained by reverse-phase HPLC (C18, 10 mmol / L ammonia, acetonitrile) as a white solid. LCMS (ESI): [M+H] + =433.2; 1 H NMR (400MHz, DMSO-d6) δ8.62(s,1H),7.57(dd,J=9.8,1.4Hz,1H),7.10(td,J=10.2,1.5Hz,1H),7. 04(dd,J=8.0,1.7Hz,2H),6.88(d,J=7.9Hz,2H),5.64(s,2H),3.03(s,6H),2.78(d,J=21.4Hz,2H); 19 F NMR(376.5MHz, DMSO-d6)δ-107.89,-112.77.

[0488] Example 61: Preparation of (4-((7,9-difluoro-4-methoxy-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0489] Step 1: Preparation of 7,9-difluoro-4-methoxy-5H-pyrimido[5,4-b]indole:

[0490] 4-Chloro-7,9-difluoro-5H-pyrimido[5,4-b]indole (500 mg, 2.1 mmol, 1.0 equivalent) was added to methanol (5 mL), and sodium methoxide (226 mg, 4.2 mmol, 2.0 equivalent) was slowly added. The reaction was continued at 70°C for 1 hour. The reaction solution was cooled, quenched with water (15 mL), and extracted three times with ethyl acetate (25 mL × 3). The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, added to silica gel and spin-dried. The crude product was separated and purified by flash chromatography (silica gel, dichloromethane: methanol (V / V = 10 / 1)) to give the title compound (380 mg, yield: 77.4%) as a yellow solid. LCMS (ESI): [M+H] + =236.0.

[0491] Step 2: Preparation of di-tert-butyl (4-((7,9-difluoro-4-methoxy-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate:

[0492] 7,9-Difluoro-4-methoxy-5H-pyrimido[5,4-b]indole (380 mg, 1.6 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (5 mL). Sodium hydride (128 mg, 3.2 mmol, 2.0 equiv) was added at 0°C. The mixture was reacted at 0°C for 30 minutes. Di-tert-butyl (4-(bromomethyl)benzyl)phosphonate (915 mg, 2.4 mmol, 1.5 equiv) was added and stirred at room temperature for 2 hours. The reaction solution was quenched with water (15 mL) and extracted three times with ethyl acetate (25 mL x 3). The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and added to silica gel for spin drying. Flash chromatography (silica gel, dichloromethane:methanol (V / V = 10 / 1)) gave the title compound (160 mg, 18.6% yield) as a white solid. LCMS (ESI): [M+H] + =532.2.

[0493] Step 3: Preparation of (4-((7,9-difluoro-4-methoxy-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0494] Di-tert-butyl (4-((7,9-difluoro-4-methoxy-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (160 mg, 0.3 mmol, 1.0 equiv) was dissolved in methanol (3 mL). A solution of hydrogen chloride in dioxane (1.5 mL, 1 mol / L) was added to the mixture, and the reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Reverse-phase HPLC (C18, 10 mmol / L aqueous ammonia, acetonitrile) yielded the title compound (91.9 mg, 73.1% yield) as a white solid. LCMS (ESI): [M+H] + =420.0; 1 H NMR (400MHz, DMSO-d6, ppm) δ8.64 (s, 1H), 7.49 (d, J = 9.2Hz, 1H), 7.09-7.01 (m, 5H), 5.66 (s, 2H), 4.10 (s, 3H), 2.61 (d, J = 20.8Hz, 2H).

[0495] Example 62: Preparation of ((6-((4-chloro-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonic acid

[0496] Step 1: Preparation of diethyl ((6-((4-chloro-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonate:

[0497] 4-Chloro-7,9-difluoro-5H-pyrimido[5,4-b]indole (500 mg, 2.1 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (5 mL). Sodium hydride (168 mg, 4.2 mmol, 2.0 equiv) was added at 0°C and allowed to react for 30 minutes. Diethyl ((6-(chloromethyl)pyridin-3-yl)methyl)phosphonate (580 mg, 2.1 mmol, 1.0 equiv) was added and stirred at room temperature for 2 hours. The reaction was quenched with water (15 mL) and extracted three times with ethyl acetate (25 mL x 3). The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then added to silica gel for spin drying. Flash chromatography (silica gel, dichloromethane:methanol (v / v = 10 / 1)) afforded the title compound (600 mg, 59.7% yield) as a yellow solid. LCMS(ESI):[M+H] + =480.9.

[0498] Step 2: Preparation of ((6-((4-chloro-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonic acid:

[0499] Diethyl ((6-((4-chloro-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonate (20 mg, 0.04 mmol, 1.0 equiv) was dissolved in dichloromethane (2 mL), and trimethylsilyl bromide (96 mg, 0.63 mmol, 15 equiv) and bis(trimethylsilyl)amine (101 mg, 0.63 mmol, 15 equiv) were added and stirred at 50 ° C for 1 hour. The reaction solution was quenched with methanol and concentrated under reduced pressure to give a brown oily crude product. The crude product was prepared by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (12.72 mg, yield: 72.0%) as a white solid. LCMS (ESI): [M+H] + =425.0; 1 H NMR(400MHz,DMSO-d6,ppm)δ8.88(s, 1H), 8.10 (s, 1H), 7.62 (d, J = 8.4Hz, 1H), 7.54 (d, J = 8.0Hz, 1H), 7.23 (t, J = 9.2Hz, 1H), 7.13 (d, J = 8.0Hz, 1H), 5.96 (s, 2H), 2.61 (d, J = 20.8Hz, 2H).

[0500] Example 63: Preparation of ((6-((4-chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonic acid

[0501] Step 1: Diethyl ((6-((4-chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonate:

[0502] 4-Chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indole (457 mg, 1.8 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (5 mL). Diethyl ((6-(chloromethyl)pyridin-3-yl)methyl)phosphonate (500 mg, 1.8 mmol, 1.0 equiv) and potassium carbonate (748 mg, 5.4 mmol, 3.0 equiv) were added sequentially. The mixture was reacted at 80°C for 1 hour. The reaction solution was cooled to room temperature, quenched with water (15 mL), and extracted three times with ethyl acetate (25 mL x 3). The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and added to silica gel for spin drying. The crude product was purified by flash chromatography (silica gel, dichloromethane:methanol (v / v = 95 / 5)) to afford the title compound (200 mg, 22.8% yield) as a white solid. LCMS(ESI):[M+H] + =495.1.

[0503] Step 2: Preparation of ((6-((4-chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonic acid:

[0504] Diethyl ((6-((4-chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonate (60 mg, 0.12 mmol, 1.0 equiv) was dissolved in dichloromethane (2 mL), and trimethylsilyl bromide (278 mg, 1.8 mmol, 15 equiv) and bis(trimethylsilyl)amine (294 mg, 1.8 mmol, 15 equiv) were added sequentially. The reaction mixture was stirred at 50 ° C for 1 hour. The reaction solution was quenched with methanol and concentrated under reduced pressure to obtain a brown oily crude product. The title compound (39.29 mg, yield: 74.6%) was obtained by reverse phase HPLC preparation (C18, 10 mmol / L ammonia water, acetonitrile) as a white solid. LCMS (ESI): [M+H] + =439.0; 1 H NMR (400MHz, DMSO-d6, ppm) δ8.11 (s, 1H), 7.63-7.46 (m, 2H), 7.19 (t, J = 10.0Hz ,1H),7.11(d,J=8.0Hz,1H),5.91(s,2H),2.72(s,3H),2.68(d,J=20.8Hz,2H).

[0505] Example 64: Preparation of ((6-((7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonic acid

[0506] Step 1: Preparation of diethyl ((6-((7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonate:

[0507] Diethyl ((6-((4-chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonate (130 mg, 0.26 mmol, 1.0 equiv) was dissolved in ethanol (2 mL), palladium on carbon (100 mg, 76 wt%) and potassium carbonate (182 mg, 1.3 mmol, 5.0 equiv) were added, and the mixture was replaced with hydrogen three times and stirred under a hydrogen atmosphere for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to give the title compound (110 mg, yield: 91.9%) as a white solid. LCMS (ESI): [M+H] + =461.3.

[0508] Step 2: Preparation of ((6-((7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonic acid:

[0509] Diethyl ((6-((7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonate (120 mg, 0.26 mmol, 1.0 equiv) was dissolved in dichloromethane (2 mL), and trimethylsilyl bromide (600 mg, 3.9 mmol, 15 equiv) was added and stirred at 50° C. for 1 hour. The reaction solution was quenched with methanol and concentrated under reduced pressure to obtain a brown oily crude product. The title compound (36.29 mg, yield: 34.5%) was obtained by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) as a white solid. LCMS (ESI): [M+H] + =405.0; 1 H NMR (400MHz, DMSO-d6, ppm) δ9.13 (s, 1H), 8.16 (s, 1H), 7.56 (dd, J = 10.0, 2.0Hz, 2H), 7.19 ( d,J=8.0Hz,1H),7.09(t,J=10.0Hz,1H),5.66(s,2H),2.74(s,3H),2.53(d,J=20.8Hz,2H).

[0510] Example 65: Preparation of ((6-((7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonic acid

[0511] Step 1: Preparation of diethyl ((6-((7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonate:

[0512] Diethyl ((6-((4-chloro-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonate (200 mg, 0.42 mmol, 1.0 equiv) was dissolved in ethanol (3 mL). Palladium on carbon (100 mg, 50 wt%) and potassium carbonate (288 mg, 2.1 mmol, 5.0 equiv) were then added to the solution. The atmosphere was replaced with hydrogen three times and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to give the title compound (150 mg, yield: 81.1%) as a colorless oil. LCMS (ESI): [M+H] + =447.1.

[0513] Step 2: Preparation of ((6-((7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonic acid:

[0514] Diethyl ((6-((7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)pyridin-3-yl)methyl)phosphonate (150 mg, 0.34 mmol, 1.0 equiv) was dissolved in dichloromethane (2 mL), and trimethylsilyl bromide (772 mg, 5.1 mmol, 15 equiv) was added. The mixture was stirred at 50 ° C for 1 hour. The reaction solution was quenched with methanol and concentrated under reduced pressure to obtain a brown oily crude product. The crude product was prepared by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (56.91 mg, yield: 42.9%) as a white solid. LCMS (ESI): [M+H] + =391.0; 1 H NMR (400MHz, DMSO-d6, ppm) δ9.26 (s, 1H), 9.07 (s, 1H), 8.15 (s, 1H), 7.60 (dd, J = 10.0, 1.6Hz, 1H), 7 .52(d,J=8.0Hz,1H),7.27(d,J=8.0Hz,1H),7.17-7.12(m,1H),5.72(s,2H),2.58(d,J=20.8Hz,2H);

[0515] 19F NMR (376.5MHz, DMSO-d6, ppm) δ-105.51,-111.38.

[0516] Example 66: Preparation of (4-((7,9-difluoro-4-hydroxy-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0517] Step 1: Preparation of diethyl (4-((4-chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate

[0518] 4-Chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indole (180 mg, 0.7 mmol, 1 equivalent) was dissolved in N,N-dimethylformamide (5 mL). Diethyl (4-(bromomethyl)benzyl)phosphonate (456 mg, 1.4 mmol, 2 equivalents) and potassium carbonate (196 mg, 1.4 mmol, 2 equivalents) were added. After stirring at 70°C under argon for 1 hour, the reaction mixture was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (145 mg, yield: 41.4%) as a yellow liquid. LCMS (ESI): [M+H] + =494.0.

[0519] Step 2: Preparation of (4-((7,9-difluoro-4-hydroxy-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0520] Diethyl (4-((4-chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (145 mg, 0.29 mmol, 1 equivalent) was dissolved in dichloromethane (5 mL), and trimethylsilyl bromide (1 mL, 6.4 mmol, 22 equivalents) was added. The mixture was stirred at 50°C under argon for 1 hour. The reaction solution was purified by reverse phase preparative purification (C18, 10 mmol / aqueous ammonia, acetonitrile) to give the title compound (4.38 mg, yield: 15.9%) as a white solid. LCMS (ESI): [M+H] + =420.1; 1H NMR (400MHz, CD3OD) δ7.27(d,J=6.4Hz,2H),7.06(d,J=7.6Hz,2H),6.93(d,J=9.6 Hz, 1H), 6.61 (t, J = 10.4Hz, 1H), 5.91 (s, 2H), 2.80 (d, J = 19.6Hz, 2H), 2.47 (s, 3H).

[0521] Example 67: Preparation of (4-((4-chloro-7,8-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0522] Step 1: Preparation of methyl 5,6-difluoro-1H-indole-2-carboxylate

[0523] Dissolve 5,6-difluoro-1H-indole-2-carboxylic acid (10 g, 40.31 mmol, 1 equivalent) in methanol (100 mL), and add thionyl chloride (9.59 g, 80.62 mmol, 2 equivalents) dropwise. Heat the reaction to 60°C and continue the reaction for 3 hours. The reaction mixture is concentrated, neutralized with saturated sodium bicarbonate aqueous solution, filtered, washed with water, and dried under vacuum to obtain the title compound (6.0 g, 70.49% yield). 1 H NMR (400MHz, DMSO-d6) δ12.14(s,1H),7.68(dd,J=11.1,8.1Hz,1H),7.36(ddd,J=11.0,7.0,0.9Hz,1H),7.16(dd,J=2.2,0.9Hz,1H),3.88(s,3H).

[0524] Step 2: Preparation of methyl 5,6-difluoro-3-nitro-1H-indole-2-carboxylate

[0525] Under ice-cooling, concentrated nitric acid (8 mL) was added dropwise to acetic anhydride (72 mL). Stirring was continued for 15 minutes after the addition was complete. Methyl 5,6-difluoro-1H-indole-2-carboxylate (5.1 g, 24.15 mmol, 1 equivalent) was dissolved in acetic anhydride (10 mL). The prepared nitric acid / acetic anhydride solution was added dropwise under ice-cooling. Stirring was continued at this temperature for 3 hours. The reaction mixture was poured into ice water to precipitate a large amount of solid. The solid was filtered, washed with water, and dried to obtain the crude title compound (6.4 g, 100% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ13.61 (s, 1H), 7.95 (dd, J = 10.7, 7.8 Hz, 1H), 7.66 (dd, J = 10.3, 6.9 Hz, 1H), 3.98 (s, 3H).

[0526] Step 3: Preparation of 5,6-difluoro-3-nitro-1H-indole-2-carboxamide:

[0527] Methyl 5,6-difluoro-3-nitro-1H-indole-2-carboxylate (6.4 g, 24.98 mmol, 1 equivalent) was dissolved in a mixture of aqueous ammonia and dioxane (60.0 mL / 60.0 mL) and the reaction was stirred at 115°C for 3 hours. The reaction mixture was concentrated under reduced pressure and dried to obtain the title compound (6.0 g, 99.6% yield). 1 H NMR (400MHz, DMSO-d6) δ13.32(s,1H),8.33(s,1H),8.06(s,1H),7.94(dd,J=11.0,8.0Hz,1H),7.55(dd,J=10.5,6.9Hz,1H).

[0528] Step 4: Preparation of 3-amino-5,6-difluoro-1H-indole-2-carboxamide

[0529] 5,6-Difluoro-3-nitro-1H-indole-2-carboxamide (6.0 g, 24.88 mmol, 1 equivalent) was dissolved in methanol (120 mL). Pd / C (600 mg, 10 wt%) was added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 16 hours. The reaction mixture was diluted with methanol (500 mL) and filtered through silica gel. The filtrate was dried and vacuum-dried to give the crude title compound (5.5 g, yield >100%). LCMS (ESI): [M+H] + =212.1.

[0530] Step 5: Preparation of 7,8-difluoro-5H-pyrimido[5,4-b]indol-4-ol:

[0531] 3-Amino-5,6-difluoro-1H-indole-2-carboxamide (2 g, 9.47 mmol, 1 equivalent) was dissolved in ethanol (20 mL) and formamidine acetate (2 g, 18.9 mmol, 2 equivalents) was added. The reaction mixture was reacted at 90°C for 2 hours. The reaction solution was cooled to room temperature and filtered. The filter cake was rinsed with ethanol and the solid was collected and dried to obtain the title compound (1.6 g, 76.4% yield). LCMS (ESI) [M+H] +=222.

[0532] Step 6: Preparation of 4-chloro-7,8-difluoro-5H-pyrimido[5,4-b]indole

[0533] 7,8-Difluoro-5H-pyrimido[5,4-b]indol-4-ol (1.6 g, 7.23 mmol, 1 equivalent) was added to phenylphosphoryl dichloride (20 mL). The reaction system was heated to 180°C and stirred for 4 hours. The reaction solution was diluted with ethyl acetate (20 mL) and neutralized with sodium bicarbonate. The mixture was extracted three times with ethyl acetate (30 mL × 3) and concentrated to obtain the title compound (300 mg, yield: 62.7%). LCMS (ESI): [M+H] + =240.0.

[0534] Step 7: Preparation of di-tert-(4-((4-chloro-7,8-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate:

[0535] 4-Chloro-7,8-difluoro-5H-pyrimido[5,4-b]indole (100 mg, 0.42 mmol, 1 equivalent) was dissolved in acetonitrile (10 mL), and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate (315 mg, 0.83 mmol, 2 equivalents) and N,N-diisopropylethylamine (1.50 mL, 11.61 mmol, 27.64 equivalents) were added. The mixture was stirred at 100°C for 2 hours. The reaction solution was quenched with saturated ammonium chloride and extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (200 mg, yield: 88.9%). LCMS (ESI): [M+H] + =424.0.

[0536] Step 8: Preparation of (4-((4-chloro-7,8-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0537] Di-tert-(4-((4-chloro-7,8-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (200 mg, 0.37 mmol, 1 equivalent) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2.00 mL, 17.54 mmol, 47.41 equivalent) was added. The mixture was reacted at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by reverse phase HPLC (C18, 10 mmol / L aqueous ammonia, acetonitrile) to give the title compound (38 mg, yield: 24.3%) as a white solid. LCMS (ESI): [M+H] + =424.0; 1 H NMR(400MHz,CD3OD)δ8.83(s,1H),8.24(t,J=8.0Hz,1H),7.66(dd,J=12.0,8.0Hz,1H), 7.22 (dd, J=8.0, 2.4Hz, 2H), 7.02 (d, J=8.0Hz, 2H), 6.01 (s, 2H), 3.04 (d, J=20.4Hz, 2H).

[0538] Example 68: Preparation of (4-((4-chloro-7,8-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0539] Step 1: Preparation of 7,8-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-4-ol:

[0540] Dissolve 3-amino-5,6-difluoro-1H-indole-2-carboxamide (500 mg, 2.37 mmol, 1 equivalent) in acetonitrile (5 mL). Add hydrogen chloride (2.5 mL, 4 mol / L dioxane solution). Stir and heat to 120°C for 2 hours. Filter the reaction mixture and dry the solid to obtain the title compound (500 mg, yield: 89.8%). LCMS (ESI): [M+H] + =236.1.

[0541] Step 2: Preparation of 4-chloro-7,8-difluoro-2-methyl-5H-pyrimido[5,4-b]indole:

[0542] Dissolve 7,8-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-4-ol (500 mg, 2.26 mmol, 1 equivalent) in phenylphosphoryl dichloride (10 mL). React at 180°C for 1 hour. Cool the reaction solution, neutralize with saturated sodium bicarbonate, and extract three times with ethyl acetate (20 mL x 3). Combine the organic phases. Dry the organic phase over anhydrous sodium sulfate and concentrate in vacuo to obtain the title compound (500 mg, yield: 92.3%). LCMS (ESI): [M+H] + =253.9.

[0543] Step 3: Preparation of di-tert-(4-((4-chloro-7,8-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate:

[0544] 4-Chloro-7,8-difluoro-2-methyl-5H-pyrimido[5,4-b]indole (200 mg, 0.79 mmol, 1 equivalent) was dissolved in N,N-dimethylformamide (10 mL), and di-tert-butyl (4-(bromomethyl)benzyl)phosphonate (892 mg, 2.37 mmol, 3 equivalents) and potassium carbonate (327 mg, 2.37 mmol, 3 equivalents) were added. The reaction mixture was stirred at 70°C for 1 hour. The reaction solution was diluted with saturated ammonium chloride and extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title compound (200 mg, yield: 46.1%).

[0545] LCMS(ESI):[M+H] + =438.0.

[0546] Step 4: Preparation of (4-((4-chloro-7,8-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0547] Di-tert-butyl (4-((4-chloro-7,8-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (100 mg, 0.18 mmol, 1 equivalent) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL, 4.38 mmol, 24.4 equivalents) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with methanol, and the crude product was purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (15 mg, yield: 16.7%). LCMS (ESI): [M+H] + =436.0; 1H NMR(400MHz,CD3OD)δ8.22-8.18(m,1H),7.62(dd,J=11.2,6.4Hz,1H),7.26-7.24 (m,2H),6.96(d,J=8.0Hz,2H),5.92(s,2H),2.92(d,J=21.0Hz,2H),2.80(s,3H).

[0548] Example 69: Preparation of (4-((7,8-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0549] Step 1: Preparation of di-tert-butyl (4-((7,8-difluoro-3,4-dihydro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate:

[0550] Di-tert-butyl (4-((4-chloro-7,8-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (200 mg, 0.37 mmol, 1 equivalent) was dissolved in anhydrous methanol (20 mL). Palladium on carbon (40 mg, 20% (weight percent)) was added, and the atmosphere was replaced with hydrogen three times. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered to remove the palladium on carbon, and the filtrate was concentrated in vacuo to obtain the title compound (150 mg, yield: 81.1%). LCMS (ESI): [M+H] + =504.2.

[0551] Step 2: Preparation of di-tert-butyl (4-((7,8-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate:

[0552] Di-tert-butyl (4-((7,8-difluoro-3,4-dihydro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (150 mg, 0.28 mmol, 1 eq) was dissolved in dichloromethane (20 mL), and manganese dioxide (97 mg, 1.12 mmol, 4 eq) was added. The reaction mixture was stirred at room temperature for 2 hours. The manganese dioxide solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (120 mg, 0.24 mmol, 85.49%). LCMS (ESI): [M+H] + =502.2.

[0553] Step 3: Preparation of (4-((7,8-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0554] Dissolve di-tert-butyl (4-((7,8-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (120 mg, 0.24 mmol, 1 eq) in dichloromethane (2 mL), add trifluoroacetic acid (2 mL, 17.5 mmol, 73 eq), and react at 50°C for 2 hours. The reaction solution was concentrated and purified by reverse-phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to afford the title compound (27 mg, 28.9% yield) as a white solid. LCMS (ESI): [M+H] + =390.0; 1 H NMR(400MHz,CD3OD)δ9.14(s,1H),9.04(s,1H),8.26-8.19(m,1H),7.76-7.67(m ,1H),7.30-7.27(m,2H),7.14-7.07(m,2H),5.67(s,2H),2.90(d,J=20.9Hz,2H).

[0555] Example 70: Preparation of (4-((7,9-difluoro-4-methoxy-2-methyl-5-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0556] Step 1: Preparation of 7,9-difluoro-4-methoxy-2-methyl-5-pyrimido[5,4-b]indole:

[0557] 4-Chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indole (300 mg, 1.18 mmol, 1 equivalent) was dissolved in anhydrous methanol (5 mL), and sodium methoxide (96 mg, 1.77 mmol, 1.5 equivalents) was added. The reaction was allowed to react at 70°C under argon for 1 hour. The reaction solution was quenched with saturated ammonium chloride (10 mL) and extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (200 mg, yield: 67.9%) as a yellow solid. LCMS (ESI): [M+H] + =250.0.

[0558] Step 2: Preparation of diethyl (4-((7,9-difluoro-4-methoxy-2-methyl-5-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate:

[0559] 7,9-difluoro-4-methoxy-2-methyl-5-pyrimido[5,4-b]indole (100 mg, 0.4 mmol, 1 equivalent) was dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (111 mg, 0.8 mmol, 2 equivalents) and diethyl (4-(bromomethyl)benzyl)phosphonate (515 mg, 1.61 mmol, 4 equivalents) were added. The reaction was allowed to react at 70°C for 2 hours under argon protection. The reaction solution was quenched with saturated ammonium chloride (10 mL) and extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title compound (180 mg, yield: 91.7%) as a yellow solid. LCMS (ESI): [M+H] + =490.2.

[0560] Step 3: Preparation of (4-((7,9-difluoro-4-methoxy-2-methyl-5-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0561] Diethyl (4-((7,9-difluoro-4-methoxy-2-methyl-5-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (100 mg, 0.2 mmol, 1 equiv) was dissolved in dichloromethane (2 mL), and HMDS (hexamethyldisilazane) (989 mg, 6.13 mmol, 30 equiv) and trimethylsilyl bromide (1 mL) were added. The mixture was stirred at 50°C for 16 hours. The reaction solution was concentrated, and the crude product was purified by reverse phase HPLC (C18, 10 mmol / L aqueous ammonia, acetonitrile) to give the title compound (3.26 mg, 3.8% yield) as a white solid. LCMS (ESI): [MH] - =432.1; 1 H NMR (400MHz, CD3OD) δ7.30 (dd, J=8.4, 1.6Hz, 2H), 7.22 (dd, J=9.6, 1.6Hz, 1H), 7.01 (d, J=8.0H z, 2H), 6.84 (t, J = 10.4Hz, 1H), 5.71 (s, 2H), 4.18 (s, 3H), 2.81 (d, J = 19.6Hz, 2H), 2.72 (s, 3H).

[0562] Example 71: Preparation of (4-((7,8-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0563] Step 1: Preparation of diethyl (4-((7,8-difluoro-2-methyl-3,4-dihydro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate:

[0564] Dissolve diethyl (4-((4-chloro-7,8-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (300 mg, 0.61 mmol, 1 equivalent) in methanol (10 mL). Add palladium on carbon (130 mg, 43% (weight percent)) and stir at room temperature under hydrogen for 1 hour. Filter and concentrate the organic phase to obtain the title compound (200 mg, 71.1% yield). LCMS (ESI): [M+H] + =462.3.

[0565] Step 2: Preparation of diethyl (4-((7,8-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate:

[0566] Diethyl (4-((7,8-difluoro-2-methyl-3,4-dihydro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (200 mg, 0.43 mmol, 1 eq) was dissolved in dichloromethane (5 mL), and manganese dioxide (75 mg, 0.87 mmol, 2 eq) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, washed with dichloromethane, and the organic phase was concentrated to give the title compound (150 mg, yield: 75.9%). LCMS (ESI): [M+H] + =460.1.

[0567] Step 3: Preparation of (4-((7,8-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0568] Diethyl (4-((7,8-difluoro-2-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (90 mg, 0.2 mmol, 1 equivalent) was dissolved in dichloromethane (2 mL), followed by the addition of trimethylsilyl bromide (0.15 mL, 0.98 mmol, 5 equivalents). The reaction mixture was heated to 50°C and stirred for 1 hour. The reaction solution was quenched with methanol, and the crude product was purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (6 mg, yield: 7.6%). LCMS (ESI): [M+H] + =404.0; 1H NMR(400MHz,CD3OD)δ9.01(s,1H),8.20(dd,J=10.0,8.0Hz,1H),7.67(dd,J=10.0,8.0Hz,1H),7.2 7 (dd, J = 8.0, 2.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 5.63 (s, 2H), 2.92 (d, J = 20.8 Hz, 2H), 2.84 (s, 3H).

[0569] Example 72: Preparation of (4-((7,9-difluoro-2,4-dimethyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0570] Step 1: Preparation of 7,9-difluoro-2,4-dimethyl-5H-pyrimido[5,4-b]indole

[0571] 4-Chloro-7,9-difluoro-2-methyl-5H-pyrimido[5,4-b]indole (200 mg, 0.79 mmol, 1 equivalent) and methylboric acid (47 mg, 0.79 mmol, 1 equivalent) were dissolved in 1,4-dioxane (3 mL), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (58 mg, 0.08 mmol, 0.1 equivalent) and cesium carbonate (771 mg, 2.37 mmol, 3 equivalents) were added. The reaction solution was heated to 120°C and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (80 mL), and the mixture was extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by preparative thin-layer plate chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 1 / 1)) to give the title compound (180 mg, yield: 97.9%) as a brown solid. LCMS (ESI): [M+H] + =234.0.

[0572] Step 2: Preparation of diethyl (4-((7,9-difluoro-2,4-dimethyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate

[0573] 7,9-Difluoro-2,4-dimethyl-5H-pyrimido[5,4-b]indole (150 mg, 0.64 mmol, 1 eq) was dissolved in tetrahydrofuran (2 mL), and sodium hydride (77 mg, 1.92 mmol, 3 eq) was added. The mixture was stirred for 0.5 h, and then diethyl (4-(bromomethyl)benzyl)phosphonate (308 mg, 0.96 mmol, 1.5 eq) was added to the mixture, and the reaction was stirred for 2 h. The reaction solution was diluted with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative thin-layer chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 1 / 1)) to afford the title compound (100 mg, 33.0% yield) as a brown solid. LCMS (ESI): [M+H] + =474.1.

[0574] Step 3: Preparation of (4-((7,9-difluoro-2,4-dimethyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0575] Diethyl (4-((7,9-difluoro-2,4-dimethyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (100 mg, 0.21 mmol, 1 equivalent) was dissolved in dichloromethane (2 mL). Trimethylsilyl bromide (647 mg, 4.22 mmol, 20 equivalents) was then added to the mixture. The reaction solution was heated to 50°C and stirred for 2 hours. Water (1 mL) was added to the reaction solution, and the aqueous phase was separated and purified using reverse-phase preparative HPLC (C18, 10 mmol / L ammonia, acetonitrile) to obtain the title compound (22 mg, 25.0% yield) as a white solid. LCMS (ESI): [M+H] + =418.1; 1 H NMR (400MHz, CD3OD, ppm) δ7.27 (dd, J=8.0, 2.0Hz, 2H), 7.21 (dd, J=9.6, 1.6Hz, 1H), 6.92 (td, J=10. 0, 2.0Hz, 1H), 6.87 (d, J = 8.0Hz, 2H), 5.79 (s, 2H), 2.96 (d, J = 20.8Hz, 2H), 2.79 (s, 3H), 2.78 (s, 3H).

[0576] Example 73: Preparation of (4-((7,9-difluoro-4-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0577] Step 1: Preparation of 7,9-difluoro-4-methyl-5H-pyrimido[5,4-b]indole

[0578] 4-Chloro-7,9-difluoro-5H-pyrimido[5,4-b]indole (300 mg, 1.25 mmol, 1 equivalent) and methylboric acid (90 mg, 1.50 mmol, 1.2 equivalents) were dissolved in 1,4-dioxane (3 mL), and then 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (92 mg, 0.13 mmol, 0.1 equivalent) and cesium carbonate (1.22 g, 3.75 mmol, 3 equivalents) were added to the mixture. The reaction solution was heated to 120°C and stirred for 2 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride (80 mL), and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by preparative thin-layer plate chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 1 / 1)) to give the title compound (80 mg, yield: 29.2%) as a brown solid. LCMS (ESI): [M+H] + =220.0.

[0579] Step 2: Preparation of diethyl (4-((7,9-difluoro-4-methyl-5-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate

[0580] 7,9-Difluoro-4-methyl-5H-pyrimido[5,4-b]indole (70 mg, 0.32 mmol, 1 eq) was dissolved in tetrahydrofuran (2 mL), and sodium hydride (38 mg, 0.96 mmol, 3 eq) was added. The mixture was stirred for 0.5 h, and then diethyl (4-(bromomethyl)benzyl)phosphonate (123 mg, 0.38 mmol, 1.2 eq) was added to the mixture and stirred for 2 h. The reaction solution was diluted with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative thin-layer chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 1 / 1)) to afford the title compound (60 mg, 40.8% yield) as a brown solid. LCMS (ESI): [M+H] + =460.1.

[0581] Step 3: Preparation of (4-((7,9-difluoro-4-methyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0582] Diethyl (4-((7,9-difluoro-4-methyl-5-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (60 mg, 0.13 mmol, 1 equivalent) was dissolved in dichloromethane (1 mL), and trimethylsilyl bromide (400 mg, 2.61 mmol, 20 equivalents) was added. The reaction solution was heated to 50°C and stirred for 2 hours. Water (1 mL) was added to the reaction solution, and the aqueous phase was separated and purified using reverse-phase HPLC (C18, 10 mmol / L ammonia, acetonitrile) to obtain the title compound (10 mg, yield: 19.0%) as a white solid. LCMS (ESI): [M+H] + =404.0; 1 H NMR (400MHz, CD3OD) δ8.88 (s, 1H), 7.29-7.25 (m, 3H), 6.97 (td, J = 10.0, 2.0Hz ,1H),6.88(d,J=7.9Hz,2H),5.83(s,2H),2.93(d,J=20.8Hz,2H),2.85(s,3H).

[0583] Example 74: Preparation of (4-((4-chloro-2-ethyl-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0584] Step 1: Preparation of 2-ethyl-7,9-difluoro-5H-pyrimido[5,4-b]indol-4-ol

[0585] Dissolve 3-amino-4,6-difluoro-1H-indole-2-carboxamide (20 g, 94.7 mmol, 1 equivalent) in triethyl orthopropionate (200 mL). Heat the reaction mixture to 150°C and stir for 16 hours. Filter the reaction mixture directly, and dry the filtered solid to obtain the crude title compound (16.0 g, yield: 67.8%). LCMS (ESI): [M+H] + =250.0.

[0586] Step 2: Preparation of 4-chloro-2-ethyl-7,9-difluoro-5H-pyrimido[5,4-b]indole

[0587] 2-Ethyl-7,9-difluoro-5H-pyrimido[5,4-b]indol-4-ol (16 g, 64.2 mmol, 1 equivalent) was dissolved in phenylphosphoryl dichloride (100 mL). The reaction solution was heated to 180°C and stirred for 5 hours. The reaction solution was quenched and diluted with saturated aqueous sodium bicarbonate (200 mL). The mixture was extracted three times with dichloromethane (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried to give the crude title compound (14.0 g, yield: 81.5%). LCMS (ESI): [M+H] + =268.0.

[0588] Step 3: Preparation of di-tert-butyl (4-((4-chloro-2-ethyl-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate:

[0589] 4-Chloro-2-ethyl-7,9-difluoro-5H-pyrimido[5,4-b]indole (200 mg, 0.75 mmol, 1 equivalent) was dissolved in N,N-dimethylformamide (10 mL), and then di-tert-butyl (4-(bromomethyl)benzyl)phosphonate (563 mg, 1.50 mmol, 2 equivalents) and potassium carbonate (310 mg, 2.25 mmol, 3 equivalents) were added. The reaction solution was heated at reflux at 80°C for 2 hours and quenched with saturated ammonium chloride. The mixture was extracted three times with ethyl acetate (100 mL × 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title compound (350 mg, yield: 82.9%). LCMS (ESI): [M+H] + =564.1.

[0590] Step 4: Preparation of (4-((4-chloro-2-ethyl-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0591] Di-tert-butyl (4-((4-chloro-2-ethyl-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (150 mg, 0.27 mmol, 1 equivalent) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL, 8.77 mmol, 33 equivalents) was added. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by reverse-phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (20 mg, 16.4% yield) as a white solid. LCMS (ESI): [M+H] + =452.0; 1H NMR (400MHz, CD3OD) δ7.29(d,J=8.4,2.0Hz,2H),7.20(d,J=9.6,2.0Hz,1H),7.01(d,J=7.6Hz,2H),6.83( dt,J=10.0,2.0Hz,1H),5.71(s,2H),3.00(q,J=7.6Hz,2H),2.81(d,J=20.0Hz,2H),1.41(t,J=7.6Hz,3H).

[0592] Example 75: Preparation of (4-((4-chloro-7,9-difluoro-2-isopropyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0593] Step 1: Preparation of 2-isopropyl-7,9-difluoro-5H-pyrimido[5,4-b]indol-4-ol

[0594] 3-Amino-4,6-difluoro-1H-indole-2-carboxamide (5 g, 23.7 mmol, 1 equivalent) and 2,6-dimethyl-3,5-heptanedione (36 g, 237 mmol, 10 equivalents) were dissolved in ethanol (100 mL). Phosphoric acid (10 mL) was slowly added dropwise. The reaction solution was heated to 100°C and stirred for 3 days. The reaction solution was directly filtered and the solid was dried to obtain the crude title compound (4.5 g, yield: 72.2%). LCMS (ESI): [M+H] + =264.0.

[0595] Step 2: Preparation of 4-chloro-2-isopropyl-7,9-difluoro-5H-pyrimido[5,4-b]indole

[0596] Dissolve 2-isopropyl-7,9-difluoro-5H-pyrimido[5,4-b]indol-4-ol (7 g, 26.6 mmol, 1 equivalent) in phenylphosphoryl dichloride (70 mL). Heat the reaction mixture to 180°C and stir for 4 hours. Quench the reaction mixture with saturated aqueous sodium bicarbonate (200 mL) and extract three times with ethyl acetate (200 mL x 3). Combine the organic phases, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give the crude title compound (6.0 g, yield: 81.1%). LCMS (ESI): [M+H] + =282.0.

[0597] Step 3: Preparation of di-tert-butyl (4-((4-chloro-2-isopropyl-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate

[0598] 4-Chloro-2-isopropyl-7,9-difluoro-5H-pyrimido[5,4-b]indole (100 mg, 0.35 mmol, 1 equivalent) was dissolved in N,N-dimethylformamide (10 mL), and then di-tert-butyl (4-(bromomethyl)benzyl)phosphonate (263 mg, 0.70 mmol, 2 equivalents) and potassium carbonate (150 mg, 1.06 mmol, 3 equivalents) were added and stirred at 70°C for 2 hours. The reaction solution was quenched with saturated ammonium chloride and extracted three times with ethyl acetate (50 mL × 3). The organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (100 mg, yield: 48.8%). LCMS (ESI): [M+H] + =578.0.

[0599] Step 4: Preparation of (4-((4-chloro-7,9-difluoro-2-isopropyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0600] Di-tert-butyl (4-((4-chloro-2-isopropyl-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (100 mg, 0.17 mmol, 1 equivalent) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (2 mL) was added. The reaction was heated to 25°C and stirred for 2 hours. The reaction solution was concentrated, and the crude product was purified by reverse-phase HPLC (C18, 10 mmol / L ammonia, acetonitrile) to give the title compound (6 mg, yield: 6.2%) as a white solid. LCMS (ESI): [M+H] + =466.0; 1 H NMR (400MHz, CD3OD) δ7.32 (dd, J=8.4, 1.6Hz, 2H), 7.26 (dd, J=10.0, 2.0Hz, 1H), 6.99-6. 92(m,3H),5.89(s,2H),3.39-3.28(m,1H),2.82(d,J=19.6Hz,2H),1.41(d,J=6.8Hz,6H).

[0601] Example 76: Preparation of (4-((2-ethyl-7,9-difluoro-4-hydroxy-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0602] Step 1: Preparation of diethyl (4-((4-chloro-2-ethyl-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate

[0603] 4-Chloro-2-ethyl-7,9-difluoro-5H-pyrimido[5,4-b]indole (200 mg, 0.74 mmol, 1 eq) was dissolved in N,N-dimethylformamide (10 mL). Diethyl (4-(bromomethyl)benzyl)phosphonate (480 mg, 1.49 mmol, 2 eq) and potassium carbonate (306 mg, 2.22 mmol, 3 eq) were added and stirred at 80°C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride and extracted three times with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford the title compound (200 mg, 52.7% yield). LCMS (ESI): [M+H] + =508.0.

[0604] Step 2: Preparation of (4-((2-ethyl-7,9-difluoro-4-hydroxy-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0605] Diethyl (4-((4-chloro-2-ethyl-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (100 mg, 0.20 mmol, 1 equivalent) was dissolved in dichloromethane (20 mL) at room temperature. Trimethylsilyl bromide (2 mL) was added, and the reaction was heated to 50°C and stirred for 4 hours. The reaction solution was concentrated, and the crude product was purified by reverse-phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (48 mg, 56.4% yield) as a white solid. LCMS (ESI): [M+H] + =434.0; 1 H NMR (400MHz, CD3OD) δ7.28(dd,J=8.4,2.0Hz,2H),7.07(d,J=8.0Hz,2H),6.93(dd,J=9.6,2.0Hz,1H),6.60 (dt,J=10.0,2.0Hz,1H),5.92(s,2H),2.80(d,J=20.0Hz,2H),2.74(q,J=7.6Hz,2H),1.32(t,J=7.6Hz,3H).

[0606] Example 77: Preparation of (4-((7,9-difluoro-4-hydroxy-2-isopropyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0607] Step 1: Preparation of diethyl (4-((7,9-difluoro-4-chloro-2-isopropyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate

[0608] 4-Chloro-2-isopropyl-7,9-difluoro-5H-pyrimido[5,4-b]indole (300 mg, 1.07 mmol, 1 eq) was dissolved in N,N-dimethylformamide (10 mL). Diethyl (4-(bromomethyl)benzyl)phosphonate (683 mg, 2.14 mmol, 2 eq) and potassium carbonate (443 mg, 3.21 mmol, 3 eq) were added and stirred at 80°C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride and extracted three times with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound (360 mg, yield: 64.6%). LCMS (ESI): [M+H] + =522.0.

[0609] Step 2: Preparation of (4-((7,9-difluoro-4-hydroxy-2-isopropyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0610] Diethyl (4-((7,9-difluoro-4-chloro-2-isopropyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (200 mg, 0.38 mmol, 1 equivalent) was dissolved in dichloromethane (20 mL). Trimethylsilyl bromide (2 mL) was added, and the reaction was heated to 50°C and stirred for 4 hours. The reaction solution was concentrated, and the crude product was purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to obtain the title compound (28 mg, yield: 16.3%) as a white solid. LCMS (ESI): [M+H] + =448.1; 1 H NMR (400MHz, CD3OD) δ7.27(d,J=6.8Hz,2H),7.06(d,J=7.6Hz,2H),6.93(d,J=9.2Hz,1H),6.60( t,J=10.0Hz,1H),5.92(s,2H),3.14-2.99(m,1H),2.80(d,J=19.6Hz,2H),1.33(d,J=7.2Hz,6H).

[0611] Example 78: Preparation of (4-((2-ethyl-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0612] Step 1: Preparation of diethyl (4-((2-ethyl-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate

[0613] Diethyl (4-((4-chloro-2-ethyl-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (180 mg, 0.35 mmol, 1 equivalent) was dissolved in anhydrous methanol (5 mL). Potassium carbonate (48 mg, 0.35 mmol, 1 equivalent) and palladium on carbon (18 mg, 10 wt%) were added. The reaction system was replaced with a hydrogen atmosphere, and the reaction solution was stirred at room temperature for 1 hour. Dichloromethane (10 mL) was added to the reaction solution, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (110 mg, yield: 66.4%). LCMS (ESI): [M+H] + =474.1.

[0614] Step 2: Preparation of (4-((2-ethyl-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0615] Diethyl (4-((2-ethyl-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (110 mg, 0.23 mmol, 1 equivalent) was dissolved in dichloromethane (2 mL). Trimethylsilyl bromide (0.5 mL, 3.79 mmol, 16 equivalents) was added. The reaction was heated to 50°C and stirred for 1 hour. Water (2 mL) was added to the reaction solution, which was filtered. The solid was washed with tetrahydrofuran (2 mL) and filtered to give the title compound (37 mg, yield: 37.1%) as a white solid. LCMS (ESI): [M+H] + =418.0; 1 H NMR (400MHz, CD3OD) δ9.37(s,1H),7.47(dd,J=8.6,2.0Hz,1H),7.30(dd,J=8.4,2.4Hz,2H),7.22(d,J=8.0Hz,2H) ,7.13(td,J=10.0,2.0Hz,1H),5.77(s,2H),3.26(q,J=7.6Hz,2H),3.08(d,J=21.6Hz,2H),1.53(t,J=7.6Hz,3H).

[0616] Example 79: Preparation of (4-((7,9-difluoro-2-isopropyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0617] Step 1: Preparation of diethyl (4-((7,9-difluoro-2-isopropyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate

[0618] Diethyl (4-((4-chloro-7,9-difluoro-2-isopropyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (150 mg, 0.29 mmol, 1 equivalent) was dissolved in tetrahydrofuran (10 mL), and palladium on carbon (30 mg, 20 wt%) and potassium carbonate (40 mg, 0.29 mmol, 1 equivalent) were added. The mixture was stirred at 50°C for 2 hours. The reaction mixture was filtered and concentrated in vacuo to give the title compound (100 mg, yield: 71.0%). LCMS (ESI): [M+H] + =488.0.

[0619] Step 2: Preparation of (4-((7,9-difluoro-2-isopropyl-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0620] Diethyl (4-((2-isopropyl-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (100 mg, 0.29 mmol, 1 equivalent) was dissolved in dichloromethane (20 mL). Trimethylsilyl bromide (2 mL) was added and the reaction was heated to 50°C and stirred for 4 hours. The reaction solution was spin-dried and the crude product was slurried twice with tetrahydrofuran / water (V / V = 1 / 1) and once with tetrahydrofuran to obtain the title compound (29 mg, yield: 23.2%) as a white solid. LCMS (ESI): [M+H] + =432.1; 1 H NMR (400MHz, CD3OD, ppm) δ8.99 (s, 1H), 7.35-7.31 (m, 3H), 7.08 (d, J = 8.0Hz, 2H), 6.89 (td, J = 1 0.0, 2.0Hz, 1H), 5.59 (s, 2H), 3.41-3.34 (m, 1H), 2.82 (d, J = 19.6Hz, 2H), 1.41 (d, J = 7.2Hz, 6H).

[0621] Example 80: Preparation of (4-((8-chloro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0622] Similarly, using commercially available 8-chloro-5H-pyrido[3,2-b]indole as a starting material, Example 80 was prepared according to Steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =387.1; 1 H NMR (400MHz, CD3OD) δ8.47(d,J=4.4,1.2Hz,1H),8.30(d,J=2.0Hz,1H),8.03(d,J=8.8,2.0Hz,1H),7.63(d,J=8.8 Hz, 1H), 7.52-7.48 (m, 2H), 7.24 (d, J = 8.0, 2.0Hz, 2H), 7.06 (d, J = 8.0Hz, 2H), 5.61 (s, 2H), 2.88 (d, J = 20.8Hz, 2H).

[0623] Example 81: Preparation of (4-((8-bromo-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0624] Similarly, using commercially available 8-bromo-5H-pyrido[3,2-b]indole as a starting material, Example 81 was prepared according to Steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =430.9; 1 H NMR (400MHz, CD3OD) δ8.48-8.45(m,2H),8.04(dd,J=8.4,1.2Hz,1H),7.66(dd,J=8.8,2.0Hz,1H),7.58(d,J=8.8Hz,1H ), 7.50 (dd, J = 8.4, 4.8 Hz, 1H), 7.23 ( dd, J = 8.0, 2.0 Hz, 2H), 7.08 ( d, J = 8.0 Hz, 2H), 5.61 ( s, 2H), 2.94 ( d, J = 21.2 Hz, 2H).

[0625] Example 82: Preparation of (4-((4-chloro-9H-pyrimido[4,5-b]indol-9-yl)methyl)benzyl)phosphonic acid

[0626] Similarly, using commercially available 4-chloro-9H-pyrimido[4,5-b]indole as a starting material, Example 82 was prepared according to Steps 3-4 of the preparation method of Example 1. LCMS (ESI) [M+1] + =388.0; 1H NMR (400MHz, DMSO-d6) δ.89 (s, 1H), 8.35 (d, J = 8.0Hz, 1H), 7.83 (d, J = 8.4Hz, 1H), 7.67 (t, J = 7.2Hz, 1H) ,7.48(t,J=7.2Hz,1H),7.21(d,J=8.0Hz,2H),7.16-7.14(m,2H),5.72(s,2H),2.88(d,J=21.4Hz,2H).

[0627] Example 83: Preparation of (4-((4-bromo-6-chloro-9H-pyrimido[4,5-b]indol-9-yl)methyl)benzyl)phosphonic acid

[0628] Step 1: Preparation of 4,6-dichloro-9H-pyrimido[4,5-b]indole

[0629] 4-Chloro-9H-pyrimido[4,5-b]indole (200 mg, 1.0 mmol, 1 equivalent) was dissolved in a mixture of dichloromethane (10 mL) and acetic acid (10 mL). N-chlorosuccinimide (131 mg, 1.0 mmol, 1 equivalent) was added and stirred at 60°C under an argon atmosphere for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (230 mg, yield: 98.6%) as a yellow liquid. LCMS (ESI): [M+H] + =237.9.

[0630] Step 2: Preparation of diethyl (4-((4,6-dichloro-9H-pyrimido[4,5-b]indol-9-yl)methyl)benzyl)phosphonate

[0631] 4,6-Dichloro-9H-pyrimido[4,5-b]indole (140 mg, 0.6 mmol, 1 equivalent) was dissolved in N,N-dimethylformamide (15 mL). Diethyl (4-(bromomethyl)benzyl)phosphonate (378 mg, 1.2 mmol, 2 equivalents) and potassium carbonate (122 mg, 0.9 mmol, 1.5 equivalents) were added. After stirring at 70°C for 1 hour under an argon atmosphere, the reaction mixture was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (170 mg, yield: 60.4%) as a yellow liquid. LCMS (ESI): [M+H] + =478.0.

[0632] Step 3: Preparation of (4-((4-bromo-6-chloro-9H-pyrimido[4,5-b]indol-9-yl)methyl)benzyl)phosphonic acid

[0633] Diethyl (4-((4,6-dichloro-9H-pyrimido[4,5-b]indol-9-yl)methyl)benzyl)phosphonate (90 mg, 0.2 mmol, 1 eq) was dissolved in dichloromethane (5 mL), and trimethylsilyl bromide (1 mL, 6.5 mmol, 33 eq) was added. The mixture was stirred at 50°C under an argon atmosphere for 1 hour. The reaction solution was purified by reverse phase HPLC (C18, 10 mmol / aqueous ammonia, acetonitrile) to give the title compound (7 mg, yield: 10.5%) as a white solid. LCMS (ESI): [MH] + =463.9; 1 H NMR (400MHz, CD3OD) δ8.76(s,1H),8.48(d,J=2.4Hz,1H),7.67(d,J=8.8Hz,1H),7.60(dd,J=8 .8,2.0Hz,1H),7.27-7.24(m,2H),7.18(d,J=8.0Hz,2H),5.69(s,2H),2.89(d,J=20.8Hz,2H).

[0634] Example 84: Preparation of (4-((6-chloro-4-hydroxy-9H-pyrimido[4,5-b]indol-9-yl)methyl)benzyl)phosphonic acid

[0635] Step 1: Preparation of (4-((6-chloro-4-hydroxy-9H-pyrimido[4,5-b]indol-9-yl)methyl)benzyl)phosphonic acid

[0636] Diethyl (4-((4,6-dichloro-9H-pyrimido[4,5-b]indol-9-yl)methyl)benzyl)phosphonate (80 mg, 0.2 mmol, 1 eq) was dissolved in dichloromethane (5 mL), and trimethylsilyl bromide (53 μL, 0.4 mmol, 2 eq) was added. The mixture was stirred at 50°C under an argon atmosphere for 1 hour. The reaction mixture was directly purified by reverse-phase HPLC (C18, 10 mmol / aqueous ammonia, acetonitrile) to give the title compound (12.9 mg, 17.7% yield) as a white solid. LCMS (ESI): [M+H] + =404.0; 1H NMR (400MHz, CD3OD) δ8.21 (s, 1H), 8.10 (d, J = 2.0Hz, 1H), 7.50 (d, J = 5.2Hz, 1H), 7.33 (dd, J = 8.4, 2.0Hz, 1H), 7.26-7.22 (m, 2H), 7.16 (d, J = 8.4Hz, 2H), 5.60 (s, 2H), 2.91 (d, J = 21.0Hz, 2H).

[0637] Example 85: Preparation of (4-((2-chloro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0638] Step 1: Preparation of 2-chloro-6-(2-nitrophenyl)pyridine:

[0639] (2-Nitrophenyl)boronic acid (2 g, 12.0 mmol, 1 equiv) was dissolved in 1,4-dioxane (5 mL), and 2,6-dichloropyridine (1.7 g, 12.0 mmol, 1 equiv) and potassium carbonate (3.3 g, 24.0 mmol, 2 equiv) were added, along with tetrakistriphenylphosphine palladium (692 mg, 0.6 mmol, 0.05 equiv). The reaction was microwaved at 120°C for 1 hour. The reaction was quenched with saturated ammonium chloride (10 mL) and extracted three times with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash chromatography (silica gel, petroleum ether:dichloromethane (V / V = 1 / 1)) to afford the title compound (200 mg, 7.1% yield). LCMS (ESI): [M+H] + =235.0.

[0640] Step 2: Preparation of 2-chloro-5H-pyrido[3,2-b]indole:

[0641] Dissolve 2-chloro-6-(2-nitrophenyl)pyridine (400 mg, 1.7 mmol, 1 equivalent) in triethyl phosphite (4 mL), heat to 180°C, react under nitrogen atmosphere for 10 hours, and concentrate the reaction solution to obtain the title compound (200 mg, yield: 57.9%). LCMS (ESI): [MH] - =201.0.

[0642] Step 3: Preparation of diethyl (4-((2-chloro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate:

[0643] 2-Chloro-5H-pyrido[3,2-b]indole (40 mg, 0.2 mmol, 1 eq) was dissolved in tetrahydrofuran (1 mL), followed by the addition of sodium hydride (32 mg, 0.8 mmol, 4 eq) and diethyl (4-(bromomethyl)benzyl)phosphonate (126.8 mg, 0.4 mmol, 2 eq). The mixture was allowed to react at room temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride (10 mL) and extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 1 / 2)) to afford the title compound (30 mg, 68.6% yield). LCMS (ESI): [M+H] + =443.0.

[0644] Step 4: Preparation of (4-((2-chloro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0645] Diethyl (4-((2-chloro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (30 mg, 0.07 mmol, 1 eq) was dissolved in dichloromethane (1 mL), and trimethylsilyl bromide (103 mg, 0.68 mmol, 10 eq) was added. The temperature was raised to 50°C and the reaction mixture was reacted for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by reverse phase chromatography (C18, 10 mmol / aqueous ammonia, acetonitrile) to give the title compound (2.57 mg, yield: 9.5%). LCMS (ESI): [M+H] + =387.0; 1 H NMR (400MHz, CD3OD) δ8.29(d,J=8.0Hz,1H),7.98(d,J=8.4Hz,1H),7.65(d,J=8.4Hz,1H),7.58-7.55(m,1H),7.42(d ,J=8.8Hz,1H),7.32-7.29(m,2H),7.16(d,J=8.0Hz,1H),7.02(d,J=8.0Hz,2H),5.57(s,2H),2.82(d,J=19.8Hz,2H).

[0646] Example 86: Preparation of (4-((2-methyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0647] Step 1: Preparation of 6-methyl-3-nitro-2-phenylpyridine

[0648] 6-Chloro-3-nitro-2-phenylpyridine (450 mg, 1.9 mmol, 1 equiv), methylboronic acid (231 mg, 3.8 mmol, 2 equiv), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (418 mg, 0.58 mmol, 0.3 equiv), and cesium carbonate (1.88 g, 5.7 mmol, 3 equiv) were dissolved in a mixture of dioxane (30 mL) and water (6 mL) under an argon atmosphere. The mixture was heated to 80°C and stirred for 2 hours. The reaction solution was cooled and quenched with water. The mixture was extracted three times with dichloromethane (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by reverse-phase HPLC (C18, 10 mmol / L pure water, acetonitrile) to afford the title compound (300 mg, 73.0% yield) as a white solid. LCMS (ESI): [M+H] + =215.0.

[0649] Step 2: Preparation of 2-methyl-5H-pyrido[3,2-b]indole

[0650] 6-Methyl-3-nitro-2-phenylpyridine (300 mg, 1.4 mmol, 1 equivalent) was dissolved in o-dichlorobenzene (5 mL). Triphenylphosphine (734.60 mg, 2.8 mmol, 2 equivalents) was added to the mixture. The reaction mixture was allowed to react at 200°C under an inert atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by flash chromatography (silica gel, dichloromethane:methanol (V / V = 10 / 1)) to obtain the title compound (200 mg, yield: 61.8%) as a white solid. LCMS (ESI): [M+H] + =183.1.

[0651] Step 3: Preparation of diethyl (4-((2-methyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate:

[0652] 2-Methyl-5H-pyrido[3,2-b]indole (110 mg, 0.6 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (5 mL). Sodium hydride (29 mg, 0.72 mmol, 1.2 equiv) was added to the reaction solution at 0°C. The reaction solution was stirred at 0°C for 20 minutes, and then diethyl (4-(bromomethyl)benzyl)phosphonate (232 mg, 0.73 mmol, 1.2 equiv) was added to the mixture. The reaction solution was stirred at room temperature for two hours. The reaction solution was quenched with water and extracted three times with ethyl acetate (100 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (110 mg, yield: 43.1%) as a yellow solid. LCMS (ESI): [M+H] + =423.1.

[0653] Step 4: Preparation of (4-((2-methyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0654] Diethyl (4-((2-methyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (110 mg, 0.26 mmol, 1 equivalent) was dissolved in dichloromethane (20 mL). Silane bromide (2 mL) was added and the reaction was heated to 50°C and stirred for 2 hours. The reaction solution was concentrated, and the crude product was purified by reverse-phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (27.8 mg, 29.1% yield) as a white solid. LCMS (ESI): [M+H] + =367.0; 1 H NMR (400MHz, CD3OD) δ8.37(d,J=8.0Hz,1H),7.99(d,J=8.4Hz,1H),7.62(d,J=8.4Hz,1H),7.58-7.54(m,1H),7.39(d,J=8.8Hz ,1H),7.33-7.29(m,1H),7.23(dd,J=8.4,2.4Hz,2H),7.06(d,J=8.0Hz,2H),5.61(s,2H),2.91(d,J=20.8Hz,2H),2.74(s,3H).

[0655] Example 87: (4-((2-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0656] Step 1: Preparation of di-tert-butyl (4-((2-chloro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate

[0657] 2-Chloro-5H-pyrido[3,2-b]indole (1.0 g, 5.0 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (5 mL). Sodium hydride (240 mg, 6 mmol, 1.2 equiv) was added to the reaction mixture at 0°C and stirred for 30 minutes at 0°C. To the mixture was added di-tert-butyl (4-(bromomethyl)benzyl)phosphonate (1.9 g, 5 mmol, 1.0 equiv). Stirring was continued for two hours, then quenched with water and extracted three times with ethyl acetate (100 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and added to silica gel for spin drying. The crude product was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 5 / 1)) to afford the title compound (1.0 g, 41.7% yield) as a yellow solid. LCMS (ESI): [M+Na] + =520.8.

[0658] Step 2: Preparation of di-tert-(4-((2-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate:

[0659] Di-tert-butyl (4-((2-chloro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (200 mg, 0.4 mmol, 1.0 equiv) was dissolved in toluene (1 mL) and methanol (1 mL). Cesium carbonate (393 mg, 1.2 mmol, 3.0 equiv), palladium acetate (9 mg, 0.04 mmol, 0.1 equiv), and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (34 mg, 0.08 mmol, 0.2 equiv) were added. Under inert gas, the reaction was continued at 100°C for 2 hours. Saturated aqueous sodium chloride solution (20 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (30 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V=2 / 3)) to give the title compound (60 mg, yield: 30.3%) as a yellow oily liquid.

[0660] Step 3: (4-((2-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0661] Di-tert-butyl (4-((2-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (65 mg, 0.13 mmol, 1.0 equiv) was dissolved in methanol (75 mL). A methanolic solution of hydrogen chloride (14.2 mg, 0.39 mmol, 3.0 equiv) was added to the mixture, and the reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was prepared by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to obtain the title compound (28 mg yield: 56.3%) as a white solid. LCMS (ESI): [M+H] + =383.3; 1 H NMR (400MHz, DMSO-d6, ppm) δ8.09(d,J=8.4Hz,1H),7.99(d,J=8.8Hz,1H),7.63(d,J=8.4Hz,1H),7.43(t,J=7.6Hz,1H),7.20(t,J= 7.2Hz, 1H), 7.06 (d, J = 6.4Hz, 2H), 6.97 (d, J = 8.0Hz, 2H), 6.86 (d, J = 8.8Hz, 1H), 5.55 (s, 2H), 3.97 (s, 3H), 2.62 (d, J = 20.8Hz, 2H).

[0662] Example 88: Preparation of (4-((2-(methylamino)-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0663] Step 1: Preparation of di-tert-butyl (4-((2-(methylamino)-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate:

[0664] Di-tert-butyl (4-((2-chloro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (500 mg, 1.00 mmol, 1.0 equiv) was dissolved in toluene (5 mL), followed by the addition of methylamine hydrochloride (338 mg, 5.01 mmol, 5.0 equiv), cesium carbonate (979 mg, 3.01 mmol, 3.0 equiv), palladium acetate (17 mg, 0.010 mmol, 0.1 equiv), and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (85 mg, 0.200 mmol, 0.2 equiv). The reaction mixture was allowed to react at 110°C under inert gas for 2 hours. Saturated aqueous sodium chloride solution (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (20 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by flash chromatography (silica gel, ethyl acetate (100%)) to give the title compound (75 mg, yield: 19.0%) as a yellow oily liquid. LCMS (ESI): [M+H] + = 494.3.

[0665] Step 2: Preparation of (4-((2-(methylamino)-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0666] Di-tert-butyl (4-((2-(methylamino)-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (75 mg, 0.152 mmol, 1.0 equiv) was dissolved in methanolic hydrogen chloride (2 mL, 3 molar methanolic solution) and stirred at 50°C for 4 hours. The reaction was concentrated under reduced pressure to give a crude brown oil. The product was then purified by reverse-phase HPLC (C18, 10 mmol / L aqueous ammonia, acetonitrile) to give the title compound (15 mg, 28.1% yield) as a white solid. LCMS (ESI): [M+H] = 382.3. 1 H NMR (400MHz, DMSO-d6, ppm) δ8.00(d,J=8.0Hz,1H),7.73(d,J=8.8Hz,1H),7.53(d,J=8.4Hz,1H),7.34(t,J=7.6Hz,1H),7.14 -7.05(m,3H),6.98(d,J=8.0Hz,2H),6.59(d,J=8.8Hz,1H),6.25(brs,1H),5.48(s,2H),2.88(s,3H),2.72(d,J=21.1Hz,2H).

[0667] Example 89: Preparation of (4-((8-fluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0668] Step 1: Preparation of 2-(3-fluorophenyl)-3-nitropyridine

[0669] 2-Chloro-3-nitropyridine (2 g, 9.9 mmol, 1 eq) was dissolved in a mixture of 1,4-dioxane (15 mL) and water (15 mL). (3-Fluorophenyl)boronic acid (1.4 g, 9.9 mmol, 1 eq), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (0.7 g, 0.9 mmol, 0.1 eq), and potassium carbonate (2.0 g, 14.8 mmol, 1.5 eq) were added. The reaction mixture was stirred at 120°C under argon for 1 hour. The mixture was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the title compound (2 g, 93.1% yield) as a yellow liquid. LCMS (ESI): [M+H] + =219.0.

[0670] Step 2: Preparation of 8-fluoro-5H-pyrido[3,2-b]indole and 6-fluoro-5H-pyrido[3,2-b]indole

[0671] 2-(3-Fluorophenyl)-3-nitropyridine (2 g, 9.2 mmol, 1 equivalent) was dissolved in 1,2-dichlorobenzene (40 mL) and triphenylphosphine (4.8 g, 18.3 mmol, 2 equivalents) was added. The reaction solution was stirred at 200°C under argon protection for 5 hours, then concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (C18, 10 mmol / ammonium bicarbonate, acetonitrile) to give the title compounds 8-fluoro-5H-pyrido[3,2-b]indole (A, 1 g, yield: 58.6%) and 6-fluoro-5H-pyrido[3,2-b]indole (B, 150 mg, yield: 8.8%).

[0672] 8-Fluoro-5H-pyrido[3,2-b]indole: LCMS(ESI):[M+H] + =187.0; 1 H NMR (400MHz, DMSO-d6, ppm) δ11.50 (s, 1H), 8.47 (d, J = 4.0Hz, 1H), 7.92-7.88 (m, 2H), 7.60-7.58 (m, 1H), 7.43-7.37 (m, 2H).

[0673] 6-Fluoro-5H-pyrido[3,2-b]indole: LCMS(ESI):[M+H] + =187.0;1 H NMR (400MHz, DMSO-d6, ppm) δ11.91 (s, 1H), 8.50 (d, J = 4.0Hz, 1H), 8.02-8.00 (m, 1H), 7.93-7.90 (m, 1H), 7.47-7.36 (m, 2H), 7.24-7.22 (m, 1H).

[0674] Step 3: Preparation of diethyl (4-((8-fluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate

[0675] 8-Fluoro-5H-pyrido[3,2-b]indole (60 mg, 0.3 mmol, 1 equiv) was dissolved in tetrahydrofuran (15 mL). Sodium hydride (64 mg, 1.6 mmol, 5 equiv) and diethyl (4-(bromomethyl)benzyl)phosphonate (207 mg, 0.6 mmol, 2 equiv) were added. The reaction mixture was stirred at room temperature under argon for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (60 mg, yield: 43.7%) as a yellow liquid. LCMS (ESI): [M+H] + =427.0.

[0676] Step 4: Preparation of (4-((8-fluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0677] Diethyl (4-((8-fluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (60 mg, 0.1 mmol, 1 equiv) was dissolved in dichloromethane (5 mL), and trimethylsilyl bromide (1 mL, 6.5 mmol, 46 equiv) was added. The reaction mixture was stirred at 50°C under argon for 1 hour. The reaction mixture was concentrated, and the crude product was purified by reverse-phase HPLC (C18, 10 mmol / aqueous ammonia, acetonitrile) to give the title compound (3.07 mg, yield: 5.9%) as a white solid. LCMS (ESI): [M+H] + =371.0; 1H NMR (400MHz, CD3OD) δ8.45(dd,J=4.8,1.2Hz,1H),8.03-7.98(m,2H),7.62(dd,J=9.2,4.0Hz,1H),7.48(dd,J=8. 4,4.4Hz,1H),7.36-7.31(m,1H),7.25-7.22(m,2H),7.06(d,J=8.0Hz,2H),5.61(s,2H),2.88(d,J=20.8Hz,2H).

[0678] Example 90: Preparation of (4-((6-fluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0679] Step 1: Preparation of diethyl (4-((6-fluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate

[0680] 6-Fluoro-5H-pyrido[3,2-b]indole (50 mg, 0.3 mmol, 1 equivalent) was dissolved in tetrahydrofuran (15 mL), and sodium hydride (60 mg, 1.5 mmol, 5 equivalents) and diethyl (4-(bromomethyl)benzyl)phosphonate (173 mg, 0.5 mmol, 2 equivalents) were added. The reaction mixture was stirred at room temperature under argon for 1 hour, then quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (60 mg, yield: 52.4%) as a yellow liquid. LCMS (ESI): [M+H] + =427.1.

[0681] Step 2: Preparation of (4-((6-fluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0682] Diethyl (4-((6-fluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (60 mg, 0.1 mmol, 1 equiv) was dissolved in dichloromethane (5 mL), and trimethylsilyl bromide (1 ml, 6.5 mmol, 46 equiv) was added. The reaction mixture was stirred at 50°C under argon for 1 hour. The reaction mixture was concentrated, and the crude product was purified by reverse-phase HPLC (C18, 10 mmol / aqueous ammonia, acetonitrile) to give the title compound (2.01 mg, 3.9% yield) as a white solid. LCMS (ESI): [M+H] + =371.0; 1H NMR (400MHz, CD3OD) δ8.48(d,J=4.8Hz,1H),8.14(d,J=8.8Hz,1H),8.06(d,J=8.8Hz,1H),7.5 1-7.48(m,1H),7.35-7.22(m,4H),7.05(d,J=7.6Hz,2H),5.74(s,2H),2.88(d,J=20.4Hz,2H).

[0683] Example 91: Preparation of (4-((7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0684] Step 1: Preparation of 2-(2,4-difluorophenyl)-3-nitropyridine:

[0685] 2-Chloro-3-nitropyridine (300 mg, 1.89 mmol, 1 equiv), (2,4-difluorophenyl)boronic acid (598 mg, 3.78 mmol, 2 equiv), and sodium carbonate (602 mg, 5.68 mmol, 3 equiv) were dissolved in a mixed solvent of toluene (4 mL), water (2 mL), and ethanol (2 mL). Palladium acetate (21 mg, 0.09 mmol, 0.05 equiv) and triphenylphosphine (100 mg, 0.38 mmol, 0.2 equiv) were then added. The mixture was heated to 90°C for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (300 mg, yield: 67.1%). LCMS (ESI): [M+H] + =236.9.

[0686] Step 2: Preparation of 7,9-difluoro-5H-pyrido[3,2-b]indole:

[0687] 2-(2,4-difluorophenyl)-3-nitropyridine (300 mg, 1.27 mmol, 1 equivalent) was dissolved in dichlorobenzene (5 mL), and triphenylphosphine (666 mg, 2.54 mmol, 2 equivalents) was added. The temperature was raised to 200°C and the reaction was stirred for 2 hours. The reaction solution was cooled and concentrated, and the crude product was purified by Prep-TLC plate (silica gel, dichloromethane:methanol (V / V=10 / 1)) to obtain the title compound (200 mg, yield: 77.1%). LCMS (ESI): [M+H] + =205.1.

[0688] Step 3: Preparation of diethyl (4-((7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate

[0689] Diethyl (4-(bromomethyl)benzyl)phosphonate (944 mg, 2.94 mmol, 3 equivalents) and 7,9-difluoro-5H-pyrido[3,2-b]indole (200 mg, 0.98 mmol, 1 equivalent) were dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (406 mg, 2.94 mmol, 3 equivalents) was added, and the temperature was raised to 70°C for 2 hours. The reaction solution was cooled and diluted with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude title compound (230 mg, yield: 83.1%). LCMS (ESI): [M+H] + =445.1.

[0690] Step 4: Preparation of (4-((7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0691] Diethyl (4-((7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (230 mg, 0.52 mmol, 1 equivalent) was dissolved in dichloromethane (5 mL), and trimethylsilyl bromide (1 mL, 6.53 mmol, 12 equivalents) was added. The mixture was stirred at 55°C for 1 hour. The reaction solution was quenched with methanol and concentrated. The crude product was purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (21 mg, yield: 10.4%). LCMS (ESI): [M+H]+=389.0; 1HNMR (400MHz, CD3OD) δ8.48 (dd, J=4.8, 1.2Hz, 1H), 8.01 (dd, J=8.4, 1.2Hz, 1H), 7.47 (dd, J=8.0, 3. 2Hz, 1H), 7.25 (dd, J = 7.6, 2.0Hz, 3H), 7.07 (d, J = 8.0Hz, 2H), 6.88 (dt, J = 10.0, 2.0Hz, 1H), 5.59 (s, 2H), 2.92 (d, J = 20.8Hz, 2H).

[0692] Example 92: Preparation of (4-((2-ethoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0693] Step 1: Preparation of di-tert-butyl (4-((2-ethoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate:

[0694] Di-tert-butyl (4-((2-chloro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (200 mg, 0.40 mmol, 1.0 equiv) was dissolved in ethanol (2 mL), followed by the addition of 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (34 mg, 0.08 mmol, 0.2 equiv), cesium carbonate (392 mg, 1.2 mmol, 3.0 equiv), and palladium acetate (7 mg, 0.04 mmol, 0.1 equiv). The reaction mixture was allowed to react at 100°C under inert gas for 2 hours. Saturated aqueous sodium chloride solution (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (20 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then added to silica gel for spin drying. The crude product was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V=3 / 1)) to give the title compound (70 mg, yield: 34.4%) as a yellow oily liquid. LCMS (ESI): [M+H] + =509.3.

[0695] Step 2: Preparation of (4-((2-ethoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0696] Di-tert-butyl (4-((2-ethoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (70 mg, 0.14 mmol, 1.0 equiv) was dissolved in methanol (1 mL) and a methanolic solution of hydrogen chloride (31 mg, 0.84 mmol, 6.0 equiv) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a brown oily crude product. The crude product was prepared by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to obtain the title compound (23.5 mg, yield: 42.3%) as a white solid. LCMS (ESI): [M+H] + =397.2,; 1H NMR (400MHz, CD3OD) δ8.19(d,J=8.0Hz,1H),7.84(d,J=8.8Hz,1H),7.53(d,J=8.4Hz,1H),7.44(t,J=7.6Hz,1H),7.23-7.19(m,3H ), 7.04 (d, J = 8.0Hz, 2H), 6.84 (d, J = 8.8Hz, 1H), 5.54 (s, 2H), 4.45 (q, J = 7.2Hz, 2H), 2.91 (d, J = 20.8Hz, 2H), 1.44 (t, J = 7.2Hz, 3H).

[0697] Examples 93 and 94: Preparation of (4-(1-(3,6-dimethoxy-9H-carbazol-9-yl)ethyl)benzyl)phosphonic acid:

[0698] Step 1: Preparation of diethyl (4-acetylbenzyl)phosphonate

[0699] 1-(4-(Bromomethyl)phenyl)ethan-1-one (2.4 g, 11.2 mmol, 1.0 equivalent) was added to triethyl phosphite (5 mL) and the reaction was continued at 120°C for 5 hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 3 / 1)) to obtain the title compound (2.5 g, yield: 83.3%) as a clear oily liquid. LCMS (ESI): [M+H] + =271.2.

[0700] Step 2: Preparation of diethyl (S)-(4-(1-hydroxyethyl)benzyl)phosphonate

[0701] 2-Methyl-CBS-oxazaborolidine (693 mg, 2.5 mmol, 0.5 equiv) was dissolved in dichloromethane (7 mL) and methyltetrahydrofuran (7 mL). Borane-tetrahydrofuran complex (7.5 mL, 7.5 mmol, 1.5 equiv) and diethyl (4-acetylbenzyl)phosphonate (1.35 g, 5.0 mmol, 1 equiv) were added to the solution at -40°C. The reaction mixture was allowed to react for 2 hours at -20°C. The reaction mixture was quenched with methanol (30 mL) and concentrated. The crude product was purified by flash chromatography (silica gel, dichloromethane:methanol (V / V = 20 / 1)) to give the title compound (600 mg, 44.1% yield) as a clear oily liquid. LCMS (ESI): [2M+H] + =545.2.

[0702] Step 3: Preparation of diethyl (4-(1-chloroethyl)benzyl)phosphonate

[0703] (S)-Diethyl (4-(1-hydroxyethyl)benzyl)phosphonate (1.0 g, 3.6 mmol, 1.0 equiv) was dissolved in dichloromethane (10 mL), and thionyl chloride (2.2 g, 18.4 mmol, 5.0 equiv) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by flash chromatography (silica gel, dichloromethane:methanol (V / V=10 / 1)) to obtain the title compound (600 mg, yield: 47.1%) as a clear oily liquid. LCMS (ESI): [M+H] + =290.9.

[0704] Step 4: Preparation of diethyl (4-(1-(3,6-dimethoxy-9H-carbazol-9-yl)ethyl)benzyl)phosphonate

[0705] 3,6-Dimethoxy-9H-carbazole (783 mg, 3.5 mmol, 2.0 equiv) was dissolved in N,N-dimethylformamide (8 mL). Sodium hydride (138 mg, 3.5 mmol, 2.0 equiv) was then added to the solution at 0°C and allowed to react for 30 minutes. Diethyl (4-(1-chloroethyl)benzyl)phosphonate (500 mg, 1.7 mmol, 1.0 equiv) was then added and stirred at room temperature for 2 hours. The reaction was quenched with water (15 mL) and extracted three times with ethyl acetate (25 mL x 3). The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, dichloromethane:methanol (V / V = 10 / 1)) to afford the title compound (400 mg, 48.2% yield) as a clear oily liquid. LCMS (ESI): [2M+H] + =963.2.

[0706] Step 5: Chiral separation of diethyl (4-(1-(3,6-dimethoxy-9H-carbazol-9-yl)ethyl)benzyl)phosphonate to give isomer A and isomer B

[0707] The racemic compound (4-(1-(3,6-dimethoxy-9H-carbazol-9-yl)ethyl)benzyl)phosphonic acid diethyl ester (100 mg) was chirally resolved by SFC (system: Waters SFC 150; column: Daicel Chiralce Column size: 250*25mm10μm; mobile phase A: supercritical CO2, mobile phase B: MeOH (+0.1% 7.0mol / l ammonia in MeOH), to obtain two single configuration compounds: Isomer A: 50mg, tR =2.137min and isomer B: 50mg, t R =2.578min.

[0708] Step 6: Preparation of R-(4-(1-(3,6-dimethoxy-9H-carbazol-9-yl)ethyl)benzyl)phosphonic acid and S-(4-(1-(3,6-dimethoxy-9H-carbazol-9-yl)ethyl)benzyl)phosphonic acid:

[0709] Isomer A or Isomer B (diethyl 4-(1-(3,6-dimethoxy-9H-carbazol-9-yl)ethyl)benzyl)phosphonate (50 mg, 0.1 mmol, 1.0 equiv) from Step 5 was dissolved in dichloromethane (2 mL). Trimethylsilyl bromide (238 mg, 1.5 mmol, 15 equiv) was then added to the mixture, and the mixture was stirred at 50°C for 1 hour. The reaction solution was quenched with methanol and concentrated under reduced pressure to obtain a colorless oily crude product. The crude product was purified by reverse-phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to obtain Example 93 (or 94) (30 mg, 68.2% yield) and Example 94 (or 93) (25 mg, 56.8% yield).

[0710] Example 93 (or 94) compound: LCMS (ESI): [M+H] + =426.2; 1 H NMR (400MHz, DMSO-d6, ppm) δ7.71(d,J=2.4Hz,2H),7.28(d,J=9.2Hz,2H),7.13(d,J=7.2Hz,2H),7.07(d,J=8.0Hz ,2H),6.92(dd,J=8.8,2.4Hz,2H),6.03-6.01(m,1H),3.83(s,6H),2.67(d,J=20.8Hz,2H),1.83(d,J=6.8Hz,3H).

[0711] Example 94 (or 93) compound: LCMS (ESI): [M+H] + =426.2; 1H NMR (400MHz, DMSO-d6, ppm) δ7.71 (d, J = 2.4Hz, 2H), 7.28 (d, J = 9.2Hz, 2H), 7.12 (d, J = 7. 2Hz,2H),7.05(d,J=8.0Hz,2H),6.92(dd,J=8.8,2.4Hz,1H),6.03-6.01(m,1H),3.82(s, 6H), 2.61 (d, J = 20.8Hz, 2H), 1.83 (d, J = 6.8Hz, 3H).

[0712] Example 95: Preparation of ((4-(4-chloro-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0713] Step 1: Preparation of 7,9-difluoro-5H-pyrimido[5,4-b]indol-4-ol:

[0714] 3-Amino-4,6-difluoro-1H-indole-2-carboxamide (2 g, 9.47 mmol, 1 equivalent) was dissolved in ethanol (20 mL), and formamidine acetate (2 g, 18.9 mmol, 2 equivalents) was added. The reaction was heated to 100°C for 2 hours. LCMS monitored the reaction completion. The reaction solution was cooled and concentrated under reduced pressure. The filter cake was rinsed with ethanol, and the solid was collected and dried to obtain the title compound (1.6 g, 76.4%), which was used directly in the next reaction. LCMS (ESI): [MH] - =220.1.

[0715] Step 2: Preparation of 4-chloro-7,9-difluoro-5H-pyrimido[5,4-b]indole

[0716] 7,9-Difluoro-5H-pyrimido[5,4-b]indol-4-ol (442 mg, 2 mmol, 1 equivalent) was added to phenylphosphoryl dichloride (8 mL). The reaction system was heated to 180°C and stirred for one hour. The reaction solution was diluted with ethyl acetate (20 mL) and neutralized with sodium bicarbonate. The solution was extracted three times with ethyl acetate (30 mL x 3) and concentrated to obtain the title compound (300 mg, yield: 62.7%). LCMS (ESI): [M+H] + =240.0.

[0717] Step 3: Preparation of di-tert-butyl ((4-(4-chloro-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate:

[0718] 4-Chloro-7,9-difluoro-5H-pyrimido[5,4-b]indole (300 mg, 1.3 mmol, 1.0 equiv) was added to N,N-dimethylformamide (3 mL), followed by di-tert-butyl (4-bromomethyl)benzylphosphonate (708 mg, 1.9 mmol, 1.5 equiv), and finally potassium carbonate (692 mg, 5.0 mmol, 4.0 equiv). The reaction mixture was allowed to react at 80°C for two hours. The reaction was quenched with water (20 mL) and extracted three times with ethyl acetate (25 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 1 / 1)) to afford the title compound (500 mg, 74.6% yield) as a yellow solid. LCMS (ESI): [M+Na] + =558.1.

[0719] Step 4: Preparation of ((4-(4-chloro-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0720] Di-tert-butyl ((4-(4-chloro-7,9-difluoro-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzyl)phosphonate (200 mg, 0.37 mmol, 1.0 equiv) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (127 mg, 1.1 mmol, 3.0 equiv) was then added to the mixture, and the reaction was stirred at room temperature for two hours. The reaction solution was adjusted to a pH of approximately 7 with aqueous ammonia and concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC (C18, 10 mmol / L aqueous ammonia, acetonitrile) to afford the title compound (42.95 mg, 27.4% yield) as a white solid. LCMS (ESI): [M+H+MeCN] + =465.2,; 1 H NMR(400MHz, DMSO-d6)δ8.90(s,1H),7.58(dd,J=9.6,2.0Hz,1H),7.25(td,J=10.1,2.0Hz,1 H), 7.07 (dd, J = 8.0, 1.6 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 5.85 (s, 2H), 2.59 (d, J = 20.0 Hz, 2H).

[0721] Example 96: Preparation of (4-((2-cyano-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0722] Step 1: Preparation of diethyl (4-((2-cyano-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate:

[0723] Diethyl (4-((2-chloro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (300 mg, 0.68 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (3 mL). Zinc cyanide (239 mg, 2.0 mmol, 3.0 equiv), bis[2-(diphenylphosphino)cyclopenta-2,4-dien-1-yl]iron (75 mg, 0.14 mmol, 0.2 equiv), and tetrakis(triphenylphosphine)palladium (157 mg, 0.14 mmol, 0.2 equiv) were then added to the mixture. The reaction mixture was stirred at 110°C under microwave conditions for 1 hour. Completion of the reaction was monitored by LCMS. The reaction mixture was quenched with water (15 mL) and extracted three times with ethyl acetate (25 mL x 3). The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by flash chromatography (silica gel, dichloromethane:methanol (V / V=10 / 1)) to give the title compound (250 mg, yield: 85.2%) as a yellow solid. LCMS (ESI): [M+H]+=434.0.

[0724] Step 2: Preparation of (4-((2-cyano-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0725] Diethyl (4-((2-cyano-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (150 mg, 0.35 mmol, 1.0 equiv) was dissolved in dichloromethane (2 mL), and trimethylsilyl bromide (803 mg, 5.3 mmol, 15 equiv) was added to the mixture. The reaction mixture was stirred at 50°C for 1 hour. The reaction was monitored by LCMS. The reaction mixture was quenched with methanol and concentrated under reduced pressure to give a brown oily crude product. The crude product was prepared by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (102.77 mg, yield: 77.8%) as a white solid. LCMS(ESI): [M+H]+=378.0; 1H NMR (400MHz, DMSO-d6) δ8.28(d,J=7.6Hz,1H),8.23(d,J=8.4Hz,1H),7.98(d,J=8.4Hz,1H),7.77(d,J=8.4H z,1H),7.63(t,J=7.6Hz,1H),7.37(t,J=7.6Hz,1H),7.08-7.01(m,4H),5.64(s,2H),2.64(d,J=15.6Hz,2H).

[0726] Example 97: Preparation of (4-((2-isopropyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0727] Step 1: Preparation of diethyl (4-((2-(prop-1-en-2-yl)-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate

[0728] Diethyl (4-((2-chloro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (200 mg, 0.45 mmol, 1 equiv), isopropenylboronic acid pinacol ester (152 mg, 0.90 mmol, 2 equiv), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (66 mg, 0.09 mmol, 0.2 equiv), and cesium carbonate (441 mg, 1.34 mmol, 3 equiv) were dissolved in a mixture of dioxane (10 mL) and water (2 mL). The reaction was heated to 100°C under argon and stirred for 2 hours. The reaction solution was cooled to room temperature and quenched with aqueous solution. The mixture was extracted three times with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound (180 mg, yield: 88.9%) as an oil. LCMS (ESI): [M+H] + = 449.1.

[0729] Step 2: Preparation of diethyl (4-((2-isopropyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate

[0730] Diethyl (4-((2-(prop-1-en-2-yl)-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (180 mg, 0.40 mmol, 1 equivalent) was dissolved in methanol (30 mL) and palladium on carbon (90 mg, 10 wt%) was added. The atmosphere was replaced with hydrogen three times. The reaction mixture was heated to 40°C and stirred for 3 hours. The reaction mixture was filtered, the filter cake was washed three times with methanol, and the filtrates were combined and concentrated under reduced pressure to give the crude title compound (150 mg, 83.4% yield) as an oil. LCMS (ESI): [M+H]+ = 451.1.

[0731] Step 3: Preparation of (4-((2-isopropyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0732] Diethyl (4-((2-isopropyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (150 mg, 0.33 mmol, 1 equivalent) was dissolved in dichloromethane (30 mL). Silane bromide (1.0 mL) was added and the reaction was heated to 50°C and stirred for 2 hours. The reaction mixture was dried by rotary evaporation, and the crude product was purified by reverse-phase HPLC (C18, 10 mmol / L ammonia, acetonitrile) to afford the title compound (63 mg, 47.9% yield) as a white solid. LCMS(ESI): [M+H]+=395.1; 1H NMR (400MHz, Methanol-d4) δ8.40(d,J=8.0Hz,1H),7.89(d,J=8.8Hz,1H),7.58(d,J=8.0Hz,1H),7.52-7.48(m,1H),7.35(d,J=8 .8Hz,1H),7.31-7.24(m,3H),7.03-7.00(m,2H),5.53(s,2H),3.29-3.20(m,1H),2.81(d,J=19.6Hz,2H),1.40(d,J=7.0Hz,6H).

[0733] Example 98: Preparation of (4-((2-(methylthio)-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0734] Step 1: Preparation of 6-(methylthio)-3-nitro-2-phenylpyridine

[0735] 6-Chloro-3-nitro-2-phenylpyridine (600 mg, 2.6 mmol, 1 equivalent) was dissolved in methanol (8 mL), and a propylene glycol solution of methyl mercaptan (1.2 g, 10 wt%, 1 equivalent) and potassium carbonate (600 mg, 4.3 mmol, 1.7 equivalent) were added. The reaction solution was stirred at 80°C under argon for 3 hours, then cooled and quenched with saturated ammonium chloride solution (10 mL). The mixture was extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, concentrated under reduced pressure, and purified on a preparative plate (PE:EA (V / V = 1 / 1)) to obtain the title compound (350 mg, yield: 55.5%) as a yellow liquid. LCMS (ESI): [M+H] + =247.0.

[0736] Step 2: Preparation of 2-(methylthio)-5H-pyrido[3,2-b]indole

[0737] 6-(Methylthio)-3-nitro-2-phenylpyridine (350 mg, 1.4 mmol, 1 equivalent) was dissolved in 1,2-dichlorobenzene (5 mL) and triphenylphosphine (373 mg, 1.4 mmol, 1 equivalent) was added. The reaction mixture was stirred at 200°C under argon for 2 hours. The reaction mixture was concentrated under reduced pressure and purified on a preparative plate (PE:EA (V / V = 3 / 1)) to give the title compound (40 mg, yield: 13.1%) as a yellow liquid. LCMS (ESI): [M+H] + =215.0.

[0738] Step 3: Preparation of diethyl (4-((2-(methylthio)-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate

[0739] 2-(Methylthio)-5H-pyrido[3,2-b]indole (40 mg, 0.2 mmol, 1 equiv) was dissolved in tetrahydrofuran (5 mL) and sodium hydride (40 mg, 60 wt%, 1.0 mmol, 5 equiv) was added. After stirring at room temperature for half an hour, diethyl (4-(bromomethyl)benzyl)phosphonate (120 mg, 0.4 mmol, 2 equiv) was added. The reaction solution was stirred at room temperature under argon for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (60 mg, yield: 70.7%) as a yellow liquid. LCMS (ESI): [M+H] + =455.1.

[0740] Step 4: Preparation of (4-((2-(methylthio)-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0741] Diethyl (4-((2-(methylthio)-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (60 mg, 0.1 mmol, 1 equivalent) was dissolved in dichloromethane (5 mL), and trimethylsilyl bromide (1.0 mL) was added. The reaction solution was stirred at 40°C under argon protection for 1 hour. LCMS monitored the reaction completion, and the title compound was purified by reverse phase HPLC (C18, 10 mmol / aqueous ammonia, acetonitrile) to obtain the title compound (3.04 mg, yield: 5.8%) as a white solid. LCMS (ESI): [M+H] + =399.0; 1 H NMR(400MHz, Methanol-d4)δ8.30(d,J=8.0Hz,1H),7.81(d,J=8.8Hz,1H),7.57-7.50(m,2H) ,7.32-7.21(m,4H),7.05(d,J=8.0Hz,2H),5.55(s,2H),2.93(d,J=21.2Hz,2H),2.67(s,3H).

[0742] Example 99: Preparation of (4-((2-chloro-7,9-difluoro-5H-pyridin[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0743] Step 1: Preparation of 6-chloro-2-(2,4-difluorophenyl)-3-nitropyridine

[0744] 2-Bromo-6-chloro-3-nitropyridine (4.20 g, 17.69 mmol, 1 equiv), (2,4-difluorophenyl)boronic acid (2.51 g, 15.92 mmol, 0.9 equiv), tetrakis(triphenylphosphine)palladium (2.04 g, 1.77 mmol, 0.1 equiv), and potassium carbonate (7.33 g, 53.07 mmol, 3 equiv) were dissolved in a mixture of dioxane (30 mL) and water (6 mL). The reaction was heated to 100°C under argon and stirred for 2 hours. After completion of the reaction, as monitored by LCMS, the reaction solution was cooled to room temperature and quenched with aqueous solution. The mixture was extracted with dichloromethane (500 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by reverse-phase HPLC (C18, 10 mmol / L formic acid, acetonitrile) to give the title compound (2.90 g, yield: 60.6%) as a white solid. LCMS (ESI): [M+H]+ =271.1.

[0745] Step 2: Preparation of 2-chloro-7,9-difluoro-5H-pyrido[3,2-b]indole:

[0746] 6-Chloro-2-(2,4-difluorophenyl)-3-nitropyridine (2.9 g, 10.72 mmol, 1 equivalent) was dissolved in o-dichlorobenzene (10 mL), and triphenylphosphine (5.62 g, 21.44 mmol, 2 equivalents) was added to the mixture. The reaction mixture was continued at 200°C under nitrogen for 2 hours. The reaction was monitored by LCMS. After the reaction solution was concentrated under reduced pressure, the crude product was separated and purified by flash chromatography (silica gel, dichloromethane:methanol (V / V=10 / 1)) to obtain the title compound (1.35 g, yield: 52.8%) as a white solid. LCMS (ESI): [M+H] + =239.0.

[0747] Step 3: Preparation of diethyl (4-((2-chloro-7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate:

[0748] 2-Chloro-7,9-difluoro-5H-pyrido[3,2-b]indole (700 mg, 2.93 mmol, 1 eq) was dissolved in tetrahydrofuran (30 mL). Sodium hydride (224 mg, 60 wt%, 5.86 mmol, 2 eq) was then added to the mixture at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, followed by the addition of diethyl (4-(bromomethyl)benzyl)phosphonate (1.88 g, 5.86 mmol, 2 eq). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored for completion by LCMS. The reaction mixture was quenched with water and extracted with ethyl acetate (200 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (585 mg, 41.7% yield) as a yellow solid. LCMS (ESI): [M+H] + =479.1.

[0749] Step 4: Preparation of (4-((2-chloro-7,9-difluoro-5H-pyridin[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0750] Diethyl (4-((2-chloro-7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (200 mg, 0.42 mmol, 1 equivalent) was dissolved in dichloromethane (20 mL), and trimethylsilyl bromide (2 mL) was added. The reaction was heated to 40°C and stirred for 2 hours. The reaction was monitored for completion by LCMS. The reaction solution was dried and the crude product was prepared by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (65 mg, yield: 36.6%) as a white solid. LCMS (ESI) [M+H] + =423.1; 1 H NMR (400MHz, Methanol-d4) δ7.99(d,J=8.8Hz,1H),7.43(d,J=8.8Hz,1H),7.32(dd,J=8.4,2.0Hz,2H),7. 26(dd,J=9.6,2.0Hz,1H),7.02(d,J=8.0Hz,2H),6.88-6.81(m,1H),5.53(s,2H),2.82(d,J=20.0Hz,2H).

[0751] Example 100: Preparation of (4-((7,9-difluoro-2-methyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0752] Step 1: Preparation of diethyl (4-((7,9-difluoro-2-methyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate

[0753] Diethyl (4-((2-chloro-7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (50 mg, 0.10 mmol, 1 equiv), methylboronic acid (13 mg, 0.20 mmol, 2 equiv), tetrakis(triphenylphosphine)palladium (20 mg, 0.02 mmol, 0.2 equiv), and cesium carbonate (102 mg, 0.30 mmol, 3 equiv) were dissolved in a mixture of dioxane (10 mL) and water (2 mL). The reaction was heated to 100°C under argon and stirred for 2 hours. After completion of the reaction, as monitored by LCMS, the reaction solution was cooled to room temperature and quenched with aqueous solution. The mixture was extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound (crude product, 60 mg) as an oil. LCMS(ESI):[M+H] + =459.1.

[0754] Step 2: Preparation of (4-((7,9-difluoro-2-methyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0755] Diethyl (4-((7,9-difluoro-2-methyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (60 mg, 0.13 mmol, 1 equivalent) was dissolved in dichloromethane (5 mL), and trimethylsilyl bromide (1 mL) was added. The reaction solution was stirred at 40°C under argon protection for 2 hours. LCMS monitored the reaction completion, and the title compound was purified by reverse phase preparative purification (C18, 10 mmol / aqueous ammonia, acetonitrile) to obtain the title compound (6.20 mg, yield: 11.8%) as a white solid. LCMS (ESI): [M+H] + =402.9; 1 H NMR (400MHz, Methanol-d4) δ7.87(d,J=8.4Hz,1H),7.32(d,J=8.4Hz,1H),7.25-7.23(m,2H),7.19(dd,J=9 .6,1.6Hz,1H),7.05(d,J=7.9Hz,2H),6.86-6.80(m,1H),5.54(s,2H),2.93(d,J=21.2Hz,2H),2.70(s,3H).

[0756] Example 101: Preparation of (4-((7,9-difluoro-2-isopropyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0757] Step 1: Preparation of diethyl (4-((7,9-difluoro-2-(prop-1-en-2-yl)-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate

[0758] Diethyl (4-((2-chloro-7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (350 mg, 0.73 mmol, 1 equiv), isopropenylboronic acid pinacol ester (245 mg, 1.46 mmol, 2 equiv), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (107 mg, 0.15 mmol, 0.2 equiv), and cesium carbonate (714 mg, 2.19 mmol, 3 equiv) were dissolved in a mixture of dioxane (15 mL) and water (3 mL). The reaction was heated to 100°C under argon and stirred for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature and quenched with aqueous solution. The mixture was extracted three times with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (300 mg, yield: 84.8%) as an oil. LCMS (ESI): [M+H] + =485.1.

[0759] Step 2: Preparation of diethyl (4-((7,9-difluoro-2-isopropyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate

[0760] Diethyl (4-((7,9-difluoro-2-(prop-1-en-2-yl)-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (250 mg, 0.52 mmol, 1 equivalent) was dissolved in methanol (40 mL), and palladium carbon (150 mg, 10 wt %) was added. The gas was replaced with hydrogen three times, and the reaction was heated to 40° C. and stirred for 3 hours. The reaction was monitored for completion by LCMS. The reaction solution was filtered, the filter residue was washed three times with methanol, the filtrate was combined, and the filtrate was concentrated under reduced pressure to give the crude title compound (200 mg, yield: 78.8%) as an oil. LCMS (ESI): [M+H] + =487.1.

[0761] Step 3: Preparation of (4-((7,9-difluoro-2-isopropyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0762] Diethyl (4-((7,9-difluoro-2-isopropyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (200 mg, 0.41 mmol, 1 equivalent) was dissolved in dichloromethane (30 mL), and trimethylsilyl bromide (627 mg, 4.10 mmol, 10 equivalents) was added. The reaction was heated to 40°C and stirred for 1 hour. The reaction was monitored for completion by LCMS, and the reaction solution was dried by rotary evaporation. The crude product was purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (117 mg, yield: 66.1%) as a white solid. LCMS (ESI): [M+H] + =431.1; 1 H NMR (400MHz, Methanol-d4) δ7.89(d,J=8.4Hz,1H),7.35(d,J=8.4Hz,1H),7.32(dd,J=8.0,2.0Hz,2H),7.18(dd,J=9.6,2.0Hz ,1H),7.01(d,J=9.6Hz,2H),6.82-6.76(m,1H),5.50(s,2H),3.31-3.21(m,1H),2.82(d,J=19.6Hz,2H),1.37(d,J=7.2Hz,6H).

[0763] Example 102: Preparation of (4-((7,9-difluoro-2-methylamino-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0764] Step 1: Preparation of diethyl (4-((7,9-difluoro-2-methylamino-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate

[0765] Diethyl (4-((2-chloro-7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (100 mg, 0.21 mmol, 1 equiv), a solution of methylamine in tetrahydrofuran (2.1 mL, 4.20 mmol, 2 M), palladium acetate (14 mg, 0.06 mmol, 0.3 equiv), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (60 mg, 0.06 mmol, 0.3 equiv), and cesium carbonate (204 mg, 0.63 mmol, 3 equiv) were dissolved in a mixture of dioxane (10 mL) and water (2 mL). The reaction was heated to 100°C under argon and stirred for 18 hours. After completion of the reaction, as monitored by LCMS, the reaction solution was cooled to room temperature and quenched with aqueous solution. The mixture was extracted three times with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (20 mg, yield: 20.2%) as an oil. LCMS (ESI): [M+H] + =474.1.

[0766] Step 2: Preparation of (4-((7,9-difluoro-2-methylamino-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0767] Diethyl (4-((7,9-difluoro-2-methylamino-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (20 mg, 0.04 mmol, 1 equivalent) was dissolved in dichloromethane (5 mL), and trimethylsilyl bromide (62 mg, 0.40 mmol, 10 equivalents) was added. The reaction was heated to 40°C and stirred for 2 hours. The reaction was monitored for completion by LCMS, and the reaction solution was dried. The crude product was purified by reverse phase HPLC (C18, 10 mmol / L formic acid, acetonitrile) to give the title compound (1.36 mg, yield: 6.3%) as a white solid. LCMS (ESI): [M+H] + =418.1; 1 H NMR (400MHz, DMSO-d6) δ7.72(d,J=8.8Hz,1H),7.33(d,J=10.0Hz,1H),7.08(d,J=7.2Hz,2H),6.98(d,J=8.0Hz,2 H), 6.85 (t, J = 10.4Hz, 1H), 6.58 (d, J = 8.8Hz, 1H), 6.36 (s, 1H), 5.46 (s, 2H), 2.84 (s, 3H), 2.69 (d, J = 20.0Hz, 2H).

[0768] Example 103: Preparation of (4-((7,8-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0769] Step 1: Preparation of 2-(3,4-difluorophenyl)-3-nitropyridine:

[0770] 2-Chloro-3-nitropyridine (1.0 g, 6.31 mmol, 1 equiv) and (3,4-difluorophenyl)boronic acid (1 g, 6.94 mmol, 1.1 equiv) were dissolved in a mixed solvent of 1,4-dioxane (8 mL) and water (2 mL). Potassium carbonate (2.6 g, 18.93 mmol, 3 equiv) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (463 mg, 0.63 mmol, 0.1 equiv) were then added. Under nitrogen protection, the mixture was heated to 120°C for 2 h. After completion of the reaction, the reaction was quenched with saturated ammonium chloride aqueous solution and extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (1.3 g, yield: 87.2%). LCMS (ESI): [M+H] + =237.0.

[0771] Step 2: Preparation of 7,8-difluoro-5H-pyrido[3,2-b]indole and 6,7-difluoro-5H-pyrido[3,2-b]indole:

[0772] 2-(3,4-Difluorophenyl)-3-nitropyridine (1.0 g, 4.23 mmol, 1 equivalent) was dissolved in dichlorobenzene (10 mL), and triphenylphosphine (2.2 g, 8.47 mmol, 2 equivalents) was added. The temperature was raised to 200°C and the reaction was stirred for 5 h. After completion of the reaction, the mixture was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase HPLC (C18, 10 mmol / L formic acid, acetonitrile) to obtain the title compound A (200 mg, yield: 23.1%) and the title compound B (15 mg, yield: 1.7%).

[0773] 7,8-Difluoro-5H-pyrido[3,2-b]indole: LCMS(ESI):[M+H] + =205.0; 1H NMR (400MHz, DMSO-d6) δ11.72(s,1H),8.47(d,J=4.4Hz,1H),8.13-8.11(m,1H),7.92(d,J=8.0Hz,1H),7.63-7.60(m,1H),7.42-7.39(m,1H).

[0774] 6,7-Difluoro-5H-pyrido[3,2-b]indole: LCMS(ESI):[M+H] + =205.0; 1 H NMR (400MHz, DMSO-d6) δ12.22 (s, 1H), 8.47 (dd, J = 4.4, 1.2Hz, 1H), 7.99-7.57 (m, 1H),7.92(dd,J=8.0,1.2Hz,1H),7.45(dd,J=8.4,2.4Hz,1H),7.28-7.23(m,1H).

[0775] Step 3: Preparation of diethyl (4-((7,8-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate:

[0776] 7,8-Difluoro-5H-pyrido[3,2-b]indole (100 mg, 0.49 mmol, 1 eq) was dissolved in tetrahydrofuran (2 mL), and sodium hydride (78 mg, 60 wt%, 1.96 mmol, 4 eq) was added. Under nitrogen, the reaction mixture was stirred at room temperature for 0.5 h. Diethyl (4-(bromomethyl)benzyl)phosphonate (315 mg, 0.98 mmol, 2 eq) was added, and stirring was continued for 1 h. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride and extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to yield the title compound (80 mg, 36.7% yield). LCMS (ESI): [M+H] + =445.1.

[0777] Step 4: Preparation of (4-((7,8-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid:

[0778] Diethyl (4-((7,8-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate (70 mg, 0.16 mmol, 1 equivalent) was dissolved in dichloromethane (1 mL), and trimethylsilyl bromide (245 mg, 1.6 mmol, 10 equivalents) was added. The temperature was raised to 40°C and the reaction was allowed to react for 2 hours. The reaction was monitored by LCMS, quenched with methanol, and the crude product was purified by reverse phase HPLC (C18, 10 mmol / L ammonia water, acetonitrile) to give the title compound (7.41 mg, yield: 11.9%). LCMS (ESI) [M+H] + =389.0; 1 H NMR (400MHz, Methanol-d4) δ8.45(dd,J=4.8,1.2Hz,1H),8.14(dd,J=10.4,8.0Hz,1H),8.03(d,J=7.2Hz,1H),7.57(dd,J=1 1.2, 6.4Hz, 1H), 7.46 (dd, J = 8.4, 4.8Hz, 1H), 7.31-7.29 (m, 2H), 7.03 (d, J = 8.0Hz, 2H), 5.56 (s, 2H), 2.84 (d, J = 20.0Hz, 2H).

[0779] Example 104: Preparation of (4-((6,7-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0780] Similarly, using the synthesized 6,7-difluoro-5H-pyrido[3,2-b]indole as the starting material, Example 104 was prepared according to Steps 3-4 of the preparation method of Example 89. LCMS (ESI) [M+1] + =389.0; 1 H NMR(400MHz,Methanol-d4)δ8.47(d,J=3.2Hz,1H),8.09-8.06(m,2H),7.48(dd,J=8.4,2.4Hz,1H),7.3 1(dd,J=8.0,2.4Hz,2H),7.22-7.16(m,1H),7.02(d,J=8.0Hz,2H),5.70(s,2H),2.82(d,J=20.0Hz,2H).

[0781] Example 105: Preparation of (4-((7,9-difluoro-3-methyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0782] Similarly, using commercially available 2-chloro-5-methyl-3-nitropyridine and 2,4-difluorophenylboronic acid as starting materials, Example 105 was prepared according to Steps 1-4 of the preparation method of Example 89. LCMS (ESI) [M+1] + =403.1; 1 H NMR (400MHz, Methanol-d4) δ8.32(s,1H),7.81(s,1H),7.25(dd,J=8.0,2.0Hz,2H),7.17(dd,J=9.6,2 .0Hz,1H),7.05(d,J=8.0Hz,2H),6.86-6.80(m,1H),5.52(s,2H),2.90(d,J=20.8Hz,2H),2.52(s,3H).

[0783] Example 106: Preparation of (4-((7,9-difluoro-4-methyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0784] Similarly, using commercially available 2-chloro-4-methyl-3-nitropyridine and 2,4-difluorophenylboronic acid as starting materials, Example 106 was prepared according to Steps 1-4 of the preparation method of Example 89. LCMS (ESI) [M+1] + =403.1; 1 H NMR (400MHz, Methanol-d4) δ8.33(d,J=4.8Hz,1H),7.32(d,J=8.0Hz,2H),7.22(d,J=4.8Hz,1H),7.10(d, J=9.6Hz,1H),6.87-6.82(m,1H),6.79(d,J=8.0Hz,2H),5.76(s,2H),2.83(d,J=20.0Hz,2H),2.70(s,3H).

[0785] Example 107: Preparation of (4-((7,9-difluoro-3-fluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid

[0786] Similarly, using commercially available 2-chloro-5-fluoro-3-nitropyridine and 2,4-difluorophenylboronic acid as starting materials, Example 107 was prepared according to Steps 1-4 of the preparation method of Example 89. LCMS (ESI) [M+1] + =407.0; 1HNMR (400MHz, Methanol-d4) δ8.38 (s, 1H), 7.87 (d, J = 9.6Hz, 1H), 7.39-7.20 (m, 3H),7.07-7.05(m,2H),6.89-6.87(m,1H),5.54(s,2H),2.82(d,J=20.0Hz,2H).

[0787] Example 108: Preparation of 2-(4-((7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)-N-hydroxyacetamide

[0788] Step 1: Preparation of methyl 2-(4-((7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)acetate

[0789] 7,9-Difluoro-5H-pyrido[3,2-b]indole (210 mg, 1.03 mmol, 1 equivalent) and methyl 2-(4-(bromomethyl)phenyl)acetate (500 mg, 2.06 mmol, 2 equivalents) were dissolved in acetonitrile (10 mL), and cesium carbonate (672 mg, 2.06 mmol, 2 equivalents) was added. The reaction was heated to 70°C and stirred for 3 hours. The reaction was monitored for completion by LCMS. The reaction solution was concentrated and then diluted with water (50 mL). The mixture was extracted three times with dichloromethane (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried to give the crude title compound (200 mg, yield: 53.0%). LCMS (ESI): [M+H] + =367.1.

[0790] Step 2: Preparation of 2-(4-((7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)-N-hydroxyacetamide

[0791] Methyl 2-(4-((7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)acetate (350 mg, 0.96 mmol, 1 equivalent) was dissolved in tetrahydrofuran:water:methanol (V / V / V=1:1:1, 12 mL), and hydroxylamine hydrochloride (2.0 g, 28.8 mmol, 30 equivalents) and potassium hydroxide (1.62 g, 28.8 mmol, 30 equivalents) were added. The reaction was stirred at room temperature for 5 hours. The reaction was monitored by LCMS for completion, and the reaction solution was concentrated under reduced pressure. The crude product was prepared by reverse phase HPLC (C18, 10 mmol / L formic acid, acetonitrile) to give the title compound (33.38 mg, yield: 9.5%) as a white solid. LCMS (ESI): [M+H] + =368.1; 1 H NMR (400MHz, DMSO-d6) δ10.58(s,1H),8.75(s,1H),8.53(d,J=3.6Hz,1H),8.08(d,J=7.2Hz,1H), 7.56(d,J=8.0Hz,1H),7.46(dd,J=8.4,4.4Hz,1H),7.17-7.08(m,5H),5.67(s,2H),3.20(s,2H).

[0792] Example 109: Preparation of 2-(4-((5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)-N-hydroxyacetamide

[0793] Similarly, using commercially available 5-pyrido[3,2-b]indole and methyl 2-(4-(bromomethyl)phenyl)acetate as starting materials, Example 109 was prepared according to Steps 1-2 of the preparation method of Example 108. LCMS (ESI) [M+1] + =332.2; 1 H NMR (400MHz, DMSO-d6) δ10.56(s,1H),8.72(s,1H),8.49(d,J=4.4Hz,1H),8.25-8.22(m,1H),8.07(d,J=8.4Hz,1H),7.71(d,J =8.8Hz,1H),7.57-7.53(m,1H),7.44(dd,J=8.4,4.8Hz,1H),7.31-7.28(m,1H),7.16-7.10(m,4H),5.67(s,2H),3.19(s,2H).

[0794] Example 110: Preparation of 2-(4-((8-chloro-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)-N-hydroxyacetamide

[0795] Similarly, using commercially available 8-chloro-5H-pyrido[3,2-b]indole and methyl 2-(4-(bromomethyl)phenyl)acetate as starting materials, Example 110 was prepared according to Steps 1-2 of the preparation method of Example 108. LCMS (ESI) [M+1] + =366.2; 1 H NMR (400MHz, DMSO-d6) δ10.57(s,1H),8.59(d,J=8.0Hz,1H),8.24(d,J=8.0Hz,2H),7 .81(d,J=8.0Hz,1H),7.63-7.59(m,2H),7.16-7.09(m,4H),5.71(s,2H),3.19(s,2H).

[0796] Example 111: Preparation of 5-(7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)-N-hydroxyvaleramide

[0797] Similarly, using commercially available methyl 5-bromopentanoate and the intermediate 7,9-difluoro-5H-pyrido[3,2-b]indole as starting materials, Example 111 was prepared according to Steps 1-2 of the preparation method of Example 108. LCMS (ESI) [M+1] + =320.1; 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),8.52(d,J=4.4Hz,1H),8.10(d,J=8.0Hz,1H),7.57-7.53(m,1H),7.48(dd,J=8. 4,4.8Hz,1H),7.10-7.04(m,1H),4.43(t,J=7.2Hz,2H),1.96(t,J=7.6Hz,2H),1.76-1.69(m,2H),1.54-1.46(m,2H).

[0798] Example 112: Preparation of 4-(7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)-N-hydroxybutyramide

[0799] Similarly, using commercially available methyl 4-bromobutyrate and the intermediate 7,9-difluoro-5H-pyrido[3,2-b]indole as starting materials, Example 112 was prepared according to Steps 1-2 of the preparation method of Example 108. LCMS (ESI) [M+1] + =306.1; 1H NMR (400MHz, DMSO-d6) δ10.35(s,1H),8.71(s,1H),8.52(d,J=4.4Hz,1H),8.09(d,J=8.4Hz,1H),7.54(dd,J =10.0,2.0Hz,1H),7.49(dd,J=8.4,4.4Hz,1H),7.11-7.05(m,1H),4.42(t,J=6.4Hz,2H),2.03-1.98(m,4H).

[0800] Example 113: Preparation of 4-((7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)-N-hydroxybenzamide

[0801] Similarly, using commercially available ethyl 4-(bromomethyl)benzoate and the intermediate 7,9-difluoro-5H-pyrido[3,2-b]indole as starting materials, Example 113 was prepared according to Steps 1-2 of the preparation method of Example 108. LCMS (ESI) [M+1] + =354.1; 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),8.98(s,1H),8.54(d,J=4.0Hz,1H),8.09(d,J=8.0Hz,1H),7.65(d,J=8.4H z,2H),7.57(d,J=8.4Hz,1H),7.48(dd,J=8.4,4.4Hz,1H),7.23(d,J=8.0Hz,2H),7.15-7.10(m,1H),5.76(s,2H).

[0802] Example 114: Preparation of 2-(4-(7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)phenyl)-N-hydroxyacetamide

[0803] Step 1: Preparation of methyl 2-(4-(7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)phenyl)acetate:

[0804] 7,9-difluoro-5H-pyrido[3,2-b]indole (400 mg, 1.96 mmol, 1.0 equiv), methyl 2-(4-bromophenyl)acetate (897 mg, 3.92 mmol, 2 equiv), iodide (38 mg, 0.40 mmol, 0.2 equiv) and cesium carbonate (1.18 g, 5.88 mmol, 3 equiv) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was stirred at 120 ° C for 16 hours. The reaction was monitored by LCMS. The reaction solution was quenched with water and extracted three times with ethyl acetate (100 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (350 mg, yield: 50.7%) as a yellow solid. LCMS (ESI): [M+H] + =353.1.

[0805] Step 2: Preparation of 2-(4-(7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)phenyl)-N-hydroxyacetamide

[0806] Methyl 2-(4-(7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)phenyl)acetate (70 mg, 0.20 mmol, 1 eq) was dissolved in 9 mL of tetrahydrofuran:water:methanol (3:3:3), and hydroxylamine hydrochloride (276 mg, 3.97 mmol, 20 eq) and potassium hydroxide (223 mg, 3.97 mmol, 20 eq) were added. The reaction was heated to 60°C for 10 hours. The reaction was monitored for completion by LCMS. The reaction solution was dried and the crude product was purified by reverse phase HPLC (C18, 10 mmol / L formic acid, acetonitrile) to give the title compound (4 mg, 5.7% yield) as a white solid. LCMS (ESI): [M+H] + =354.1; 1 H NMR (400MHz, DMSO-d6) δ10.76(s,1H),8.92(s,1H),8.61(d,J=3.6Hz,1H),7.76(d,J=8.4Hz,1H),7.63- 7.57(m,4H),7.47(dd,J=8.4,4.4Hz,1H),7.24-7.18(m,1H),7.05(dd,J=9.2,1.6Hz,1H),3.46(s,2H).

[0807] Example 115: Preparation of 3-(7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)-N-hydroxypropionamide

[0808] Similarly, using commercially available methyl 3-bromopropionate and the intermediate 7,9-difluoro-5H-pyrido[3,2-b]indole as starting materials, Example 115 was prepared according to Steps 1-2 of the preparation method of Example 108. LCMS (ESI) [M+1] + =291.1; 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.51(d,J=4.4Hz,1H),8.05(d,J=8.0Hz, 1H),7.49-7.47(m,2H),7.10-7.06(m,1H),4.63(t,J=6.4Hz,2H),2.52(s,2H).

[0809] Example 116: Preparation of 3-(4-((7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)-N-hydroxypropionamide

[0810] Similarly, using commercially available methyl 3-(4-(bromomethyl)phenyl)propanoate and the intermediate 7,9-difluoro-5H-pyrido[3,2-b]indole as starting materials, Example 116 was prepared according to Steps 1-2 of the preparation method of Example 108. LCMS (ESI) [M+1] + =382.2; 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),8.54(dd,J=4.8,1.6Hz,1H),8.12(dd,J=8.4,1.2Hz,1H),7.58(dd,J=10.0,2. 0Hz,1H),7.48(dd,J=8.4,4.8Hz,1H),7.13-7.08(m,5H),5.66(s,2H),2.73(t,J=7.2Hz,2H),2.18(t,J=8.0Hz,2H).

[0811] Example 117: Preparation of 2-(4-((2-chloro-7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)-N-hydroxyacetamide

[0812] Similarly, using commercially available methyl 2-(4-(bromomethyl)phenyl)acetate and the intermediate 2-chloro-7,9-difluoro-5H-pyrido[3,2-b]indole as starting materials, Example 117 was prepared according to Steps 1-2 of the preparation method of Example 108. LCMS (ESI) [M+1] + =402.1; 1H NMR (400MHz, DMSO-d6) δ10.58(s,1H),8.75(d,J=1.6Hz,1H),8.19(d,J=8.8Hz,1H),7.6 0(d,J=8.0Hz,1H),7.56(d,J=8.8Hz,1H),7.17-7.12(m,5H),5.69(s,2H),3.20(s,2H).

[0813] Example 118: Preparation of 2-(4-((7,9-difluoro-2-methyl-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)-N-hydroxyacetamide

[0814] Step 1: Preparation of 2-(4-((7,9-difluoro-2-methyl-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)-N-hydroxyacetamide

[0815] Methyl 2-(4-((2-chloro-7,9-difluoro-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)acetate (12 mg, 0.03 mmol, 1 equiv), 2,4,6-trimethyl-1,3,5-trioxotriborane (8 mg, 0.06 mmol, 2 equiv), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (4.4 mg, 0.01 mmol, 0.2 equiv), and cesium carbonate (29 mg, 0.09 mmol, 3 equiv) were dissolved in a mixture of dioxane (2.5 mL) and water (0.5 mL). The reaction was heated to 120°C under argon and stirred in a microwave for 1 hour. The reaction was monitored for completion by LCMS, and the reaction solution was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (C18, 10 mmol / L formic acid, acetonitrile) to afford the title compound (4.86 mg, 11.4% yield) as a white solid. LCMS (ESI): [M+H] + =382.1; 1 H NMR(400MHz,DMSO-d6)δ10.58 (s,1H),8.75(s,1H),7.97(d,J=8.8Hz,1H),7.51(d,J=10.0Hz,1H),7.33(d,J=8.4Hz, 1H),7.16-7.08(m,4H),7.04(d,J=10.4Hz,1H),5.63(s,2H),3.20(s,2H),2.63(s,3H).

[0816] Example 119: Preparation of 2-(4-((7,9-dichloro-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)-N-hydroxyacetamide

[0817] Similarly, using commercially available 2-bromo-3-nitropyridine and 2,4-dichlorophenylboronic acid as starting materials, following steps 1-2 of the preparation method of Example 89, and then following steps 1-2 of the preparation method of Example 108, Example 119 was prepared. LCMS (ESI) [M+1] + =399.9; 1 H NMR (400MHz, DMSO-d6, ppm) δ10.59(s,1H),8.61(s,1H),8.14(d,J=8.8Hz,1H),7.93(s,1H),7.55- 7.52(m,1H),7.43(s,1H),7.17(d,J=8.4Hz,2H),7.09(d,J=8.0Hz,2H),5.73(s,2H),3.21(s,2H).

[0818] Example 120: Preparation of 4-((5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide

[0819] Step 1: Preparation of 4-((5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide:

[0820] 5H-pyrido[3,2-b]indole (100 mg, 0.59 mmol, 1.0 equiv) was added to N-(N-(dimethylformamide)) (1 mL). Sodium hydride (35 mg, 0.89 mmol, 1.5 equiv) was then added at 0°C. The resulting mixture was purged with argon three times and allowed to react at room temperature for 30 minutes. 4-(Bromomethyl)benzenesulfonamide (149 mg, 0.59 mmol, 1.0 equiv) was then added portionwise. The reaction mixture was allowed to react at room temperature for 16 hours. Upon completion of the reaction, LCMS was used to quench th...

Claims

1. A compound of formula (I), and its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs, in L is selected from -(NR L3 )SO2N(R L1 )(R L2 ),-SO2R L1 、-C(O)OR L1 、-C(O)N(R L1 )(R L2 )、-C(O)NHOR L1 、-P(O)(OR L1 )(OR L2 )、-P(O)(NHR L1 )(OR L2 )、-P(O)(OR L1 )(R L2 )、-P(O)(NHR L1 )(NHR L2 )、-P(O)(NHR L1 )(R L2 )、-P(O)(R L1 )(R L2 )、-P(O)(SR L1 )(SR L2 )、-P(O)(NHR L1 )(SR L2 )、-P(O)(SR L1 )(R L2 ) or -B(OH)2, where R L1 , R L2 and R L3 R is independently selected from hydrogen, deuterium, halogen, amino, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl or optionally substituted aryl; or R L1 and R L2 connected to form an optionally substituted ring structure; A is selected from optionally substituted alkylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylenealkylene, optionally substituted heterocyclylenealkylene, optionally substituted arylenealkylene, or optionally substituted heteroarylenealkylene; Z is selected from —(chemical bond), —O—, —S—, —CO—, —SO—, —SO2—, —C(R Z1 )(R Z2 )-、-N(RZ1 )-、-CH2N(R Z1 )-、-N(R Z1 )CH2-、-CON(R Z1 )-、-N(R Z1 )CO-、-SON(R Z1 )-、-SO2N(R Z1 )-、-N(R Z1 )SO-、-N(R Z1 )SO2- or Where R Z1 and R Z2 is independently selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl or optionally substituted heterocyclyl; R 1 is selected from deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, -OR 3 、-SR 3 、-NR 3 R 4 、-COOR 3 、-CONR 3 R 4 、-NR 3 COR 4 、-COR 3 、-OCOR 3 ,-SONR 3 R 4 、-SO2NR 3 R 4 、-NR 3 SOR 4 、-NR 3 S02R 4 or -Si(R 3 )(R 4 )(R 5 ), where R 3 , R 4 or R 5 is independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; n = 0, 1, 2 or 3; X 1 , X 2 , X 3 and X 4 are independently selected from N or C(RX ), where R X are independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, -OR a 、-SR a 、-NR a R b 、-COOR a 、-CONR a R b 、-NR b COR a 、-COR a 、-OCOR a ,-SONR a R b 、-SO2NR a R b 、-NR b SOR a 、-NR b S02R a or -Si(R a )(R b )(R c ), where R a , R b and R c X is independently selected from hydrogen, deuterium, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; or X 1 With X 2 are linked to form an optionally substituted ring structure; or X 2 With X 3 are linked to form an optionally substituted ring structure; or X 3 With X 4 are linked to form an optionally substituted ring structure; or X 1 and Z are linked together to form an optionally substituted ring structure.

2. The compound according to claim 1, wherein R L1 , R L2 and R L3 are independently selected from hydrogen, deuterium, halogen, amino, cyano, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 4-6 membered heterocyclic group or optionally substituted C 6-10 Aryl.

3. The compound according to claim 1, wherein RL1 , R L2 and R L3 independently selected from hydrogen, deuterium, halogen, amino, cyano; unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl; and alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, thiol, amino, cyano, alkyl (e.g., C 1-6 Alkyl), alkenyl (e.g. C 2-6 alkenyl), alkynyl (e.g. 2-6 Alkynyl), cycloalkyl (e.g. C 3-6 cycloalkyl), heterocyclyl (e.g., 4-6 membered heterocyclyl), -OC(O)-alkyl (e.g., -OC(O)-C 1-6 alkyl), -C(O)O-alkyl (e.g. -C(O)OC 1-6 alkyl), -OC(O)O-alkyl (e.g. -OC(O)OC 1-6 alkyl), phenyl or halogenated phenyl (e.g. chlorophenyl or fluorophenyl).

4. The compound according to claim 1, wherein L is selected from: -(NR L3 )SO2N(R L1 )(R L2 ),-SO2R L1 、-C(O)OR L1 、-C(O)NHOR L1 、-P(O)(OR L1 )(OR L2 )、-P(O)(NHR L1 )(OR L2 )、-P(O)(NHR L1 )(NHR L2 ) or -B(OH)2.

5. The compound according to claim 1, wherein R L1 , R L2 and R L3 are independently selected from hydrogen, amino, optionally substituted alkyl (e.g., C 1-6 alkyl) and optionally substituted aryl (e.g. C 6-10 Aryl); Preferably, R L1 , R L2 and R L3 independently selected from hydrogen, unsubstituted alkyl and phenyl, and alkyl substituted with one or more substituents independently selected from: -OC(O)-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, phenyl or halogenated phenyl.

6. The compound of claim 1, wherein L is selected from: -P(O)(OH)2, -C(O)OH, -C(O)NHOH, -B(OH)2, -SO2NH2, -NHSO2NH2, -P(O)(OCH2OC(O)C(CH3)3)2, -P(O)(OCH2OC(O)OCH(CH3)2)2, -P(O)(NHCH(CH3)C(O)OCH(CH3)2)2, -P(O)(OC6H5)(NHCH(CH3)C(O)OCH(CH3)2).

7. The compound according to claim 1, wherein R L1 and R L2 connected to form an optionally substituted 5- or 6-membered ring structure; Preferably, R L1 and R L2 connected to form a ring structure, the ring structure is substituted by one or more substituents independently selected from the following: deuterium, halogen, hydroxyl, thiol, amino, cyano, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl (eg, halophenyl), or optionally substituted 5-6 membered heteroaryl; More preferably, R L1 and R L2 connected to form a ring structure, the ring structure is substituted by one or more substituents independently selected from the following: deuterium; halogen; hydroxyl; thiol; amino; cyano; unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; or C substituted by a substituent independently selected from deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, carboxyl, alkyl, cycloalkyl or alkoxy 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.

8. The compound according to claim 1, wherein L is -P(O)(OR L1 )(OR L2 ), R L1 and R L2 is independently an optionally substituted alkyl group (eg, C 1-3 alkyl, such as methyl or ethyl), and RL1 and R L2 connected to form an optionally substituted 5- or 6-membered ring structure; Preferably, L is -P(O)(OR L1 )(OR L2 ), R L1 is ethyl and R L2 is a methyl group substituted by a phenyl group or a halogenated phenyl group (eg, a chlorophenyl group or a fluorophenyl group), and R L1 and R L2 They are linked together to form a 6-membered ring structure substituted with a phenyl group or a halogenated phenyl group (eg, a chlorophenyl group or a fluorophenyl group).

9. The compound according to claim 1, wherein A is selected from optionally substituted C 1-6 Alkylene, optionally substituted C 3-6 Cycloalkylene, optionally substituted 4-10 membered heterocyclylene, optionally substituted C 6-10 arylene, optionally substituted 5-10 membered heteroarylene, optionally substituted C 3-6 Cycloalkylene C 1-3 Alkylene, optionally substituted 4-10 membered heterocyclylene C 1-3 Alkylene, optionally substituted C 6-10 Arylene C 1-3 Alkylene or optionally substituted 5-10 membered heteroarylene C 1-3 Alkylene.

10. Compound according to claim 1, wherein A is selected from unsubstituted alkylene, cycloalkylene, heterocyclylene, arylene, heteroarylene, cycloalkylene alkylene, heterocyclylene alkylene, arylene alkylene or heteroarylene alkylene; and alkylene, cycloalkylene, heterocyclylene, arylene, heteroarylene, cycloalkylene alkylene, heterocyclylene alkylene, arylene alkylene or heteroarylene alkylene substituted by one or more substituents independently selected from the following: deuterium, halogen, hydroxyl, sulfhydryl, amino, cyano, acetyl, alkyl (e.g., C 1-6 Alkyl), alkenyl (e.g. C 2-6 alkenyl), alkynyl (e.g. 2-6 Alkynyl), cycloalkyl (e.g. C 3-6 Cycloalkyl), heterocyclic group (e.g., 4-6 membered heterocyclic group), -O-alkyl (e.g., -OC 1-6 Alkyl), -NH-alkyl (e.g. -NHC 1-6 Alkyl), -S-alkyl (e.g. -SC 1-6 Alkyl), -O-cycloalkyl (e.g. -OC 1-6 Cycloalkyl), -NH-cycloalkyl (e.g. -NHC 1-6 Cycloalkyl) or -S-cycloalkyl (e.g. -SC 1-6 cycloalkyl).

11. The compound according to claim 1, wherein A is selected from optionally substituted C 1-4 alkylene (e.g., methylene, ethylene, propylene, butylene), optionally substituted arylene (e.g., phenylene), optionally substituted cycloalkylene C 1-4 Alkylene, optionally substituted arylene C 1-4 Alkylene or optionally substituted heteroarylene C 1-4 Alkylene; Preferably, A is selected from methylene, ethylene, propylene, butylene, phenylene, phenylene, 1-2 Alkylene (e.g. phenylene methylene or phenylene ethylene), cyclohexylene C 1-2 Alkylene (e.g. cyclohexylene methylene), pyridylene C 1-2 Alkylene (eg, pyridylenemethylene); or Preferably, A is selected from halogen (eg, fluorine or chlorine) or -O-alkyl (eg, -OC 1-6 Alkyl, such as methoxy) substituted phenylene C 1-2 Alkylene (e.g. phenylenemethylene or phenyleneethylene); more preferably, A is selected from fluorophenylene-methylene, chlorophenylene-methylene, methoxyphenylene-methylene.

12. The compound according to claim 1, wherein R Z1 and R Z2 are independently selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, cyano, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 Cycloalkyl or an optionally substituted 4-6 membered heterocyclic group.

13. The compound according to claim 1, wherein R Z1 and R Z2 independently selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, cyano; unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl; and alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl substituted with one or more substituents independently selected from the following: deuterium, halogen, hydroxyl, thiol, amino, cyano, alkyl (e.g., C 1-6 Alkyl), alkenyl (e.g. C 2-6 alkenyl), alkynyl (e.g. 2-6 Alkynyl), cycloalkyl (e.g. C 3-6 cycloalkyl) or a heterocyclic group (e.g., a 4- to 6-membered heterocyclic group).

14. The compound according to claim 1, wherein Z is selected from -(chemical bond) or -C(R Z1 )(R Z2)-; Preferably, R Z1 and R Z2 are independently selected from hydrogen and optionally substituted alkyl (e.g., C 1-6 alkyl, such as methyl); more preferably, Z is selected from —(chemical bond), —CH 2 — or —CH(CH 3 ) —.

15. The compound according to claim 1, wherein Z is -CH(CH3)- having the (R) or (S) configuration.

16. The compound according to claim 1, wherein R 1 is selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclic group, optionally substituted C 6-10 Aryl, -OR 3 、-SR 3 、-NR 3 R 4 、-COOR 3 、-CONR 3 R 4 、-NR 3 COR 4 、-COR 3 、-OCOR 3 ,-SONR 3 R 4 、-SO2NR 3 R 4 、-NR 3 SOR 4 、-NR 3 S02R 4 or -Si(R 3 )(R 4 )(R 5 ).

17. The compound according to claim 1, wherein R 1 is selected from unsubstituted alkyl, alkenyl, cycloalkyl, heterocyclyl or aryl; and alkyl, alkenyl, cycloalkyl, heterocyclyl or aryl substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxy, thiol, amino, cyano, nitro, carboxyl, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted alkoxy.

18. The compound according to claim 1, wherein R 1alkyl, alkenyl, cycloalkyl, heterocyclyl or aryl substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, carboxyl, and alkyl, cycloalkyl or alkoxy substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, carboxyl, alkyl, cycloalkyl or alkoxy; Preferably, R 1 Selected from alkyl, alkenyl, cycloalkyl, heterocyclyl or aryl substituted with one or more substituents independently selected from the group consisting of deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, cyano, nitro, alkyl, cycloalkyl, alkoxy, alkylamino, carboxy, haloalkyl, haloalkoxy.

19. The compound according to claim 1, wherein R 3 , R 4 and R 5 are independently selected from hydrogen, deuterium, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclic group, optionally substituted C 6-10 Aryl or optionally substituted 5-6 membered heteroaryl; Preferably, R 3 , R 4 and R 5 independently selected from hydrogen; deuterium; unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; and alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, thiol, amino, cyano, nitro, carboxyl, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted alkoxy.

20. The compound according to claim 1, wherein R 3 , R 4 and R 5 independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituted with one or more substituents independently selected from the group consisting of deuterium; halogen; hydroxyl; mercapto; amino; cyano; nitro; carboxyl; and alkyl, cycloalkyl or alkoxy substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, carboxyl, alkyl, cycloalkyl or alkoxy; Preferably, R 3 , R 4 and R 5Independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituted with one or more substituents independently selected from the following: deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, cyano, nitro, alkyl, cycloalkyl, alkoxy, alkylamino, carboxy, haloalkyl, haloalkoxy.

21. The compound according to claim 1, wherein R 1 is selected from deuterium, halogen, hydroxyl, amino, cyano; unsubstituted or halogen-substituted alkyl, alkenyl, cycloalkyl or aryl (eg phenyl); or -OR 3 Preferably, R 3 independently selected from unsubstituted or halogen-substituted alkyl (e.g., C 1-6 alkyl); Preferably, R 1 Selected from fluorine, chlorine, bromine, iodine, cyano, methyl, tert-butyl, methoxy.

22. The compound of claim 1, wherein n is 0, 1 or 2.

23. The compound according to claim 1, wherein R X are independently selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, -OR a 、-SR a 、-NR a R b 、-COOR a 、-CONR a R b 、-NR b COR a 、-COR a 、-OCOR a ,-SONR a R b 、-SO2NR a R b 、-NR b SOR a 、-NR b S02R a or -Si(R a )(R b )(R c ), where R a , R b and R c are independently selected from hydrogen, deuterium, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclic group, optionally substituted C 6-10 aryl or optionally substituted 5-6 membered heteroaryl; and R X The substituents in the optional substitutions are selected from one or more of the following: hydrogen, deuterium, halogen, hydroxyl, thiol, amino, cyano, alkyl (e.g., C 1-6 Alkyl), alkenyl (e.g. C 2-6 alkenyl), alkynyl (e.g. 2-6 Alkynyl), cycloalkyl (e.g. C 3-6 cycloalkyl), heterocyclic group (e.g. 4-6 membered heterocyclic group), aryl group (e.g. C 6-10 aryl) or heteroaryl (e.g., 5-6 membered heteroaryl).

24. The compound according to claim 1, wherein R X are independently selected from hydrogen, deuterium, halogen, hydroxyl, thiol, amino, cyano, nitro, optionally substituted alkyl, -OR a 、-SR a and-NR a R b , where R a and R b are independently selected from hydrogen, deuterium, and optionally substituted alkyl; Preferably, R X are independently selected from unsubstituted alkyl (e.g., C 1-6 Alkyl) or alkyl substituted by deuterium or halogen (e.g. C 1-6 alkyl).

25. The compound according to claim 1, wherein R a and R b are independently selected from unsubstituted alkyl (e.g., C 1-6 Alkyl) or alkyl substituted by deuterium or halogen (e.g. C 1-6 alkyl).

26. The compound according to claim 1, wherein R X are independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl (e.g., C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, tert-butyl), halogenated alkyl, deuterated alkyl, -OR a 、-SR a or -NR a R b , where R a and R b are independently selected from hydrogen, deuterium, alkyl (e.g., C 1-4 alkyl, such as methyl or ethyl), deuterated alkyl or haloalkyl; Preferably, R Xare independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, cyano, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, deuterated alkyl, methoxy, ethoxy, methylthio, methylamino or dimethylamino.

27. The compound according to claim 1, wherein X 1 , X 2 , X 3 and X 4 Independently C(R X ); preferably, X 1 , X 2 , X 3 and X 4 For CH.

28. The compound according to claim 1, wherein X 1 , X 2 , X 3 and X 4 One of the following (e.g. X 1 , X 2 , X 3 or X 4 ) or two (for example X 1 and X 3 ) are independently C(R X ), where R X As defined in claim 1 but excluding hydrogen and the remainder being CH; or X 1 , X 2 , X 3 and X 4 One of the following (e.g. X 1 , X 2 , X 3 or X 4 ) or two (for example X 1 and X 3 ;X 2 and X 4 ) are independently N, and the rest are independently C(R X ), where R X As defined in claim 1.

29. The compound according to claim 1, wherein X 1 , X 2 , X 3 and X 4 One of them is N and the rest are CH.

30. The compound according to claim 1, wherein the compound is selected from:

31. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 30 and its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs as active ingredients.

32. The pharmaceutical composition of claim 31, further comprising additional drugs (such as small molecules, polypeptides, nucleic acids, antibodies, antibody-drug conjugates) for preventing and / or treating cancer or tumors, and / or additional therapeutic agents for treating inflammatory diseases, autoimmune diseases, and immune-mediated diseases.

33. The pharmaceutical composition according to claim 32, wherein the additional drugs for preventing and / or treating cancer or tumors include, but are not limited to, cell signal transduction inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin , daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin analogs, megestrol acetate, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alpha, folinic acid, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusetib, dasatinib, dovitinib, erlotinib, foretinib, gane tespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saricatinib, saridegib, sorafenib, sunitinib, tiratinib, tivantinib, tivozanib , tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, berentuzumab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, PI3K inhibitor, CSF1R inhibitor, A2A and / or A2B receptor antagonist, IDO inhibitor, anti-PD-1 antibody, anti-PD-L1 antibody, LAG3 antibody, TIM-3 antibody, TIGIT antibody, CD47 antibody, CLAUDIN 18.2 antibody, anti-CTLA-4 antibody, or any combination thereof.

34. The pharmaceutical composition according to claim 32, wherein the antibody-drug conjugate includes but is not limited to: trastuzumab enmetuzumab, brentuximab, olivacetuzumab, vedicituzumab, gosartan, delutec-trastuzumab or any combination thereof.

35. The pharmaceutical composition of claim 32, wherein the additional therapeutic agent for treating inflammatory diseases, autoimmune diseases and immune-mediated diseases is selected from steroidal drugs (e.g., prednisone, hydroprednisolone, methylhydroprednisolone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFα agents (e.g., etanercept, infliximab, adalimumab, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.), antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.) or any combination thereof.

36. Use of a compound of formula (I) according to any one of claims 1 to 30 and its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotope-labeled analogs or a pharmaceutical composition according to any one of claims 31 to 35 in the preparation of a medicament for preventing and / or treating a disease mediated by ENPP1.

37. The use according to claim 36, wherein the disease mediated by ENPP1 is selected from cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease.

38. The use according to claim 37, wherein the cancer and tumors include: Skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis cancer, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, Hodgkin lymphoma, non-Hodgkin Lymphoma, Burkitt's lymphoma, leukemia, acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma and plasmacytoma.

39. The use according to claim 37, wherein the inflammatory diseases, autoimmune diseases and immune-mediated diseases include: Arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, atopic dermatitis, pain, lung disease, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory diseases, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjögren's syndrome, autoimmune thyroid disease, urticaria (urticaria), multiple sclerosis, scleroderma, organ transplant rejection, xenotransplantation, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis and allergic sinusitis.

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