Exonucleotide pyrophosphatase-phosphodiesterase-1 inhibitors and pharmaceutical compositions containing same

Abstract

The present disclosure relates to a compound or a pharmaceutically acceptable salt thereof for the inhibition of exonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP-1).

Description

[0001] Related Applications

[0002] This application claims the benefit of priority to Korean Patent Application No. 10-2022-0072041 filed on Jun. 14, 2022; the contents of which are incorporated herein by reference in their entirety. Background Art

[0003] Ectonucleotide pyrophosphatase / phosphodiesterase-1 (ie, ENPP-1) is a type II transmembrane glycoprotein with pyrophosphatase and phosphodiesterase activities and is highly expressed in bone and cartilage.

[0004] ATP is a substrate for ENPP-1 and is hydrolyzed to AMP and PPi, and AMP is converted to adenosine and inorganic phosphate (Pi) by CD73. As part of the functions mediated by nucleotide pyrophosphatases / phosphodiesterases (NPPs), ENPP-1 hydrolysis of nucleotide pyrophosphate bonds (e.g., in ATP) and phosphodiester bonds (e.g., in oligonucleotides) is essential in numerous cellular processes, including nucleotide pyrophosphate recycling, purinergic receptor signaling, and ATP-mediated apoptosis.

[0005] Recently, ENPP-1 has been found to play a key role in immune responses to various stimuli through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Damage-associated molecular patterns (DAMPs) as well as pathogen-associated molecular patterns (PAMPs) activate the immune system through STING. cGAS senses cytoplasmic DNA and catalyzes the conversion of GTP and ATP to cyclic GMP-AMP (cGAMP). Subsequently, 2,3'-cGAMP triggers an inflammatory response to produce type 1 interferons (IFNs) and other cytokines through the TANK binding kinase 1 (TBK1)-interferon regulatory factor (IRF) 3 pathway. A link has been established between the cGAS-STING pathway and ENPP-1, whereby ENPP-1 hydrolysis of cGAMP attenuates cGAS-STING signaling. ENPP-1 plays a regulatory function in immune cells such as neutrophils, macrophages, dendritic cells, natural killer cells, and B lymphocytes. ENPP-1 expression in M2 macrophages is increased in the presence of cancer and promotes tumor growth and spread. The role of ENPP-1 in cancer is exemplified by the observation of enhanced tumor metastasis from breast cancer to bone, for example, due to overexpression of ENPP-1.

[0006] Recent reports indicate that cyclic dinucleotides, which are substrates of ENPP-1, stimulate innate immunity through STING-dependent activation of interferon genes. Similar to checkpoint inhibitors (e.g., anti-PD-1 or PD-L1), which are promising immunotherapeutic agents for various cancers, ENPP-1 inhibition of STING pathway activation is critical for tumor control.

[0007] Since STING activation is a promising therapeutic strategy for treating cancer, an increasing number of compounds that activate the STING pathway have been reported. ENPP-1 is a highly efficient cGAMP degrading enzyme, and ENPP-1 inhibitors are suitable for anti-tumor therapy.

[0008] ADP ribosylation is a conserved post-translational modification of proteins that plays a role in all major cellular processes, especially DNA repair, transcription, translation, stress response and cell death. Poly ADP ribosylation (PARylation), mediated by poly ADP-ribose polymerase (PARP), plays a key role in DNA damage repair. Inhibition of poly ADP ribosylation by PARP inhibitors can inhibit DNA damage repair and induce the death of DNA repair-deficient tumor cells. Therefore, PARP inhibitors have been approved by the US FDA for the treatment of various types of cancer.

[0009] However, the latest studies have shown that de-poly ADP ribosylation (dePARylation) also plays a key role in DNA damage repair. De-poly ADP ribosylation is used as a downstream step of poly ADP ribosylation in DNA damage repair rather than antagonizing poly ADP ribosylation. Protein poly ADP ribosylation can be reversed by a large domain (comprising proteins PARG, TARG1, MacroD1, MacroD2 and ENPP-1). Recently known, ENPP-1 plays a role in the de-poly ADP ribosylation process by hydrolyzing the ester bond known to connect proteins to ADP-ribose. De-poly ADP ribosylation inhibitors represent new types of inhibitors that replace PARP inhibition and can overcome the anticancer drug resistance of PARPi. Therefore, ENPP-1 inhibitors can play a key role in the DNA damage repair process.

[0010] Based on the above principles, there is an increasing need for anti-tumor compounds that can inhibit ENPP-1 and treat various types of cancer. Summary of the invention

[0011] The present invention relates to inhibitors of ectonucleotide pyrophosphatase / phosphodiesterase-1 (ENPP-1) and pharmaceutically acceptable salts thereof.

[0012] In certain aspects, the present invention provides a compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof:

[0013]

[0014] in

[0015] Each R 1 are independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide;

[0016] A is aryl, heteroaryl or heterocyclic;

[0017] Y is CH, CR 1 or N;

[0018] R 2 is aralkyl, heteroaralkyl, heterocyclylalkyl or cycloalkylalkyl; and

[0019] n is 0, 1, 2, 3 or 4.

[0020] In certain aspects, the present invention provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0021] In certain aspects, the present invention provides methods of treating a disease or disorder characterized by ENPP-1 in a subject in need thereof, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION

[0022] Hereinafter, the present invention will be described in more detail.

[0023] The compounds of the present invention are novel agents that exhibit high inhibitory activity against ENPP-1 and simultaneously activate the STING pathway, and thus can be used to treat, prevent and alleviate diseases caused by abnormal cell growth mediated by ENPP-1 (eg, cancer).

[0024] In certain aspects, the present invention provides a compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof:

[0025]

[0026] in

[0027] Each R 1are independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide;

[0028] A is aryl, heteroaryl or heterocyclic;

[0029] Y is CH, CR 1 or N;

[0030] R 2 is aralkyl, heteroaralkyl, heterocyclylalkyl or cycloalkylalkyl; and

[0031] n is 0, 1, 2, 3 or 4.

[0032] In certain embodiments, A is heteroaryl (e.g., pyridinyl, pyrimidinyl, or pyridazinyl, preferably pyridinyl). In other embodiments, A is heterocyclyl (e.g., piperidinyl, piperidonyl, tetrahydropyridazinonyl).

[0033] In certain preferred embodiments, Y is CH. In other embodiments, Y is N.

[0034] In certain embodiments, the compound has a structure represented by Formula Ia, or a pharmaceutically acceptable salt thereof:

[0035]

[0036] in,

[0037] X 1 CR 3 or N;

[0038] X 2 CR 4 or N;

[0039] X 3 CR 5 or N;

[0040] X 4 CR 6 or N; and

[0041] R 3 , R 4 , R 5 and R 6 Each is independently selected from H, alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl and sulfonamide.

[0042] In certain preferred embodiments, X 1 is N. In other embodiments, X 1 CR 3 .

[0043] In certain embodiments, X 1 is N. In other embodiments, X 1 CR 3 .

[0044] In certain embodiments, X 2 is N. In other embodiments, X 2 CR 4 .

[0045] In certain embodiments, X 3 is N. In other embodiments, X 3 CR 5 .

[0046] In certain embodiments, X 4 is N. In other embodiments, X 4 CR 6 .

[0047] In certain embodiments, R 3 For H.

[0048] In certain preferred embodiments, R 4 For H.

[0049] In certain preferred embodiments, R 5 For H.

[0050] In certain preferred embodiments, R 6 For H.

[0051] In certain embodiments, n is 1. In other embodiments, n is 2.

[0052] In certain embodiments, the compound has a structure represented by Formula Ib, or a pharmaceutically acceptable salt thereof:

[0053]

[0054] In certain embodiments, the compound has a structure represented by Formula Ic, or a pharmaceutically acceptable salt thereof:

[0055]

[0056] In certain embodiments, the compound has a structure represented by Formula Id, or a pharmaceutically acceptable salt thereof:

[0057]

[0058] in,

[0059] R 7 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide.

[0060] In certain embodiments, the compound has a structure represented by Formula le, or a pharmaceutically acceptable salt thereof:

[0061]

[0062] in,

[0063] R 7 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide.

[0064] In certain embodiments, the compound has a structure represented by Formula If, or a pharmaceutically acceptable salt thereof:

[0065]

[0066] in,

[0067] R 7 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide.

[0068] In certain preferred embodiments, R 2 is benzyl, and is preferably substituted by iminothiolononyl (eg (imino)(methyl)thioanonyl).

[0069] In certain embodiments, the compound has a structure represented by Formula IIa, or a pharmaceutically acceptable salt thereof:

[0070]

[0071] in,

[0072] Each R 8are independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide;

[0073] R 9 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, phosphoramidite, phosphoramidite, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl, sulfonamide, imidothioanone or aminosulfonamide; and

[0074] y is 1, 2, 3, or 4.

[0075] In certain embodiments, the compound has a structure represented by Formula IIb, or a pharmaceutically acceptable salt thereof:

[0076]

[0077] in,

[0078] Each R 8 are independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide;

[0079] R 9 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, phosphoramidite, phosphoramidite, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl, sulfonamide, imidothioanone or aminosulfonamide; and

[0080] y is 1, 2, 3, or 4.

[0081] In certain embodiments, the compound has a structure represented by Formula IIc, or a pharmaceutically acceptable salt thereof:

[0082]

[0083] in,

[0084] R 7is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide;

[0085] Each R 8 are independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide;

[0086] R 9 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, phosphoramidite, phosphoramidite, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl, sulfonamide, imidothioanone or aminosulfonamide; and

[0087] y is 1, 2, 3, or 4.

[0088] In certain embodiments, the compound has a structure represented by Formula IId, or a pharmaceutically acceptable salt thereof:

[0089]

[0090] in,

[0091] R 7 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide;

[0092] Each R 8 are independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide;

[0093] R 9is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, phosphoramidite, phosphoramidite, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl, sulfonamide, imidothioanone or aminosulfonamide; and

[0094] y is 1, 2, 3, or 4.

[0095] In certain embodiments, the compound has a structure represented by Formula IIe, or a pharmaceutically acceptable salt thereof:

[0096]

[0097] in,

[0098] R 7 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide;

[0099] Each R 8 are independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide;

[0100] R 9 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, phosphoramidite, phosphoramidite, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl, sulfonamide, imidothioanone or aminosulfonamide; and

[0101] y is 0, 1, 2, 3, or 4.

[0102] In certain embodiments, R 1 In certain preferred embodiments, R 1 is alkoxy (eg, methoxy, trifluoromethoxy or ethoxy, preferably methoxy). 1 is a halogen group (eg, fluorine or chlorine).

[0103] In certain embodiments, R 7 is alkyl (eg, methyl). 7is an alkoxy group (eg, a methoxy group). 7 is a halogen group (eg, fluorine or chlorine).

[0104] In certain embodiments, y is 0. In other embodiments, y is 1.

[0105] In certain embodiments, R 8 is a halogen group (eg, fluorine or chlorine). 8 is alkyl (eg, methyl or trifluoromethyl). 8 is an alkoxy group (eg, a methoxy group).

[0106] In certain preferred embodiments, R 9 is iminothiolone (e.g., (imino)(methyl)thioanone, (imino)(ethyl)thioanone, (imino)(benzyl)thioanone or imino)(cyclopropyl)thioanone). In other embodiments, R 9 is a sulfonamide group (e.g., a methylsulfonamide group). 9 In other embodiments, R 9 is alkyl (eg, phosphorylalkyl, such as phosphorylmethyl or phosphoryldifluoromethyl). In other embodiments, R 9 In other embodiments, R 9 It is a phosphoramide group.

[0107] In certain embodiments, R 11 for and

[0108] In certain embodiments, the compound is selected from:

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115] or a pharmaceutically acceptable salt thereof.

[0116] Many compounds useful in the methods and compositions of the invention (e.g., those cited above) have at least one stereogenic center in their structure (e.g., due to the presence of a lone pair of electrons on a sulfur atom). This stereogenic center may exist in either an R or S configuration, the R and S configurations being used according to the rules set forth in Pure Appl. Chem. (1976), 45, 11-30. The present invention contemplates all stereoisomeric forms, such as enantiomeric and diastereomeric forms, of the compounds, salts, prodrugs, or mixtures thereof (including all possible mixtures of stereoisomers). See, for example, WO 01 / 062726.

[0117] In other embodiments, the present invention provides a compound represented by the following Formula 1, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0118] [Formula 1]

[0119]

[0120] in,

[0121] A1 is a substituted or unsubstituted C3-30 cycloalkyl ring, a substituted or unsubstituted C2-30 heterocycloalkyl ring, a substituted or unsubstituted C6-30 aryl ring, or a substituted or unsubstituted C3-30 heteroaryl ring, which is fused to an adjacent ring;

[0122] A2 is a substituted or unsubstituted C3-20 cycloalkylene group, a substituted or unsubstituted C2-20 heterocycloalkylene group, a substituted or unsubstituted C6-30 arylene group, or a substituted or unsubstituted C3-30 heteroarylene group;

[0123] X1 to X4 are each independently CR or N;

[0124] R is hydrogen, hydroxyl, halogen, C1-10 alkyl, C1-10 alkoxy, C6-20 aryl, C3-20 heteroaryl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, amino, nitro, amide, carboxylic acid, nitrile, urea or sulfonamide;

[0125] L1 is C1-10 alkylene or C2-10 alkenylene;

[0126] Z represent;

[0127] R1 is O or NR5;

[0128] R2 is hydrogen, hydroxyl, cyano, C1-C10 alkyl, C1-10 alkoxy, C6-C12 aryl, C3-C10 cycloalkyl, C2-C12 heterocycloalkyl, -C(=O)OR6 or -NR8R9;

[0129] L 21 , L 22 and L3 are each independently a single bond, a substituted or unsubstituted C1-C5 alkylene group or -NR7-;

[0130] R3 to R7 are each independently hydrogen or C1-C5 alkyl;

[0131] R8 and R9 are each independently hydrogen, -C(=O)R 10 (The condition is R 10 is C1-C5 alkyl) or -Boc(tert-butoxycarbonyl); and

[0132] * is a point connected to A2 in Formula 1.

[0133] In certain embodiments, the compound represented by Formula 1 of the present invention exhibits extremely high inhibitory activity against ENPP-1 and simultaneously activates the STING pathway, and thus can be used to treat, prevent, and alleviate cancer caused by abnormal cell growth mediated by ENPP-1.

[0134] In the compounds of the embodiments of the present invention, A1 in the above formula 1 can be represented by the following formula 2 or formula 3:

[0135] [Formula 2]

[0136]

[0137] in,

[0138] Y 11 To Y 14 Each independently is CR a or N;

[0139] R a is hydrogen, hydroxyl, halogen, C1-10 alkyl, C1-10 alkoxy, C6-20 aryl, C3-20 heteroaryl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, amino, nitro, amide, carboxylic acid, nitrile, urea or sulfonamide; and

[0140] * is the point of attachment to each of the two adjacent carbon atoms on the fused ring to which A1 is attached, and

[0141] [Formula 3]

[0142]

[0143] in:

[0144] Y 21 To Y 24 Each independently is CR b R c , -C(=O)- or NR d ;

[0145] R b to R d are each independently hydrogen, hydroxyl, halogen, C1-10 alkyl, C1-10 alkoxy, C6-20 aryl, C3-20 heteroaryl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, amino, nitro, amide, carboxylic acid, nitrile, urea or sulfonamide; and

[0146] * is the point of attachment to each of the two adjacent carbon atoms on the fused ring to which A1 is attached.

[0147] In the compounds of the embodiments of the present invention, A1 in Formula 1 may be a substituted or unsubstituted C3-10 cycloalkyl ring, a substituted or unsubstituted C2-10 heterocycloalkyl ring, a substituted or unsubstituted C6-10 aryl ring, or a substituted or unsubstituted C3-10 heteroaryl ring fused to an adjacent ring;

[0148] A2 may be a substituted or unsubstituted C3-10 cycloalkylene group, a substituted or unsubstituted C2-10 heterocycloalkylene group, a substituted or unsubstituted C6-10 arylene group, or a substituted or unsubstituted C3-10 heteroarylene group;

[0149] X1 to X4 can each independently be CR or N;

[0150] R may be hydrogen, hydroxyl, halogen group, C1-10 alkyl group, C1-10 alkoxy group, C6-10 aryl group, C3-10 heteroaryl group, C3-10 cycloalkyl group, C3-10 heterocycloalkyl group, amino group, nitro group, amide group, carboxylic acid group, nitrile group, urea group or sulfonamide group;

[0151] L1 may be a C1-10 alkylene group.

[0152] In the compounds of the embodiments of the present invention, A1 in Formula 1 may be a substituted or unsubstituted C5 heterocycloalkyl ring, a substituted or unsubstituted C6 aryl ring, or a substituted or unsubstituted C4-5 heteroaryl ring fused to an adjacent ring;

[0153] A2 may be a substituted or unsubstituted C5 heterocycloalkylene group, a substituted or unsubstituted C6 arylene group, or a substituted or unsubstituted C5 heteroarylene group;

[0154] X1 to X4 can each independently be CR or N;

[0155] R may be hydrogen, a halogen group, a C1-2 alkyl group or a C1-2 alkoxy group; and

[0156] L1 may be a C1-2 alkylene group.

[0157] In the compounds of the embodiments of the present invention, preferably, Y in the above formula 2 is 11 To Y 14 Can be independently CR a or N; and R a It may be hydrogen, hydroxy, C1-10 alkyl or C1-10 alkoxy.

[0158] In the compounds of the embodiments of the present invention, preferably, Y in the above formula 3 is 21 To Y 24 Can be independently CR b R c , -C(=O)- or NR d ; and R b to R d They may each independently be hydrogen, hydroxy, C1-10 alkyl or C1-10 alkoxy.

[0159] In the compounds of the embodiments of the present invention, A1 in the compound represented by the above formula 1 can be selected from the following structures: (provided that * and ** in the above structure respectively indicate points of attachment to each of two adjacent carbon atoms on the fused ring to which A1 is attached in the compound represented by Formula 1).

[0160] In the compounds of the embodiments of the present invention, A2 in the compound represented by the above formula 1 can be selected from the following structures:

[0161] (Provided that * and ** in the above structure indicate points of attachment to L1 and Z in the compound represented by Formula 1, respectively).

[0162] In the compounds of the embodiments of the present invention, Z in the compound represented by the above formula 1 can be selected from the following structures: (Provision is made that * is a point connected to A2 in Formula 1).

[0163] Representative compounds of Formula 1 of the present invention may include (but are not limited to) the following compounds:

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170] Salts of the compounds mentioned herein are provided, for example, pharmaceutically acceptable salts.The present invention also encompasses any and all stereochemical forms, including any enantiomeric or diastereomeric forms and any tautomeric or other forms of the described compounds.

[0171] In certain embodiments, the compounds presented herein may exist as salts (even when no salt is shown), and may include all salts and solvates of the presented compounds as well as non-salt and non-solvate forms of the compounds.

[0172] In the case where any compound described herein can exist in tautomeric forms, each and every tautomeric form is intended to be one or a portion of the tautomeric forms, even if it may be explicitly shown. When used in the methods described herein, the specifically shown tautomeric form may or may not be the predominant form in solution.

[0173] The novel compounds of the embodiments of the present invention may have an asymmetric carbon center and may exist as a racemate or individual optical isomers. Of course, any form of isomers (including these optical isomers) may also belong to the category of the embodiment compounds. As used herein, the term "isomer" may collectively refer to different compounds with the same molecular formula, and "optical isomers" may collectively refer to any stereoisomers (including the same geometric isomers) that may exist for the embodiment compounds.

[0174] In the compound represented by Formula 1 of the embodiment of the present invention, it is understood that each substituent can be connected to the chiral center of the carbon atom. In addition, any asymmetric carbon atom on the embodiment compound can exist in any form of (R)-, (S)- or (R, S)- configuration, and can be appropriately present in any (R)- or (S)- configuration (each in its separate form). In addition, the embodiment compound can exist in any form of any possible isomer or mixture thereof, and (for example) can exist in any form of pure geometric isomers, diastereomers, optical isomers, racemates or mixtures thereof. In addition, when the embodiment compound has a double bond, each substituent bonded to the double bond can be in E or Z configuration. In addition, when the embodiment compound contains a disubstituted cycloalkyl, each substituent of the cycloalkyl can have a cis or trans configuration.

[0175] Solvates and / or polymorphs of the compounds provided herein or their pharmaceutically acceptable salts are also contemplated. Solvates contain stoichiometric or non-stoichiometric amounts of solvents and are typically formed during the crystallization process. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include different crystal packing arrangements of compounds having the same elemental composition. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optical and electrical properties, stability and / or solubility. Single crystal forms may be affected by various factors, such as recrystallization solvents, crystallization rates, and storage temperatures.

[0176] In another aspect, the present invention provides a pharmaceutical composition for preventing, alleviating or treating cancer, which comprises a compound represented by Formula 1 of the present invention, a hydrate thereof, a solvate thereof, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

[0177] The pharmaceutical composition of the present invention can be used to inhibit ENPP-1 activity in the body. Therefore, the pharmaceutical composition of the present invention can be used for the purpose of treating, preventing and alleviating cancer diseases, and the cancer diseases may include (but are not limited to) gastric cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenosis, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, hematological malignancies (including leukemia, multiple myeloma and myelodysplastic syndrome), lymphoma (including Hodgkin's disease and non-Hodgkin's lymphoma), psoriasis, fibroadenoma and the like, and any cancer disease caused by abnormal cell growth can be prevented, treated or alleviated by treatment using the pharmaceutical composition of the present invention.

[0178] In another aspect, the present invention provides an ENPP-1 inhibitor comprising, as an active ingredient, a compound represented by Formula 1 of the present invention, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0179] Those skilled in the art can appropriately adjust the amount of the compound represented by the above Formula 1, its hydrate, its solvate, its isomer or its pharmaceutically acceptable salt as an active ingredient by selecting according to the aspect and method of using the pharmaceutical composition of the present invention.

[0180] For example, the pharmaceutical composition of the present invention includes the compound represented by the above Formula 1, its hydrate, its solvate, its isomer or its pharmaceutically acceptable salt in an amount of 0.1 to 10 wt % or 0.1 to 5 wt % based on the total weight of the total composition.

[0181] The compound represented by the above Formula 1, its hydrate, its solvate, its isomer or its pharmaceutically acceptable salt may be contained in the pharmaceutical composition alone, or may also be contained in combination with other pharmacologically acceptable carriers, excipients, diluents or auxiliary ingredients.

[0182] Examples of pharmacologically acceptable carriers, excipients or diluents may be, but are not limited to, one or more agents selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, dextrin, calcium carbonate, propylene glycol, liquid paraffin and physiological saline, and all conventional carriers, excipients or diluents may be used. In addition, the pharmaceutical composition may further include conventional fillers, extenders, binders, disintegrants, anticoagulants, lubricants, wetting agents, pH adjusters, nutrients, vitamins, electrolytes, alginic acid and its salts, pectinic acid and its salts, protective colorants, glycerin, flavoring agents, emulsifiers, preservatives or the like.

[0183] The compound represented by Formula 1 of the present invention, its hydrate, its solvate, its isomer or its pharmaceutically acceptable salt can enhance the therapeutic effect of anticancer drugs by co-administering with other anticancer drugs for treating cancer or tumor.

[0184] The method of administering the pharmaceutical composition may be oral or parenteral, and as an example, it may be administered by various routes, including oral, transdermal, subcutaneous, intravenous or intramuscular routes. In addition, the formulation of the composition may vary depending on the method of use, and may be formulated using methods well known in the industry to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. In general, solid formulations for oral administration include tablets, lozenges, soft or hard capsules, pills, powders, granules and the like, and the formulations may be prepared by mixing one or more excipients, such as starch, calcium carbonate, sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations for oral administration include suspensions, internal solutions, emulsions, syrups and the like, and may include various excipients (e.g., wetting agents, sweeteners, flavoring agents, preservatives and the like) in addition to commonly used simple diluents (e.g., water and liquid paraffin). The form for parenteral administration may be in the form of creams, lotions, ointments, plasters, liquids and solutions, aerosols, fluid extracts, elixirs, infusions, medicine bags, patches, injections or the like, and in the case of injectable formulations may preferably be in the form of isotonic aqueous solutions or suspensions.

[0185] In addition, the pharmaceutical composition may further include adjuvants (such as sterilizers, preservatives, stabilizers, hydrating agents or emulsification accelerators, salts and / or buffers for controlling osmotic pressure and the like, and other therapeutically useful substances), and can be formulated according to conventional mixing, granulating or coating methods, and can also be formulated using appropriate methods known in the industry.

[0186] In addition, the present invention provides a method for preparing the compound represented by Formula 1 above.

[0187] Pharmaceutical composition

[0188] The compositions and methods of the present invention can be used to treat individuals in need. In certain embodiments, the individual is a mammal, such as a human or non-human mammal. When administered to an animal (e.g., a human), the composition or compound is preferably administered in the form of a pharmaceutical composition including, for example, a compound of the present invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the industry and include, for example, aqueous solutions, such as water or physiologically buffered saline; or other solvents or vehicles, such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when the pharmaceutical composition is used for human administration, particularly for invasive administration routes (that is, routes that circumvent transport or diffusion through epithelial barriers, such as injection or transplantation), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients may be selected, for example, to achieve delayed release of the agent or selective targeting of one or more cells, tissues, or organs. The pharmaceutical composition may be in the form of a dosage unit, such as a tablet, capsule (including a dispersed capsule and a gelatin capsule), granules, lyophiles for reconstitution, powders, solutions, syrups, suppositories, injections, or the like. The composition may also be presented in a transdermal delivery system, such as a skin patch. The composition may also be presented in a solution suitable for topical administration, such as a lotion, cream or ointment.

[0189] A pharmaceutically acceptable carrier may contain a physiologically acceptable agent, which is used, for example, to stabilize a compound such as a compound of the invention, increase its solubility, or increase its absorption. The physiologically acceptable agent includes, for example, a carbohydrate (e.g., glucose, sucrose, or polydextrose), an antioxidant (e.g., ascorbic acid or glutathione), a chelating agent, a low molecular weight protein, or other stabilizer or excipient. The selection of a pharmaceutically acceptable carrier (including a physiologically acceptable agent) is based on, for example, the route of administration of the composition. The preparation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be a liposome or other polymer matrix into which, for example, a compound of the invention may be incorporated. For example, liposomes including phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively simple to make and administer.

[0190] The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound pharmaceutical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0191] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, and cellulose acetate. oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other nontoxic compatible substances used in pharmaceutical formulations.

[0192] The pharmaceutical composition (formulation) can be administered to a subject by any of a variety of routes of administration, including, for example, oral (e.g., drenches in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including dispersible capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (e.g., in the form of a patch applied to the skin); and topically (e.g., in the form of a cream, ointment, or spray applied to the skin). The compound can also be formulated for inhalation. In certain embodiments, the compound can be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions useful therefor can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896, and patents cited therein.

[0193] The formulation can be conveniently presented in unit dosage form and can be prepared by any method well known in the pharmaceutical industry. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending on the subject being treated, the specific mode of administration. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will generally be the amount of compound that produces a therapeutic effect. Typically, based on 100%, this amount will be in the range of about 1% to about 99%, preferably about 5% to about 70%, and most preferably about 10% to about 30% of the active ingredient.

[0194] The method for preparing these formulations or compositions comprises the step of combining an active compound such as a compound of the invention with a carrier and optionally one or more auxiliary ingredients. In general, the formulation is prepared by uniformly and intimately combining a compound of the invention with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product.

[0195] The formulations of the present invention suitable for oral administration may be in the form of capsules (including dispersible capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophiles, powders, granules; or as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion; or as an elixir or syrup; or as a soft tablet (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as a mouthwash and the like, each containing a predetermined amount of the compound of the present invention as the active ingredient. The composition or compound may also be administered in the form of a bolus, elixir or paste.

[0196] To prepare solid dosage forms for oral administration (capsules (including dispersible capsules and gel capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers (e.g., sodium citrate or dicalcium phosphate) and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as Glycerol; (4) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retarder, such as paraffin; (6) absorption accelerator, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glyceryl monostearate; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) complexing agents, such as modified or unmodified cyclodextrin; and (11) coloring agents. In the case of capsules (including dispersible capsules and gel capsules), tablets and pills, the pharmaceutical composition may also include a buffer. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose (lactose or milk sugar) and high molecular weight polyethylene glycols and the like.

[0197] Tablets may be made by compression or molding, optionally containing one or more auxiliary ingredients. Compressed tablets may be prepared using a binder (e.g., gelatin or hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surfactant or a dispersant. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0198] Tablets and other solid dosage forms of pharmaceutical compositions (e.g., dragees, capsules (including dispersible capsules and gel capsules), pills and granules) may be optionally scored or prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation industry. Hydroxypropylmethylcellulose, other polymer matrices, liposomes and / or microspheres in different proportions that provide the desired release characteristics may also be used, for example, to formulate them so as to provide slow or controlled release of the active ingredient therein. The solid dosage form may be sterilized, for example, by filtering with a bacterial retention filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifiers and may also be compositions that release the active ingredient only (or preferentially) in a certain part of the gastrointestinal tract in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. If appropriate, the active ingredient may also be in a microencapsulated form containing one or more of the above-mentioned excipients.

[0199] Liquid dosage forms that can be used for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the industry, such as water or other solvents; cyclodextrin and its derivatives; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol; oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil); glycerol; tetrahydrofuran alcohol; polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof.

[0200] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0201] Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0202] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants that may be required.

[0203] Ointments, pastes, creams and gels may contain, in addition to the active compounds, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0204] Powders and sprays may contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorocarbons and unsubstituted volatile hydrocarbons, such as butane and propane.

[0205] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the invention to the body. The dosage form can be prepared by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate of this flux can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0206] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration include a combination of one or more active compounds with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions; or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostats, solutes or suspending or thickening agents that render the formulation isotonic with the blood of the intended recipient.

[0207] Examples of suitable aqueous and nonaqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils (e.g., olive oil) and injectable organic esters (e.g., ethyl oleate). Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size (in the case of dispersions), and by the use of surfactants.

[0208] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. Prevention of microbial action may be ensured by incorporating various antibacterial and antifungal agents, such as p-hydroxybenzoic acid, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to incorporate isotonic agents (such as sugars, sodium chloride and the like) into the compositions. In addition, long-acting absorption of injectable pharmaceutical forms may be achieved by incorporating agents that delay absorption (e.g., aluminum monostearate and gelatin).

[0209] In some cases, to prolong the effect of a drug, it is desirable to slow down the absorption of a drug from a subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The absorption rate of the drug then depends on its dissolution rate, which in turn can depend on the crystal size and crystalline form. Alternatively, delayed absorption of the drug can be achieved by dissolving or suspending the parenterally administered drug form in an oil vehicle.

[0210] Injectable depot forms are prepared by forming a microencapsulation matrix of the target compound in a biodegradable polymer (e.g., polylactide-polyglycolide). Depending on the ratio of drug to polymer and the nature of the specific polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

[0211] For use in the methods of the invention, the active compound may be administered as such or in the form of a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0212] The introduction method can also be provided by a rechargeable or biodegradable device. In recent years, a variety of slow-release polymeric devices have been developed and tested in vivo for controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels) including both biodegradable and non-degradable polymers can be used to form implants for sustained release of compounds at specific target sites.

[0213] Actual dosage levels of active ingredients in pharmaceutical compositions may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0214] The selected dosage level will depend upon a variety of factors including the activity of the specific compound or combination of compounds employed, or the esters, salts or amides thereof, the route of administration, the time of administration, the rate of excretion of the specific compound employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the specific compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical art.

[0215] A physician or veterinarian familiar with the art can easily determine and prescribe the therapeutically effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can start the dosage of the pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. "Therapeutically effective amount" means a concentration of the compound sufficient to induce the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the individual's weight, sex, age, and medical history. Other factors affecting the effective amount may include, but are not limited to, the severity of the patient's condition, the condition being treated, the stability of the compound, and (if necessary) another class of therapeutic agents administered with the compounds of the present invention. Larger total doses can be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al., (1996) Harrison's Principles of Internal Medicine, 13th edition, 1814-1882, which is incorporated herein by reference).

[0216] In general, a suitable daily dose of the active compound used in the compositions and methods of the invention will be the amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally be determined based on the factors described above.

[0217] If desired, the effective daily dose of the active compound may be administered as 1, 2, 3, 4, 5, 6 or more sub-doses, which are administered separately at appropriate intervals throughout the day, optionally in unit dosage form. In certain embodiments of the invention, the active compound may be administered twice or three times a day. In a preferred embodiment, the active compound will be administered once a day.

[0218] Patients receiving such treatment are any animal in need thereof, including primates, particularly humans; and other mammals, such as horses, cattle, pigs, sheep, cats, and dogs in general; poultry; and pets.

[0219] In certain embodiments, the compounds of the present invention may be used alone or administered in combination with another class of therapeutic agents.

[0220] The present invention includes the use of pharmaceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. In certain embodiments, the salts of the present invention encompassed include, but are not limited to, alkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium salts. In certain embodiments, the salts of the present invention encompassed include, but are not limited to, L-arginine, phenethylbenzylamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium salts, L-lysine, magnesium salts, 4-(2-hydroxyethyl)morpholine, piperazine, 1-(2-hydroxyethyl)pyrrolidine potassium, sodium salts, triethanolamine, tromethamine, and zinc salts. In certain embodiments, the salts of the present invention encompassed include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts. In certain embodiments, the salts of the invention encompassed include, but are not limited to, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid, decanoic acid, caproic acid, hexanoic acid, caprylic acid, octanoic acid. acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucose formic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, l-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, l-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, l-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid and undecylenic acid.

[0221] Pharmaceutically acceptable acid addition salts may also exist in the form of various solvates with, for example, water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates may also be prepared. The source of such solvates may be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or incidental to the solvent.

[0222] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0223] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0224] definition

[0225] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those skilled in the art. Generally, the nomenclature used in conjunction with and the techniques of the following disciplines described herein are well known and commonly used in the art: chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry.

[0226] The methods and techniques of the present invention are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. See, e.g., Principles of Neural Science, McGraw-Hill Medical, New York, NY (2000); Motulsky, Intuitive Biostatistics, Oxford University Press, Inc. (1995); Lodish et al., Molecular Cell Biology, 4th Edition, WH Freeman & Co., New York (2000); Griffiths et al., Introduction to Genetic Analysis, 7th Edition, WH Freeman & Co., New York (1999); and Gilbert et al., Developmental Biology, 6th Edition, Sinauer Associates, Inc., Sunderland, MA (2000).

[0227] Unless otherwise defined herein, chemical terms used herein are used according to conventional usage in the industry as exemplified in "The McGraw-Hill Dictionary of Chemical Terms", Parker S., ed., McGraw-Hill Publishers, San Francisco, CA (1985).

[0228] All publications, patents, and published patent applications mentioned above, as well as any other publications, patents, and published patent applications mentioned in this application, are expressly incorporated herein by reference. In the event of a conflict, the present specification (including its explicit definitions) controls.

[0229] The term "agent" is used herein to refer to a chemical compound (e.g., an organic or inorganic compound, a mixture of chemical compounds), a biomacromolecule (e.g., a nucleic acid, an antibody (including portions thereof), and humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portions thereof (e.g., a peptide, a lipid, a carbohydrate)), or an extract prepared from a biological substance (e.g., a bacterial, plant, fungal, or animal (especially mammalian) cell or tissue). The agent includes, for example, agents of known structure and those of unknown structure. The ability of the agent to inhibit AR or promote AR degradation may make it suitable as a "therapeutic agent" in the methods and compositions of the present invention.

[0230] "Patient", "subject" or "individual" are used interchangeably and refer to human or non-human animals. These terms include mammals, such as humans, primates, livestock animals (including cattle, pigs, etc.), companion animals (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats).

[0231] "Treating" a condition or patient means taking steps to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or symptoms, reduction in extent of disease, stabilization of the disease state (i.e., not worsening), prevention of disease spread, delay or slowing of disease progression, improvement or palliation of the disease state, and detectable or undetectable remission (partial or complete) of the condition. "Treatment" may also mean prolonging survival as compared to the expected survival of a person not receiving treatment.

[0232] The term "prevention" is art-recognized and well-known in the art when used with respect to conditions such as local recurrences (e.g., pain), diseases such as cancer, symptom complexes such as heart failure, or any other medical condition, and includes administering a composition that reduces the frequency of symptoms of the medical condition in an individual or delays the onset of the same relative to an individual not receiving the composition. Thus, cancer prevention includes, for example, reducing the number of detectable cancerous growths in a patient population receiving prophylactic treatment relative to an untreated control population and / or delaying the appearance of detectable cancerous growths in a treated population relative to an untreated control population, e.g., by a statistically and / or clinically significant amount.

[0233] A substance, compound, or agent may be "administered" or "administered of" to a subject using one of a variety of methods known to those skilled in the art. For example, the compound or agent may be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, for example, through a skin catheter). The compound or agent may also be suitably introduced by a rechargeable or biodegradable polymeric device or other device (e.g., a patch and a pump) or a formulation that provides for extended, slow, or controlled release of the compound or agent. Administration may also be performed, for example, once, multiple times, and / or over one or more extended periods of time.

[0234] The appropriate method of administering a substance, compound, or agent to an individual also depends on, for example, the age and / or physical condition of the individual and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In certain embodiments, the compound or agent is orally administered to an individual, for example, by ingestion. In certain embodiments, the orally administered compound or agent is an extended release or slow release formulation, or is administered using a device for such slow or extended release.

[0235] As used herein, the phrase "combination" refers to any form of administration of two or more different therapeutic agents, wherein the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., both agents are effective in the patient at the same time, which may include a synergistic effect of the two agents). For example, different therapeutic compounds may be administered simultaneously or sequentially in the same formulation or in separate formulations. Thus, an individual receiving such treatment may benefit from the combined effects of the different therapeutic agents.

[0236] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or agent is an amount of the drug or agent that will have the intended therapeutic effect when administered to a subject. The full therapeutic effect may not occur when one dose is administered, and may only occur after a series of doses are administered. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount required for a subject depends, for example, on the size, health, and age of the subject and the nature and extent of the condition being treated (e.g., cancer or MDS). One skilled in the art can readily determine the effective amount for a given situation by routine experimentation.

[0237] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs as well as instances where it does not occur. For example, "optionally substituted alkyl" means that the alkyl group may be substituted as well as the alkyl group is unsubstituted.

[0238] It is understood that one skilled in the art can select substituents and substitution patterns on the compounds of the invention to produce chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art and those set forth below. If a substituent is substituted with more than one group, it is understood that the multiple groups may be located on the same carbon or on different carbons, as long as a stable structure results.

[0239] As used herein, the term "optionally substituted" refers to the replacement of 1 to 6 hydrogen groups in a given structure with the group of a specified substituent, including but not limited to: hydroxy, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2, or -CH2-OP(O)(O-alkyl)2. Preferably, "optionally substituted" refers to the replacement of one to four hydrogen groups in a given structure with the substituents mentioned above. More preferably, one to three hydrogen groups are replaced by substituents as mentioned above. It should be understood that the substituents may be further substituted.

[0240] As used herein, "alkyl" refers to a straight or branched aliphatic saturated hydrocarbon group, and may preferably be an alkyl group having 1 to 6 carbon atoms, and more preferably an alkyl group having 1 to 4 carbon atoms. Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl. "Alkyl" may be optionally substituted. In addition, the term "alkyl" used throughout the specification, examples and claims is intended to include unsubstituted and substituted alkyl groups, the latter referring to an alkyl moiety having a substituent replacing hydrogen on one or more carbons of the hydrocarbon backbone, including halogenated alkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc.

[0241] The term "acyl" is art recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0242] The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbyl C(O)NH-.

[0243] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0244] The term "alkoxy" refers to an alkyl group attached to an oxygen. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0245] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and can be represented by the general formula alkyl-O-alkyl.

[0246] The term "C x-y " or "C x -C y " when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is intended to include groups containing from x to y carbons in the chain. C0 alkyl indicates a hydrogen if the group is in a terminal position and a bond if internal. 1-6 Alkyl groups, for example, contain from one to six carbon atoms in the chain.

[0247] The term "alkylamino" as used herein refers to an amino group substituted with at least one alkyl group.

[0248] The term "alkylthio" as used herein refers to a thiol group substituted with an alkyl group and can be represented by the general formula alkylS-.

[0249] As used herein, the term "amide" refers to a group

[0250]

[0251] Where R 9 and R 10 Each independently represents hydrogen or a hydrocarbon group, or R 9 and R 10 Together with the nitrogen atom to which it is attached it forms a heterocyclic ring having 4 to 8 atoms in the ring structure.

[0252] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, such as the moiety represented by the formula:

[0253]

[0254] Where R 9 , R 10 and R 10 ' each independently represents hydrogen or a hydrocarbon group, or R 9 and R 10 Together with the nitrogen atom to which it is attached it forms a heterocyclic ring having 4 to 8 atoms in the ring structure.

[0255] The term "aminoalkyl" as used herein refers to an alkyl group substituted with an amino group.

[0256] As used herein, "aryl" refers to a carbocyclic aromatic group that may be further fused to a second 5- or 6-membered carbocyclic group that may be aromatic, saturated or unsaturated, and examples of aryl may include, but are not limited to, phenyl, indanyl, 1-naphthyl, 2-naphthyl, tetrahydronaphthyl, and the like. The aryl may be attached to other groups at appropriate positions on the aromatic ring. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. Aryl includes benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0257] The term "carbamate" is recognized in the industry and refers to the following group:

[0258]

[0259] Where R 9 and R 10 Each independently represents hydrogen or a hydrocarbon group.

[0260] The term "carbocyclylalkyl" as used herein refers to an alkyl group substituted with a carbocyclyl group.

[0261] The term "carbocycle" includes 5-7 membered monocyclic rings and 8-12 membered bicyclic rings. Each ring of the bicyclic carbocycle can be selected from saturated, unsaturated and aromatic rings. The carbocycle includes bicyclic molecules that share one, two or three or more atoms between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with another ring. Each ring of the fused carbocycle can be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring (such as phenyl) can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane or cyclohexene. Where valence permits, any combination of saturated, unsaturated and aromatic bicyclic rings is included in the definition of carbocyclic. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo [2.2.1] heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo [4.2.0] oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decahydronaphthalene, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. "Carbocycle" may be substituted at any position or positions capable of having a hydrogen atom.

[0262] The term "carbocyclylalkyl" as used herein refers to an alkyl group substituted with a carbocyclyl group.

[0263] The term "carbonate" is art-recognized and refers to the group -OCO2-.

[0264] The term "carboxyl" as used herein refers to a group represented by the formula -CO2H.

[0265] The term "cycloalkyl" includes substituted or unsubstituted non-aromatic monocyclic structures, preferably 4 to 8 membered rings, more preferably 4 to 6 membered rings. The term "cycloalkyl" also includes polycyclic ring systems having two or more rings, wherein two or more carbon atoms are common to two adjacent rings, wherein at least one ring is a cycloalkyl group and the substituents (e.g., R 100 ) is attached to a cycloalkyl ring, for example, the other ring can be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. Heteroaryl includes, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, benzodioxane, tetrahydroquinoline and the like.

[0266] As used herein, the term "ester" refers to the group -C(O)OR 9 , where R 9 Represents a hydrocarbon group.

[0267] The term "ether" as used herein refers to another hydrocarbon group connected to a hydrocarbon group via an oxygen. Thus, an ether substituent of a hydrocarbon group may be hydrocarbon-O-. An ether may be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which may be represented by the general formula alkyl-O-alkyl.

[0268]

[0046] The terms "halo" and "halogen" as used herein refer to halogen and include chlorine, fluorine, bromine and iodine.

[0269] As used herein, the terms "hetaralkyl" and "heteroaralkyl" refer to an alkyl group substituted with a heteroaryl group.

[0270] As used herein, unless otherwise specified, "heteroaryl" refers to a heteroaromatic compound containing at least one heteroatom selected from the group consisting of N, O and S, and preferably heteroaryl may include, but is not limited to, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, imidazole, triazole, indole, oxadiazole, thiadiazole, quinoline, isoquinoline, isoxazole, oxazole, thiazole and pyrrole. The term "heteroaryl" and "hetaryl" also include polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one of the rings is an aromatic ring, for example, the other ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic group. Heteroaryl includes, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine and the like.

[0271] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen and sulfur.

[0272] The term "heterocyclylalkyl" as used herein refers to an alkyl group substituted with a heterocyclyl group.

[0273] As used herein, "heterocycle" refers to an aromatic or non-aromatic ring containing, in addition to carbon atoms, a heteroatom selected from nitrogen atoms, sulfur atoms and oxygen atoms as a ring member atom, and preferably includes a 4- to 10-membered and more preferably a 5- to 9-membered aromatic or non-aromatic ring containing 1 to 4 of the above heteroatoms. Examples of the aromatic ring include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and benzothiazolyl. In addition, examples of the non-aromatic ring include tetrahydrothiophenyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl and azobenzene. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more rings in which two or more carbon atoms are common to two adjacent rings, wherein at least one of the rings is heterocyclic, for example, the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl.

[0274] As used herein, "arylene" and "heteroarylene" refer to divalent radicals of aromatic and heteroaromatic rings.

[0275] As used herein, the term "hydrocarbyl" refers to a group that is bonded through a carbon atom and does not have a =O or =S substituent, and which typically has at least one carbon-hydrogen bond and a (primarily) carbon backbone, but may optionally contain heteroatoms. Thus, for the purposes of this application, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl may be considered hydrocarbyl, but substituents such as acetyl (which has a =O substituent on the attached carbon) and ethoxy (which is attached through an oxygen rather than a carbon) are not hydrocarbyl. Hydrocarbyl includes, but is not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, alkynyl, and combinations thereof.

[0276] The term "hydroxyalkyl" as used herein refers to an alkyl group substituted with a hydroxy group.

[0277] The term "lower" when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy is intended to include groups having ten or fewer, preferably six or fewer atoms in the substituent. For example, "lower alkyl" refers to an alkyl group containing ten or fewer, preferably six or fewer carbon atoms. In certain embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy substituents defined herein are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl or lower alkoxy, respectively, whether they appear alone or in combination with other substituents (e.g., in the description of hydroxyalkyl and aralkyl) (in such cases, for example, when counting carbon atoms in an alkyl substituent, atoms in the aryl group are not counted).

[0278] The term "phosphoryl" is art-recognized and refers to a group represented by the following general formula:

[0279]

[0280] Where R 9 and R 10 Each independently represents a negative charge, hydrogen or a hydrocarbon group.

[0281] The term "phosphoramidite" is recognized in the art and refers to a group represented by the following general formula:

[0282]

[0283] Where R 9 represents a negative charge, hydrogen or a hydrocarbon group; and each R 10 independently represents hydrogen or a hydrocarbon group.

[0284] The term "phosphoramido" is art-recognized and refers to a group represented by the following general formula:

[0285]

[0286] Each R 9 and R 10 independently represents hydrogen or a hydrocarbon group.

[0287] The terms "polycyclic group", "polycyclic" and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings". Each ring of the polycyclic ring may be substituted or unsubstituted. In certain embodiments, each ring of the polycyclic ring contains 3 to 10, preferably 5 to 7 atoms in the ring.

[0288] The term "sulfate" is art-recognized and refers to the group -OSO3H or a pharmaceutically acceptable salt thereof.

[0289] The term "sulfonamide" is art-recognized and refers to a group represented by the following general formula:

[0290]

[0291] Each R 9 and R 10 independently represents hydrogen or a hydrocarbon group.

[0292] The term "sulfoxide" is art-recognized and refers to the group -S(O)-.

[0293] The term "sulfonate" is art-recognized and refers to the group SO3H or a pharmaceutically acceptable salt thereof.

[0294] The term "sulfone" is art-recognized and refers to the group -S(O)2-.

[0295] The term "iminothiolone group" is recognized in the industry and refers to a group represented by the following general formula:

[0296]

[0297] Where R 9 and R 10 Each independently represents hydrogen or a hydrocarbon group.

[0298] In certain embodiments, as used herein, "substituents" include halogen groups, cyano groups, nitro groups, substituted or unsubstituted amino groups (including substituted or unsubstituted alkyl groups and substituted or unsubstituted carboxyl groups), substituted or unsubstituted hydrocarbon groups, substituted or unsubstituted heterocyclic groups, acyl groups, substituted or unsubstituted amino groups, substituted or unsubstituted carbamoyl groups, substituted or unsubstituted thiolcarbamoyl groups, substituted or unsubstituted sulfonamide groups, substituted or unsubstituted hydroxyl groups, substituted or unsubstituted sulfonyl (SH) groups, and substituted or unsubstituted silicon groups.

[0299] The term "substituted" refers to a moiety having a substituent that replaces a hydrogen on one or more carbons in the skeleton. It should be understood that "substituted" or "substituted by..." includes an implicit premise that the substitution is consistent with the allowed valence of the substituted atom and the substituent, and the substitution will produce a stable compound, for example, it will not spontaneously transform (e.g., by rearrangement, cyclization, elimination, etc.). As used herein, the term "substituted" is expected to include all allowed substituents of organic compounds. In a broad sense, the allowed substituents include non-cyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For appropriate organic compounds, the allowed substituents may be one or more and may be the same or different. For the purposes of the present invention, a heteroatom (e.g., nitrogen) may have a hydrogen substituent that satisfies the heteroatom valence requirements and / or any allowed organic compound substituent described herein. Substituents may include any of the substituents described herein, such as halogen, hydroxy, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphite, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfonamide, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that substituents may themselves be substituted if appropriate.

[0300] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group.

[0301] As used herein, the term "thioester" refers to the group -C(O)SR 9 or -SC(O)R 9

[0302] Where R 9 Represents a hydrocarbon group.

[0303] As used herein, the term "thioether" is equivalent to an ether in which the oxygen is replaced by sulfur.

[0304] The term "urea" is recognized in the industry and can be represented by the following general formula:

[0305]

[0306] Where R 9 and R 10 Each independently represents hydrogen or a hydrocarbon group.

[0307] As used herein, the term "modulate" encompasses inhibiting or suppressing a function or activity (eg, cell proliferation) as well as enhancing a function or activity.

[0308] As used herein, the term "pharmaceutically acceptable salt" of the present invention is equivalent to retain the biological effectiveness and properties of the compounds disclosed herein according to one embodiment, and can collectively refer to any preferred salts with respect to medicine, biology or other properties. Non-limiting examples of these salts can be salts or acid addition salts of inorganic bases or organic bases added to the compounds disclosed herein. Examples of organic acids capable of forming the acid addition salts can be acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like, and examples of inorganic acids can be hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.

[0309] The term "pharmaceutically acceptable acid addition salt" as used herein means any non-toxic organic or inorganic salt of any base compound represented by Formula I. Illustrative inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono-, di- and tricarboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid and salicylic acid, and sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. Monoacid or di-acid salts may be formed, and the salts may exist in hydrated, solvated or substantially anhydrous form. In general, acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents than the free base form, and generally exhibit higher melting points. The selection of appropriate salts is known to those skilled in the art. Other non-pharmaceutically acceptable salts, such as oxalates, may be used, for example, to isolate compounds of formula I for laboratory use or for subsequent conversion into pharmaceutically acceptable acid addition salts.

[0310] The term "pharmaceutically acceptable basic addition salt" as used herein means any non-toxic organic or inorganic base addition salt of any acid compound represented by Formula I or any of its intermediates. Illustrative inorganic bases that form suitable salts include hydroxides of lithium, sodium, potassium, calcium, magnesium or barium. Illustrative organic bases that form suitable salts include aliphatic, alicyclic or aromatic organic amines, such as methylamine, trimethylamine and picoline or ammonia. The selection of appropriate salts is known to those skilled in the art.

[0311] "Prodrug" or "pharmaceutically acceptable prodrug" refers to a compound that is metabolized (e.g., hydrolyzed or oxidized) in the host after administration to form a compound of the invention (e.g., a compound of formula I). ​​Typical examples of prodrugs include compounds having biologically labile or cleavable (protecting) groups on the functional portion of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminized, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of prodrugs using esters or phosphoramidates as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of the invention are metabolized to produce compounds of formula I. The present invention includes within its scope prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

[0312] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, that can be used to formulate a drug for medical or therapeutic applications.

[0313] As used herein, the term "logarithm of solubility", "LogS" or "logS" is used in the industry to quantify the aqueous solubility of a compound. The aqueous solubility of a compound significantly affects its absorption and distribution characteristics. Low solubility is generally associated with poor absorption. The LogS value is the unit exfoliation logarithm (base 10) of the solubility measured in mol / liter.

[0314] Examples

[0315] The present invention will now be summarized and will be more readily understood by reference to the following examples, which are included for the purpose of illustrating certain aspects and embodiments of the invention only and are not intended to limit the invention.

[0316] Example 1: Synthesis of intermediates

[0317] [Preparation Example 1] Preparation of 4-(bromomethyl)benzenesulfonamide (Intermediate 1)

[0318]

[0319] (Step 1) Preparation of 4-(bromomethyl)benzenesulfonyl chloride

[0320]

[0321] p-Toluenesulfonyl chloride (5.00 g, 26.2 mmol) was dissolved in benzene (10.0 mL), and then N-bromosuccinimide (5.60 g, 31.5 mmol) and a, a'-azobis(isobutyronitrile) (4.70 g, 28.8 mmol) were added to the mixture in sequence. The reaction mixture was stirred at 100 ° C and nitrogen for 12 hours. After cooling to room temperature, distilled water was added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:20) to obtain the title compound in the form of a white solid. (5.12 g, 72%) MS m / z: 267 [M+1] +

[0322] (Step 2) Preparation of 4-(bromomethyl)benzenesulfonamide (Intermediate 1)

[0323]

[0324] The above (Step 1) The prepared compound (3.30 g, 12.2 mmol) was dissolved in tetrahydrofuran (34.0 mL), and then cooled to 0 ° C, and 28-30% ammonia solution (4.80 mL) was slowly added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 2 hours. After the reaction was completed, distilled water was added and extracted twice with ethyl acetate. The organic layer was washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The title compound was obtained as a white solid without further purification. (2.84 g, 93%) MS m / z: 251 [M + 1] +1 H NMR (400MHz, CDCl3) δppm: 7.81 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.39 (s, 2H), 4.76 (s, 2H).

[0325] [Preparation Example 2] Preparation of tert-butyl ((4-(bromomethyl)piperidin-1-yl)sulfonyl)carbamate (Intermediate 2) Preparation

[0326]

[0327] (Step 1) Preparation of tert-butyl ((4-(hydroxymethyl)piperidin-1-yl)sulfonyl)carbamate

[0328]

[0329] 1-(tert-Butoxycarbonylaminosulfonyl)piperidine-4-carboxylic acid (200mg, 0.65mmol) was dissolved in tetrahydrofuran (2.00mL), and then cooled to 0°C, and lithium aluminum hydride (36.9mg, 0.97mmol) was added to the mixture. It was stirred at 0°C and nitrogen for 2 hours. After the reaction was completed, a mixed solvent of methanol: 15% sodium carbonate solution: distilled water ratio = 1: 1: 3 was added, and then extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3) to obtain the title compound in the form of a colorless oil. (95.0mg, 50%) MS m / z: 295 [M+1] +

[0330] (Step 2) Preparation of tert-butyl ((4-(bromomethyl)piperidin-1-yl)sulfonyl)carbamate (Intermediate 2)

[0331]

[0332] The above (Step 1) The prepared compound (95.0 mg, 0.32 mmol) was dissolved in dichloromethane (1.00 mL), and then phosphorus tribromide (118 mg, 0.36 mmol) and triphenylphosphine (76.2 mg, 0.29 mmol) were slowly added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 5 hours. After the reaction was completed, distilled water was slowly added thereto, and ethyl acetate was extracted twice. The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 5) to obtain the title compound in the form of a white solid. (56.0 mg, 49%) MS m / z: 358 [M+1] +1 H NMR (400MHz, CDCl3) δ6.93 (s, 1H), 3.91 (d, J = 12.6Hz, 2H), 3.31 (d, J = 6.3Hz, 2H), 2.93 (t, J = 12.5Hz, 2H), 1.93 (d, J = 13.2Hz, 2H), 1.63-1.45 (m, 11H).

[0333] [Preparation Example 3] Preparation of tert-butyl ((4-(bromomethyl)phenyl)sulfonyl)(methyl)carbamate (Intermediate 3) preparation

[0334]

[0335] (Step 1) Preparation of N,4-dimethylbenzenesulfonamide

[0336]

[0337] Para-toluenesulfonyl chloride (1.50 g, 7.87 mmol) was dissolved in dichloromethane (8.00 mL), and then cooled to 0 ° C, and an aqueous solution of methylamine (40 wt.% in H2O, 2.04 mL, 23.6 mmol) and N, N-diisopropylethylamine (2.70 mL, 15.7 mmol) were slowly added to the mixture. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, distilled water and saturated aqueous ammonium chloride solution were added, and extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4 to 1: 1) to obtain the title compound in the form of a white solid. (1.40 g, 97%) MS m / z: 186 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 7.74 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 4.27 (d, J = 4.5 Hz, 1H), 2.65 (d, J = 5.5 Hz, 3H), 2.44 (s, 3H).

[0338] (Step 2) Preparation of tert-butyl methyl(tosyl)carbamate

[0339]

[0340] The above (Step 1) The compound obtained (600 mg, 3.24 mmol) was dissolved in dichloromethane (16.0 mL), and di-tert-butyl dicarbonate (0.90 mL, 3.89 mmol), N, N-diisopropylethylamine (1.70 mL, 9.72 mmol) and 4-dimethylaminopyridine (39.6 mg, 0.32 mmol) were slowly added to the mixture in sequence. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added and extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 3:7) to obtain the title compound in the form of a colorless liquid. (922 mg, 99%) MS m / z: 286 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 7.77 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 7.9 Hz 2H), 3.35 (s, 3H), 2.44 (s, 3H), 1.35 (s, 9H).

[0341] (Step 3) Preparation of tert-butyl ((4-(bromomethyl)phenyl)sulfonyl)(methyl)carbamate (Intermediate 3)

[0342]

[0343] The above (Step 2) The compound obtained (920 mg, 3.22 mmol) was dissolved in carbon tetrachloride (5.00 mL), and then N-bromosuccinimide (545.1 mg, 3.06 mmol) and a, a'-azobis(isobutyronitrile) (37.1 mg, 0.23 mmol) were added to the mixture in sequence. The reaction mixture was stirred at 80 ° C and nitrogen for 3 hours. After cooling to room temperature, it was concentrated under reduced pressure, and distilled water was added, and then extracted twice with ethyl acetate. The organic layer was washed with distilled water and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to obtain the title compound in the form of a colorless liquid. (662 mg, 56%) MS m / z: 365 [M+1] +1 HNMR (400MHz, CDCl3) δppm: 7.86 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 4.50 (s, 2H), 3.36 (s, 3H), 1.35 (s, 9H).

[0344] [Preparation Example 4] Preparation of tert-butyl (4-(bromomethyl)phenyl)carbamate (Intermediate 4)

[0345]

[0346] (Step 1) Preparation of tert-butyl (4-(hydroxymethyl)phenyl)carbamate

[0347]

[0348] 4-Aminobenzyl alcohol (300 mg, 2.43 mmol) was dissolved in tetrahydrofuran (5.00 mL), and sodium carbonate (309 mg, 2.92 mmol) and di-tert-butyl dicarbonate (0.56 mL, 2.43 mmol) were slowly added to the mixture in sequence. The reaction mixture was stirred at room temperature and nitrogen for 24 hours. After the reaction was completed, 2N HCl (10.0 mL) was added and extracted twice with ethyl acetate. The organic layer was washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The title compound was obtained in the form of a yellow liquid without further purification. (542 mg, 99%) MS m / z: 224 [M+1] +1 HNMR (400MHz, CDCl3) δ7.43–7.15 (m, 4H), 6.48 (s, 1H), 4.63 (d, J = 2.3Hz, 2H), 1.57–1.42 (m, 9H).

[0349] (Step 2) Preparation of tert-butyl (4-(bromomethyl)phenyl)carbamate (Intermediate 4)

[0350]

[0351] The above (Step 1) The prepared compound (300 mg, 1.34 mmol) was dissolved in dichloromethane (6.00 mL), and then phosphorus tribromide (400 mg, 1.48 mmol) was slowly added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 5 hours. After the reaction was completed, distilled water was added and extracted twice with ethyl acetate. The organic layer was washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The title compound was obtained as a white solid without further purification. (146 mg, 38%) MS m / z: 287 [M+1] +1 H NMR (400MHz, CDCl3) δ7.36-7.27 (m, 4H), 6.56 (d, J = 15.4Hz, 1H), 4.47 (s, 2H), 1.51 (s, 9H).

[0352] [Preparation Example 5] Preparation of 4-vinylbenzenesulfonamide (Intermediate 5)

[0353]

[0354] (Step 1) Preparation of 4-(2-bromoethyl)benzenesulfonyl chloride

[0355]

[0356] (2-Bromoethyl)benzene (2.00 g, 10.8 mmol) was dissolved in dichloromethane anhydride (10.8 mL), and then cooled to 0 ° C, and chlorosulfonic acid (2.20 mL, 32.4 mmol) was slowly added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 3 hours. After the reaction was completed, the reaction mixture was slowly dripped into ice water, and then extracted twice with dichloromethane. The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The title compound was obtained as a white solid without further purification. (2.10 g, 67%) MS m / z: 284 [M+1] +1 HNMR (400MHz, CDCl3) δppm: 7.89 (d, J = 5.6Hz, 2H), 7.36 (s, 2H), 3.55 (s, 2H), 3.21 (s, 2H).

[0357] (Step 2) Preparation of 4-(2-bromoethyl)benzenesulfonamide

[0358]

[0359] The above (Step 1) The prepared compound (2.10 g) was dissolved in tetrahydrofuran (6.00 mL) and then cooled to 0 ° C, and 28-30% aqueous ammonia solution (2.00 mL) was slowly added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 2 hours. The mixture was dissolved in distilled water, and then the resulting solid was filtered and dried to obtain the title compound in the form of a white solid. (1.06 g, 55%) MS m / z: 265 [M+1] +1 H NMR (400MHz, DMSO-d6) δppm: 7.76 (d, J = 5.5Hz, 2H), 7.56-7.40 (m, 2H), 7.31 (s, 2H), 3.78 (s, 2H), 3.21 (s, 2H).

[0360] (Step 3) Preparation of 4-vinylbenzenesulfonamide (Intermediate 5)

[0361]

[0362] The above (Step 2) The prepared compound (300 mg, 1.14 mmol) was dissolved in tetrahydrofuran (5.00 mL), and then cooled to 0 ° C, and potassium tert-butoxide (1.0 M tetrahydrofuran solution, 3.3 mL, 3.40 mmol) was slowly added. The reaction mixture was stirred at 60 ° C and nitrogen for 3 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The title compound was obtained as a white solid without further purification. (157 mg, 75%) MS m / z: 184 [M + 1] +1 HNMR (400MHz, CDCl3) δppm: 7.87 (d, J = 9.1Hz, 2H), 7.52 (d, J = 8.5Hz, 2H), 6.79-6.68 (m, 1H), 5.87 (d, J = 17.5Hz, 1H), 5.43 (d, J = 9.1Hz, 1H), 4.77 (s, 2H).

[0363] [Preparation Example 6] Preparation of 4-(bromomethyl)phenyl)(methyl)sulfane (Intermediate 6)

[0364]

[0365] (4-Methylsulfanylphenyl)methanol (5.00 g, 32.4 mmol) was dissolved in dichloromethane (20.0 mL), and then tetrabromomethane (13.9 g, 42.1 mmol) and triphenylphosphine (9.30 g, 35.7 mmol) were added to the mixture at 0 ° C. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, distilled water was slowly added and extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0: 10 to 1: 4) to obtain the title compound in the form of a white solid. (5.40 g, 77%) MSm / z: 218 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 7.30 (d, J = 8.4Hz, 2H), 7.2 (d, J = 8.5Hz, 2H), 4.48 (s, 2H), 2.48 (s, 3H).

[0366] [Preparation Example 7] Preparation of (4-(bromomethyl)phenyl)(ethyl)sulfane (Intermediate 7)

[0367]

[0368] (4-Ethylsulfanylphenyl)methanol (0.50 g, 2.97 mmol) was dissolved in dichloromethane (10.0 mL), and then tetrabromomethane (1.30 g, 3.86 mmol) and triphenylphosphine (857.4 mg, 3.27 mmol) were added to the mixture at 0°C. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, distilled water was added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0:10 to 1:4) to obtain the title compound in the form of a colorless liquid. (232 mg, 34%) MS m / z: 232 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 7.29 (d, J = 8.5Hz, 2H), 7.25 (d, J = 8.6Hz, 2H), 4.47 (s, 2H), 2.95 (q, J = 7.4Hz, 2H), 1.33 (t, J = 7.4Hz, 3H).

[0369] [Preparation Example 8] Preparation of benzyl (4-(bromomethyl)phenyl)sulfane (Intermediate 8)

[0370]

[0371] (Step 1) Preparation of 4-(benzylthio)benzaldehyde

[0372]

[0373] 4-Fluorobenzaldehyde (1.00 g, 8.06 mmol) was dissolved in N, N-dimethylformamide (4.00 mL), and then benzyl mercaptan (1.10 g, 8.86 mmol) and potassium carbonate (1.70 g, 12.1 mmol) were added to the mixture. The reaction mixture was stirred at 100 ° C and nitrogen for 4 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0: 10 to 1: 4) to obtain the title compound in the form of a green solid. (1.10 g, 59%) MS m / z: 229 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 9.92 (s, 1H), 7.73 (d, J = 8.4Hz, 2H), 7.39-7.36 (m, 4H), 7.31 (t, J = 7.2Hz, 2H), 7.27 (d, J = 7.0Hz, 1H), 4.24 (s, 2H).

[0374] (Step 2) Preparation of (4-(benzylthio)phenyl)methanol

[0375]

[0376] The above (Step 1) The prepared compound (1.10 g, 4.77 mmol) was dissolved in methanol (7.00 mL) and then cooled to 0 ° C., and sodium borohydride (199 mg, 5.25 mmol) was added to the mixture and stirred for 3 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The title compound was obtained as a white solid without further purification. (978 mg, 89%) MS m / z: 231 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 7.31-7.24 (m, 9H), 4.64 (d, J = 5.9Hz, 2H), 4.11 (s, 2H).

[0377] (Step 3) Preparation of benzyl(4-(bromomethyl)phenyl)sulfane (Intermediate 8)

[0378]

[0379] The above (Step 2)The prepared compound (0.50 g, 2.17 mmol) was dissolved in dichloromethane (10.0 mL), and then tetrabromomethane (936 mg, 2.82 mmol) and triphenylphosphine (626 mg, 2.39 mmol) were added to the mixture at 0 ° C. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, distilled water was added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0: 10 to 1: 4) to obtain the title compound in the form of a white solid. (468 mg, 74%) MS m / z: 294 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 7.36-7.20 (m, 9H), 4.45 (s, 2H), 4.13 (s, 2H).

[0380] [Preparation Example 9] Preparation of diethyl (4-(bromomethyl)benzyl)phosphonate (Intermediate 9)

[0381]

[0382] 1,4-bis(bromomethyl)benzene (396mg, 1.50mmol) was dissolved in N,N-dimethylformamide (0.80mL), and then triethyl phosphite (128μl, 0.75mmol) was added. The reaction mixture was stirred in a microwave reactor at 150°C for 2 minutes. After the reaction was completed, distilled water was slowly added to the mixture and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:9 to 10:0) to obtain the title compound in the form of a white oil. (130mg, 54%) MS m / z: 322 [M+1] +1 HNMR (400MHz, CDCl3) δ7.34 (d, J = 8.1Hz, 2H), 7.30-7.26 (m, 2H), 4.48 (s, 2H), 4. 08-3.96(m,4H),3.16(d,J=7.2Hz,1H),3.11(d,J=5.8Hz,1H),1.29-1.17(m,6H).

[0383] [Preparation Example 10] Preparation of 4-(bromomethyl)-3-fluorobenzenesulfonamide (Intermediate 10)

[0384]

[0385] (Step 1) Preparation of 3-fluoro-4-methylbenzenesulfonamide

[0386]

[0387] 3-Fluoro-4-methyl-benzenesulfonyl chloride (500 mg, 2.40 mmol) was dissolved in 28% aqueous ammonia solution (10.0 mL) and then stirred for 4 hours at room temperature and nitrogen. After the reaction was completed, distilled water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The title compound was obtained as a white solid without further purification. (387 mg, 85%) MS m / z: 190 [M+1] +

[0388] (Step 2) Preparation of 4-(bromomethyl)-3-fluorobenzenesulfonamide (Intermediate 10)

[0389]

[0390] 3-Fluoro-4-methyl-benzenesulfonamide (387 mg, 2.05 mmol) was dissolved in chloroform (16.0 mL), and then N-bromosuccinimide (546 mg, 3.07 mmol) and a, a'-azobis(isobutyronitrile) (33.6 mg, 0.20 mmol) were added to the mixture in sequence. The reaction mixture was stirred at 90 ° C and nitrogen for 8 hours. After cooling to room temperature, distilled water was added and extracted twice with ethyl acetate. The organic layer was washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 8) to obtain the title compound in the form of a white solid. (491 mg, 90%) MS m / z: 269 [M+1] +

[0391] [Preparation Example 11] Preparation of 4-(bromomethyl)-3-chlorobenzenesulfonamide (Intermediate 11)

[0392]

[0393] (Step 1) Preparation of 3-chloro-4-methylbenzenesulfonamide

[0394]

[0395] 3-Chloro-4-methyl-benzenesulfonyl chloride (1.00 g, 4.44 mmol) was dissolved in 28% aqueous ammonia solution (20.0 mL) and then stirred for 4 hours at room temperature and under nitrogen. After the reaction was completed, distilled water was added thereto and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The title compound was obtained as a white solid without further purification. (745 mg, 82%) MS m / z: 206 [M+1] +

[0396] (Step 2) Preparation of 4-(bromomethyl)-3-chlorobenzenesulfonamide (Intermediate 11)

[0397]

[0398] 3-Chloro-4-methyl-benzenesulfonamide (500mg, 2.43mmol) was dissolved in chloroform (16.0mL), and then N-bromosuccinimide (649mg, 3.64mmol) and a, a'-azobis(isobutyronitrile) (39.9mg, 0.24mmol) were added to the mixture in sequence. The reaction mixture was stirred at 90°C and nitrogen for 8 hours. After cooling to room temperature, distilled water was added and extracted twice with ethyl acetate. The organic layer was washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:8) to obtain the title compound in the form of a white solid. (499mg, 72%) MS m / z: 285 [M+1] +1 H NMR (400MHz, DMSO-d6) δppm: 7.88 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.44 (s, 2H), 4.78 (s, 2H).

[0399] [Preparation Example 12] Preparation of (4-(bromomethyl)-3-fluorophenyl)(methyl)sulfane (Intermediate 12)

[0400]

[0401] (Step 1) Preparation of 2-fluoro-4-(methylthio)benzaldehyde

[0402]

[0403] 1-Bromo-2-fluoro-4-methylsulfanylbenzene (1.00 g, 4.52 mmol) was dissolved in tetrahydrofuran anhydride (11.0 mL), and then cooled to 0 ° C, and isopropylmagnesium chloride (2.0 M tetrahydrofuran solution, 2.60 mL, 5.20 mmol) was added and stirred for 30 minutes. N, N-dimethylformamide anhydride (0.50 mL, 6.78 mmol) was added to the reaction mixture at 0 ° C, and the reaction mixture was then stirred at room temperature and nitrogen for 1 hour. After the reaction was completed, 1N aqueous hydrogen chloride solution was slowly added at 0 ° C and extracted twice with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0: 10 to 1: 9) to obtain the title compound in the form of a white solid. (483 mg, 63%) MS m / z: 171 [M+1] +1H NMR (400MHz, CDCl3) δppm: 10.25 (s, 1H), 7.78-7.74 (m, 1H), 7.06 (d, J = 8.4Hz, 1H), 6.94 (d, J = 11.3Hz, 1H), 2.53 (s, 3H).

[0404] (Step 2) Preparation of (2-fluoro-4-(methylthio)phenyl)methanol

[0405]

[0406] The above (Step 1) The prepared compound (483 mg, 2.84 mmol) was dissolved in methanol (7.00 mL) and then cooled to 0 ° C., and sodium borohydride (118 mg, 3.12 mmol) was added to the mixture and stirred for 3 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound in the form of a colorless liquid. (473 mg, 97%) MS m / z: 173 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 7.34-7.29 (m, 1H), 7.01 (d, J = 9.7Hz, 1H), 7.92 (d, J = 10.7Hz 1H), 4.70 (s, 2H), 2.48 (s, 3H).

[0407] (Step 3) Preparation of (4-(bromomethyl)-3-fluorophenyl)(methyl)sulfane (Intermediate 12)

[0408]

[0409] The above (Step 2) The prepared compound (473mg, 2.75mmol) was dissolved in dichloromethane (5.40mL), and then tetrabromomethane (1.20g, 3.57mmol) and triphenylphosphine (792mg, 3.02mmol) were added to the mixture at 0°C. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, distilled water was added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0:10 to 1:4) to obtain the title compound in the form of a white solid. (552mg, 85%) MS m / z: 236 [M+1] +1H NMR (400MHz, CDCl3) δppm: 7.29-7.25 (m, 1H), 6.97 (d, J = 8.7Hz, 1H), 6.91 (d, J = 10.2Hz, 1H), 4.50 (s, 2H), 2.48 (s, 3H).

[0410] [Preparation Example 13] Preparation of (4-(bromomethyl)-3-methoxyphenyl)(methyl)sulfane (Intermediate 13)

[0411]

[0412] (Step 1) Preparation of 2-methoxy-4-(methylthio)benzaldehyde

[0413]

[0414] 4-Fluoro-2-methoxy-benzaldehyde (500mg, 3.24mmol) was dissolved in acetonitrile anhydride (7.00mL), and then sodium thiomethoxide (239mg, 3.41mmol) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0:10 to 1:4) to obtain the title compound in the form of a white solid. (427mg, 72%) MS m / z: 183 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 10.35 (s, 1H), 7.74 (d, J = 8.3Hz, 1H), 6.83 (d, J = 8.3Hz, 1H), 6.79 (s, 1H), 3.93 (s, 3H), 2.54 (s, 3H).

[0415] (Step 2) Preparation of (2-methoxy-4-(methylthio)phenyl)methanol

[0416]

[0417] The above (Step 1) The prepared compound (427 mg, 2.34 mmol) was dissolved in methanol (7.00 mL) and then cooled to 0 ° C., and sodium borohydride (97.5 mg, 2.58 mmol) was added to the mixture and stirred for 3 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound in the form of a colorless liquid. (429 mg, 99%) MS m / z: 185 [M+1] +1H NMR (400MHz, CDCl3) δppm: 7.19 (d, J = 7.8 Hz, 1H), 6.84-6.80 (m, 2H), 4.63 (d, J = 6.3 Hz, 2H), 3.87 (s, 3H), 2.50 (s, 3H).

[0418] (Step 3) Preparation of (4-(bromomethyl)-3-methoxyphenyl)(methyl)sulfane (Intermediate 13)

[0419]

[0420] The above (Step 2) The prepared compound (429 mg, 2.33 mmol) was dissolved in dichloromethane (10.0 mL), and then tetrabromomethane (1.00 g, 3.03 mmol) and triphenylphosphine (672 mg, 2.56 mmol) were added to the mixture at 0 ° C. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, distilled water was added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0: 10 to 1: 4) to obtain the title compound in the form of a colorless liquid. (113 mg, 20%) MS m / z: 248 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 7.23 (d, J = 7.9Hz, 1H), 6.80-6.77 (m, 2H), 4.54 (s, 2H), 3.89 (s, 3H), 2.49 (s, 3H).

[0421] [Preparation Example 14] Preparation of (4-(bromomethyl)-3-methylphenyl)(methyl)sulfane (Intermediate 14)

[0422]

[0423] (Step 1) Preparation of 2-methyl-4-(methylthio)benzaldehyde

[0424]

[0425] 4-Fluoro-2-methyl-benzaldehyde (1.00 g, 7.23 mmol) was dissolved in acetonitrile anhydride (14.0 mL), and then sodium thiomethoxide (558 mg, 7.96 mmol) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0: 10 to 1: 4) to obtain the title compound in the form of a colorless liquid. (1.03 g, 85%) MS m / z: 167 [M+1]+1 H NMR (400MHz, CDCl3) δppm: 10.16 (s, 1H), 7.69 (d, J = 8.1Hz, 1H), 7.15 (d, J = 8.3Hz, 1H), 7.05 (s, 1H), 2.64 (s, 3H), 2.52 (s, 3H).

[0426] (Step 2) Preparation of (2-methyl-4-(methylthio)phenyl)methanol

[0427]

[0428] The above (Step 1) The prepared compound (1.00 g, 6.18 mmol) was dissolved in methanol (10.0 mL) and then cooled to 0 ° C., and sodium borohydride (257 mg, 6.80 mmol) was added to the mixture and stirred for 3 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 3: 7) to obtain the title compound in the form of a colorless liquid. (972 mg, 93%) MS m / z: 169 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 7.28 (s, 1H), 7.13-7.04 (m, 2H), 4.66 (s, 2H), 2.48 (s, 3H), 2.35 (s, 3H).

[0429] (Step 3) Preparation of (4-(bromomethyl)-3-methylphenyl)(methyl)sulfane (Intermediate 14)

[0430]

[0431] The above (Step 2) The prepared compound (472mg, 2.81mmol) was dissolved in dichloromethane (10.0mL), and then tetrabromomethane (1.20g, 3.65mmol) and triphenylphosphine (809mg, 3.08mmol) were added to the mixture at 0°C. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, distilled water was added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0:10 to 1:9) to obtain the title compound in the form of a colorless liquid. (573mg, 88%) MS m / z: 232 [M+1] +1H NMR (400MHz, CDCl3) δppm: 7.21 (d, J = 7.9Hz, 1H), 7.06-7.03 (m, 2H), 4.50 (s, 2H), 2.47 (s, 3H), 2.39 (s, 3H).

[0432] [Preparation Example 15] Preparation of (4-(bromomethyl)-2-fluorophenyl)(methyl)sulfane (Intermediate 15)

[0433]

[0434] (Step 1) Preparation of 3-fluoro-4-(methylthio)benzaldehyde

[0435]

[0436] 3,4-difluorobenzaldehyde (800mg, 5.63mmol) was dissolved in acetonitrile anhydride (11.0mL), and then sodium thiomethoxide (434mg, 6.19mmol) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0:10 to 1:3) to obtain the title compound in the form of a colorless liquid. (616mg, 64%) MS m / z: 171 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 9.91 (s, 1H), 7.63 (d, J = 8.2Hz, 1H), 7.51 (d, J = 10.0Hz 1H), 7.35-7.29 (m, 1H), 2.54 (s, 3H).

[0437] (Step 2) Preparation of (3-fluoro-4-(methylthio)phenyl)methanol

[0438]

[0439] The above (Step 1) The prepared compound (616 mg, 3.62 mmol) was dissolved in methanol (7.00 mL) and then cooled to 0 ° C., and sodium borohydride (151 mg, 3.98 mmol) was added to the mixture and stirred for 3 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The title compound was obtained in the form of a colorless liquid without further purification. (656 mg) MS m / z: 173 [M+1] +1H NMR (400MHz, CDCl3) δppm: 7.26 (s, 1H), 7.12-7.06 (m, 2H), 4.67 (s, 2H), 2.46 (s, 3H).

[0440] (Step 3) Preparation of (4-(bromomethyl)-2-fluorophenyl)(methyl)sulfane (Intermediate 15)

[0441]

[0442] The above (Step 2) The prepared compound (656mg, 3.62mmol) was dissolved in dichloromethane (7.20mL), and then tetrabromomethane (1.60g, 4.71mmol) and triphenylphosphine (1.00g, 3.98mmol) were added to the mixture at 0°C. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, distilled water was added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0:10 to 1:4) to obtain the title compound in the form of a colorless liquid. (825mg, 97%) MS m / z: 236 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 7.21-7.07 (m, 3H), 4.44 (s, 2H), 2.47 (s, 3H).

[0443] [Preparation Example 16] Preparation of (4-(bromomethyl)phenyl)(cyclopropyl)sulfane (Intermediate 16)

[0444]

[0445] (Step 1) Preparation of (4-bromophenyl)(cyclopropyl)sulfane

[0446]

[0447] 4-Bromobenzenethiol (1.50g, 7.93mmol) is dissolved in dimethyl sulfoxide (10.0mL), and then potassium tert-butoxide (979.3mg, 8.73mmol) and bromocyclopropane (1.58mL, 19.83mmol) are added to the mixture. The reaction mixture is stirred at 80°C and under reduced pressure for 24 hours. After the reaction is completed, the reaction mixture is cooled to room temperature. Distilled water is slowly added and adjusted to pH 2-3 using 1M HCl aqueous solution, and then extracted three times with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate: n-hexane = 0:10 to 1:9) to obtain the title compound in the form of a light yellow liquid. (1.66g, 92%). 1H NMR (400MHz, CDCl3) δppm: 7.39 (d, J = 8.4Hz, 2H), 7.22 (d, J = 8.3Hz, 2H), 2.16 (td, J = 8.3, 3.5Hz, 1H), 1.16-1.01 (m, 2H), 0.72-0.66 (dd, J = 4.8, 2.0Hz, 2H).

[0448] (Step 2) Preparation of 4-(cyclopropylthio)benzoic acid

[0449]

[0450] The compound (1.66g, 7.24mmol) prepared in the above (step 1) is dissolved in anhydrous tetrahydrofuran (25.0mL), and then cooled to -78 ° C, and n-butyl lithium (5.4mL, 8.69mmol, 1.6M in hexane) is added to the mixture and stirred for 20 minutes. Carbon dioxide gas (CO2) is injected into the reaction mixture and stirred for 1 hour. After completing the reaction, distilled water is slowly added and adjusted to pH 2-3 using a 1M HCl aqueous solution, and then extracted three times with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound in the form of a light yellow solid. (1.48g). MS m / z:195[M+1]+1H NMR (400MHz, DMSO-d6) δppm: 7.74-7.63 (m, 2H), 7.27 (d, J = 8.5Hz, 2H), 2.14 (td, J = 7.1, 4.4Hz, 1H), 0.97 (dd, J = 7.3, 2.3Hz, 2H), 0.48-0.38 (m, 2H).

[0451] (Step 3) Preparation of (4-(cyclopropylthio)phenyl)methanol

[0452]

[0453] The compound (700mg, 3.60mmol) prepared in the above (step 2) is dissolved in anhydrous tetrahydrofuran (6.00mL), and then lithium aluminum hydride (7.20mL, 7.20mmol, 1M in THF) is added to the mixture at 0°C. The reaction mixture is stirred for 2 hours at 0°C and nitrogen. After the reaction is completed, distilled water is slowly added, and 1N aqueous sodium hydroxide solution (1.00mL) is added thereto. The reaction mixture is filtered through diatomaceous earth, and then washed with ethyl acetate. The filtrate is concentrated under reduced pressure, and the mixture is then purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:9 to 1:1) to obtain the title compound in the form of a colorless liquid. (411mg, 63%). MS m / z:181[M+1]+1H NMR (400MHz, CDCl3,) δppm: 7.36 (d, J = 8.4Hz, 2H), 7.29 (d, J = 8.3Hz, 2H), 4.65 (s, 2H), 2.25-2.15 (m, 1H), 1.10-1.04 (m, J = 5.9Hz, 2H), 0.72-0.66 (q, J = 4.6Hz, 2H).

[0454] (Step 4) Preparation of (4-(bromomethyl)phenyl)(cyclopropyl)sulfane

[0455]

[0456] The compound (411 mg, 2.28 mmol) prepared in the above (step 3) was dissolved in dichloromethane (10.0 mL), and then tetrabromomethane (982.9 mg, 2.96 mmol) and triphenylphosphine (657.8 mg, 2.51 mmol) were added to the mixture at 0 ° C. The reaction mixture was stirred for 18 hours at room temperature and nitrogen. After the reaction was completed, distilled water was added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0: 10 to 1: 4) to obtain the title compound in the form of a colorless liquid. (460 mg, 83%). 1H NMR (400MHz, CDCl3) δppm: 7.34-7.29 (m, 4H), 4.48 (s, 2H), 2.20-2.15 (m, 1H), 1.11-1.06 (m, 2H), 0.74-0.65 (m, 2H).

[0457] [Preparation Example 17] Preparation of (4-(bromomethyl)-3-(trifluoromethyl)phenyl)(methyl)sulfane (Intermediate 17)

[0458]

[0459] (Step 1) Preparation of (4-(methylthio)-2-(trifluoromethyl)phenyl)methanol

[0460]

[0461] 4-Fluoro-2-(trifluoromethyl)benzaldehyde (1.00 g, 5.21 mmol) was dissolved in tetrahydrofuran (10.0 mL), and then sodium thiomethoxide (547 mg, 7.81 mmol) was added to the mixture. The reaction mixture was stirred at 70 ° C and under reduced pressure for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature. Distilled water was slowly added and extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: ether = 1: 100 to 1: 3) to obtain the title compound in the form of a colorless liquid. (400 mg, 34%). 1H NMR (400 MHz, CDCl3) δ ppm: 7.61 (d, J = 8.1 Hz, 1H), 7.49 (s, 1H), 7.42 (d, J = 8.1 Hz, 1H), 4.82 (s, 2H), 2.52 (s, 3H).

[0462] (Step 2) Preparation of (4-(bromomethyl)-3-(trifluoromethyl)phenyl)(methyl)sulfane (Intermediate 17)

[0463]

[0464] The compound prepared above (step 1) (400 mg, 1.80 mmol) was dissolved in dichloromethane (5.00 mL), and then thionyl bromide (1.87 g, 9.00 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 3 hours. After confirming that the reaction was complete, the reaction mixture was concentrated under reduced pressure. The title compound was obtained as a colorless liquid without further purification. (350 mg, 68%). 1H NMR (400 MHz, CDCl3) δ ppm: 7.46-7.51 (m, 2H), 7.38 (dd, J = 8.2, 1.7 Hz, 1H), 4.61 (s, 2H), 2.53 (s, 3H).

[0465] [Preparation Example 18] Preparation of diethyl ((4-(bromomethyl)phenyl)difluoromethyl)phosphonate (Intermediate 18)

[0466]

[0467]

[0468] (Step 1) Preparation of diethyl (difluoro(p-tolyl)methyl)phosphonate

[0469]

[0470] Diethyl (bromodifluoromethyl)phosphonate (1.47g, 5.5mmol) was dissolved in N, N-dimethylformamide (5.0mL), and then zinc (359mg, 5.5mmol) was added to the mixture. The reaction mixture was stirred at 55°C and nitrogen for 30 minutes. The mixture was ultrasonicated for 3 hours, copper (I) bromide (770mg, 5.37mmol) was added, and further stirred at room temperature for 30 minutes. 4-iodotoluene (300mg, 1.38mmol) dissolved in N, N-dimethylformamide (5.0mL) was slowly added to the mixture and stirred for 18 hours at 25°C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 19 to 10: 0) to obtain the title compound in the form of a colorless oil. (147.0mg, 38%). MS m / z: 279[M+1]+1H NMR (400MHz, CDCl3) δ7.50 (d, J = 7.9Hz, 2H), 7.24 (s, 2H), 4.23-4.11 (m, 4H), 2.40 (d, J = 5.0Hz, 3H), 1.31 (t, J = 7.1Hz, 6H).

[0471] (Step 2) Preparation of diethyl ((4-(bromomethyl)phenyl)difluoromethyl)phosphonate (Intermediate 18)

[0472]

[0473] The compound (70.0 mg, 0.25 mmol) prepared above (step 1) was dissolved in carbon tetrachloride (1.00 mL), and then N-bromosuccinimide (53.4 mg, 0.30 mmol) and a, a'-azobis(isobutyronitrile) (1.00 mg) were added to the mixture. The mixture was stirred at 80 ° C and nitrogen for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4 to 10: 0) to obtain the title compound (in the form of a mixture) in the form of a white solid. (41.0 mg, 46%). MS m / z: 358 [M+1] +

[0474] Example 2: Synthesis of Examples

[0475] [Example 1] (4-((9H-pyrido[3,4-b]indol-9-yl)methyl)phenyl)(imino)(methyl)-16-thio Preparation of ketone (Compound 1)

[0476]

[0477] (Step 1) Preparation of 9-(4-(methylthio)benzyl)-9H-pyrido[3,4-b]indole

[0478]

[0479] 9H-pyrido [3,4-b] indole (50.0 mg, 0.30 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (35.6 mg, 0.89 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 6 (77.4 mg, 0.36 mmol) dissolved in N, N-dimethylformamide (1.00 mL) was slowly added to the reaction mixture, and then stirred at 0 ° C and nitrogen for 0.50 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9 to 1: 8) to obtain the title compound in the form of a yellow solid. (32.0 mg, 35%) MS m / z: 305 [M+1] +

[0480] (Step 2) Preparation of (4-((9H-pyrido[3,4-b]indol-9-yl)methyl)phenyl)(imino)(methyl)-16-thione (Compound 1)

[0481]

[0482] The above (Step 1) The prepared compound (32.0 mg, 0.11 mmol) was dissolved in ethanol (1.00 mL), and then iodobenzene diacetate (98.1 mg, 0.30 mmol) and ammonium acetate (30.8 mg, 0.40 mmol) were added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (5.80 mg, 16%) MS m / z: 336 [M+1] +1H NMR (400MHz, CD3OD) δ9.37(s,1H),8.81(d,J=6.3Hz,1H),8.58(d,J=6.3Hz,1H),8.55(d,J=8.0Hz,1H),8.04-7.99(m,2H),7.86(ddd,J =8.4,7.0,1.3Hz,1H),7.78(d,J=8.5Hz,1H),7.57(ddd,J=8.1,6.9,1.1Hz,1H),7.49(dd,J=8.7,2.1Hz,2H),6.07(s,2H),3.36(s,3H).

[0483] [Example 2] 4-((6-methoxy-9H-pyrido[3.4-b]indol-9-yl)methyl)benzenesulfonamide (Compound 2) Preparation

[0484]

[0485] (Step 1) Preparation of 6-methoxy-9H-pyrido[3.4-b]indole

[0486]

[0487] 6-Methoxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.8 g, 8.90 mmol) was dissolved in cumene (150 mL), and then Pd / C (10 wt%, 1.00 g) was added to the mixture. The reaction mixture was stirred at 110 ° C and nitrogen for 16 hours. The precipitate was removed by filtration using diatomaceous earth, and the filtrate was then concentrated under reduced pressure. The residue was purified by medium pressure liquid chromatography (ethyl acetate: methanol = 10: 0 to 9: 1) to obtain the title compound in the form of a yellow solid. (1.0 g, 56%) MS m / z: 199 [M+1] +1 H NMR (400MHz, CDCl3) δ8.92(d,J=0.8Hz,1H),8.46(d,J=5.6Hz,1H),7.93(d,J=5.2Hz, 1H), 7.59 (d, J = 2.4Hz, 1H), 7.45 (d, J = 8.8Hz, 1H), 7.24 (d, J = 6.4Hz, 1H), 3.95 (s, 3H).

[0488] (Step 2) Preparation of 4-((6-methoxy-9H-pyrido[3.4-b]indol-9-yl)methyl)benzenesulfonamide (Compound 2)

[0489]

[0490] The above (Step 1)The prepared compound (50.0 mg, 0.25 mmol) was dissolved in N, N-dimethylformamide (2.50 mL), and then cooled to 0 ° C, and 60% sodium hydride (20.2 mg, 0.50 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (75.7 mg, 0.30 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (45.4 mg, 49.0%) MS m / z: 368 [M+1] +1 H NMR (400MHz, DMSO-d6) δ9.48(s,1H),8.75(d,J=6.0Hz,1H),8.60(d,J=6.0Hz,1H),8.11(d,J=2.4Hz ,1H),7.75-7.71(m,3H),7.44(dd,J=2.6,9.0Hz,1H),7.34-7.30(m,4H),5.97(s,2H),3.90(s,3H).

[0491] [Example 3] Imino(4-((6-methoxy-9H-pyrido[3,4-b]indol-9-yl)methyl)phenyl)(methyl Preparation of 1-6-thiocanone (compound 3)

[0492]

[0493] (Step 1) Preparation of 6-methoxy-9-(4-(methylthio)benzyl)-9H-pyrido[3,4-b]indole

[0494]

[0495] Example 2 (Step 1)The prepared compound (50.0 mg, 0.252 mmol) was dissolved in N, N-dimethylformamide (2.50 mL), and then cooled to 0 ° C, and 60% sodium hydride (20.2 mg, 0.50 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 6 (65.7 mg, 0.30 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred at 80 ° C and nitrogen for 15 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (64.4 mg, 76%) MS m / z: 335 [M+1] +

[0496] (Step 2) Preparation of imino(4-((6-methoxy-9H-pyrido[3,4-b]indol-9-yl)methyl)phenyl)(methyl)-16-thiocanone (Compound 3)

[0497]

[0498] The above (Step 1) The prepared compound (64.4 mg, 0.19 mmol) was dissolved in ethanol (1.90 mL), and then iodobenzene diacetate (180 mg, 0.56 mmol) and ammonium acetate (56.4 mg, 0.73 mmol) were added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (22.6 mg, 32%) MS m / z: 366 [M+1] +1 H NMR (400MHz, DMSO-d6) δ9.54(s,1H),8.81(d,J=6.0Hz,1H),8.64(d,J=5.6Hz,1H),8.15(d,J=2.0Hz,1H),7.87(d,J=8.4H z, 1H), 7.79 (d, J = 9.2Hz, 2H), 7.48 (dd, J = 2.0, 9.2Hz, 1H), 7.39 (d, J = 8.0Hz, 2H), 6.03 (s, 2H), 3.92 (s, 3H), 3.10 (s, 3H).

[0499] [Example 4] 4-((8-methoxy-5H-pyrido[4.3-b]indol-5-yl)methyl)benzenesulfonamide (Compound 4) Preparation

[0500]

[0501]

[0502] (Step 1) Preparation of tert-butyl 8-methoxy-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0503]

[0504] Mix 1,3-dimethylurea (5.30g, 60.2mmol) and L-(+)-tartaric acid (2.26g, 15.0mmol), and then stir the reaction mixture at 80°C and nitrogen for 2 hours. 4-Methoxyphenylhydrazine hydrochloride (1.05g, 6.02mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (1.00g, 5.01mmol) are added to the reaction mixture in sequence, and then stirred at 80°C for 2 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution are added, and extracted twice with dichloromethane. The organic layer is dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate: n-hexane = 0:10 to 3:7) to obtain the title compound in the form of a yellow solid. (391mg, 26%) MS m / z: 303 [M+1] +1 H NMR(400MHz,DMSO-d6)δ10.73(s,1H),7.26-7.14(m,1H),6.91(s,1H),6.68(dd,J=8.7,2.5Hz, 1H), 4.51 (s, 2H), 3.77 (d, J = 1.3Hz, 3H), 3.71 (t, J = 5.8Hz, 2H), 2.76 (s, 2H), 1.57-1.39 (m, 9H).

[0505] (Step 2) Preparation of 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4.3-b]indole-trifluoroacetic acid

[0506]

[0507] The above (Step 1)The compound obtained in (105mg, 0.35mmol) was dissolved in dichloromethane (3.00mL), and then trifluoroacetic acid (1.00mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ether, and then n-hexane was added. The obtained solid was filtered, washed with a mixed solution of ether / n-hexane, and dried to obtain the title compound in the form of a brown solid. (110mg, 100%) MS m / z: 203 [M+1] +

[0508] (Step 3) Preparation of 8-methoxy-5H-pyrido[4.3-b]indole

[0509]

[0510] The above (Step 2) The compound prepared in (110 mg, 0.35 mmol) was dissolved in dimethyl sulfoxide (0.60 mL), and then iodine (22.1 mg, 0.09 mmol) and aqueous hydrogen peroxide (11.0 μl, 0.35 mmol) were added to the mixture. The reaction mixture was stirred at 100° C. and nitrogen for 6 hours. After the reaction was completed, distilled water was slowly added, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, acetonitrile: distilled water = 5:95 to 100:0) to obtain the title compound in the form of a yellow solid. (5.30 mg, 8%) MS m / z: 199 [M+1] +

[0511] Step 4) Preparation of 4-((8-methoxy-5H-pyrido[4,3-b]indol-5-yl)methyl)benzenesulfonamide (Compound 4)

[0512]

[0513] The above (Step 3)The prepared compound (5.30 mg, 0.03 mmol) was dissolved in N, N-dimethylformamide (0.30 mL), and then cooled to 0 ° C, and 60% sodium hydride (2.10 mg, 0.05 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (8.00 mg, 0.03 mmol) dissolved in N, N-dimethylformamide (0.10 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (1.30 mg, 21%) MS m / z: 368 [M+1] +1 H NMR(400MHz,CD3OD)δ9.60(d,J=2.9Hz,1H),8.58-8.49(m,1H),8.09(s,1H),7.99(s,1H) ,7.83(d,J=7.8Hz,2H),7.71-7.56(m,2H),7.40-7.28(m,2H),5.93(s,2H),3.96(s,3H).

[0514] [Example 5] 4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 5) Preparation

[0515]

[0516] (Step 1) Preparation of tert-butyl 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0517]

[0518] 4-Methoxyphenylhydrazine hydrochloride (5.00g, 28.6mmol) was dissolved in toluene (95.4mL), and then tert-butyl 3-oxopiperidin-1-carboxylate (6.85g, 34.4mmol) and propanephosphonic anhydride (2.90mL, 5.73mmol) were added to the mixture in sequence. The reaction mixture was stirred at 90°C and nitrogen for 6 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:9 to 1:8) to obtain the title compound in the form of a yellow solid. (4.20g, 48%) MS m / z: 303 [M+1] +

[0519] (Step 2) Preparation of 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0520]

[0521] The above (Step 1) The prepared compound (8.30 g, 27.5 mmol) was dissolved in dichloromethane (109 mL), and trifluoroacetic acid (10.0 mL) was then added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ether, and then normal hexane was added. The obtained solid was filtered, washed with a mixed solution of ether / normal hexane, and dried to obtain the title compound in the form of a brown solid.

[0522] (8.70g, 100%)

[0523] MS m / z:203[M+1]+

[0524] (Step 3) Preparation of 8-methoxy-5H-pyrido[3,2-b]indole

[0525]

[0526] The above (Step 2) The prepared compound (4.00 g, 12.6 mmol) was dissolved in toluene (126 mL), and then Pd / C (10 wt%, 2.00 g) was added to the mixture. The reaction mixture was stirred at 90 ° C and nitrogen for 36 hours. The precipitate was removed by filtration using diatomaceous earth, and the filtrate was then concentrated under reduced pressure. The residue was purified by medium pressure liquid chromatography (ethyl acetate: methanol = 10: 0 to 9: 1) to obtain the title compound in the form of a yellow solid. (1.23 g, 49%) MS m / z: 199 [M+1] +1 H NMR (400MHz, DMSO-d6) δ11.2(s,1H),8.41(d,J=4.4Hz,1H),7.84(d,J=8.0Hz,1H),7.66(d,J=2.4Hz ,1H),7.47(d,J=8.8Hz,1H),7.35(dd,J=4.6,8.2Hz,1H),7.14(dd,J=2.4,8.8Hz,1H),3.86(s,3H).

[0527] (Step 4) Preparation of ((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 5)

[0528]

[0529] The above (Step 3) The compound obtained (100 mg, 0.51 mmol) was dissolved in N, N-dimethylformamide (5.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (40.4 mg, 1.01 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (151 mg, 0.61 mmol) dissolved in N, N-dimethylformamide (1.00 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (23.2 mg, 13%) MS m / z: 368 [M+1] +1 H NMR (400MHz, CD3OD) δ8.53(d,J=4.4Hz,1H),8.44(d,J=8.4Hz,1H),7.77(s,1H),7.72-7.70(m,3H ), 7.56 (d, J = 9.2Hz, 1H), 7.31 (d, J = 9.2Hz, 1H), 7.20 (d, J = 8.0Hz, 2H), 5.77 (s, 2H), 3.85 (s, 3H).

[0530] [Example 6] 4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)piperidine-1-sulfonamide (compound Preparation of 6)

[0531]

[0532] (Step 1) Preparation of tert-butyl ((4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)piperidin-1-yl)sulfonyl)carbamate

[0533]

[0534] Example 5 (Step 3)The prepared compound (20.0 mg, 0.10 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (8.00 mg, 0.20 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 2 (39.0 mg, 0.11 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred at 80 ° C and nitrogen for 15 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (17.0 mg, 35%) MS m / z: 475 [M+1] +

[0535] Step 2) Preparation of 4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)piperidine-1-sulfonamide (Compound 6)

[0536]

[0537] The above (Step 1) The compound obtained (17.0 mg, 0.04 mmol) was dissolved in dichloromethane (1.00 mL), and then trifluoroacetic acid (1.00 mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5:95 to 100:0) to obtain the title compound in the form of a yellow solid. (1.20 mg, 9%) MS m / z: 375 [M+1] +1 H NMR (400MHz, CD3OD) δ8.04(s,1H),7.88(s,1H),7.83(s,1H),7.60(s,1H),7.51(s,1H),7.24(s, 1H),5.55(s,2H),4.53(s,1H),4.34(s,2H),3.90(s,3H),3.58(s,2H),3.41(s,2H),3.10(s,2H).

[0538] [Example 7] 4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)-N-methylbenzenesulfonamide (Chemical Preparation of Compound 7)

[0539]

[0540] (Step 1) Preparation of tert-butyl ((4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)sulfonyl)(methyl)carbamate

[0541]

[0542] Example 5 (Step 3) The prepared compound (30.0 mg, 0.15 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (7.20 mg, 0.18 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 3 (66.2 mg, 0.18 mmol) dissolved in N, N-dimethylformamide (1.00 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9 to 3: 2) to obtain the title compound in the form of a yellow solid. (46.0 mg, 63%) MS m / z: 482 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 8.56 (dd, J=4.7, 1.3Hz, 1H), 7.90 (d, J=2.4Hz, 1H), 7.79 (d, J=8.6Hz, 2H), 7.55 (dd, J=8.3, 1.4Hz, 1H), 7.30(dd,J=8.3,4.8Hz,1H),7.24-7.19(m,3H),7.15(dd,J=8.9,2.5Hz,1H),5.56(s,2H),3.95(s,3H),3.31(s,3H),1.29(s,9H).

[0543] (Step 2) Preparation of 4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)-N-methylbenzenesulfonamide (Compound 7)

[0544]

[0545] The above (Step 1)The prepared compound (46.0 mg, 0.10 mmol) was dissolved in dichloromethane (1.00 mL), and trifluoroacetic acid (1.00 mL) was then added to the mixture. The reaction mixture was stirred for 2 hours at room temperature and under nitrogen. After the reaction was completed, distilled water and sodium bicarbonate aqueous solution were slowly added to neutralize, and extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 3: 7 to 9: 1) to obtain the title compound in the form of a yellow solid. (12.0 mg, 32%) MS m / z: 382 [M+1] +1 H NMR (400MHz, DMSO-d6) δppm: 8.47 (dd, J=4.6, 1.4Hz, 1H), 8.02 (dd, J=8.4, 1.4Hz, 1H), 7.73 (d, J=2.5Hz, 1H), 7.67 (d, J=8.5Hz, 2H), 7.60 (d, J=9.0Hz, 1H) ,7.41(dd,J=8.4,4.6Hz,1H),7.37(d,J=4.8Hz,1H),7.30(d,J=8.5Hz,2H),7 .18(dd,J=9.0,2.6Hz,1H),5.78(s,2H),3.88(s,3H),2.35(d,J=4.4Hz,3H).

[0546] [Example 8] N-(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)aminosulfonamide Preparation of (Compound 8)

[0547]

[0548]

[0549] (Step 1) Preparation of tert-butyl (4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)carbamate

[0550]

[0551] Example 5 (Step 3)The prepared compound (50.0 mg, 0.17 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (14.0 mg, 0.34 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 4 (38.1 mg, 0.19 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 2 hours at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9 to 1: 8) to obtain the title compound in the form of a yellow solid. (36.0 mg, 51%) MS m / z: 404 [M+1] +

[0552] (Step 2) Preparation of 4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)aniline

[0553]

[0554] The above (Step 1) The compound obtained (36.0 mg, 0.09 mmol) was dissolved in dichloromethane (0.50 mL), and then trifluoroacetic acid (0.50 mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ether, and then n-hexane was added. The obtained solid was filtered, washed with a mixed solution of ether / n-hexane, and dried to obtain the title compound in the form of a red solid. (27.0 mg, 99%) MS m / z: 304 [M+1] +

[0555] (Step 3) Preparation of N-(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)aminosulfonamide (Compound 8)

[0556]

[0557] The above (Step 2)The compound obtained (31.0 mg, 0.10 mmol) was dissolved in acetonitrile (1.00 mL), and then N, N-diisopropylethylamine (37.0 μl, 0.20 mmol) and aminosulfonic acid (4-nitrophenyl) ester (223 mg, 1.01 mmol) were added to the mixture in sequence. The reaction mixture was stirred at room temperature and nitrogen for 3 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a white solid. (2.30 mg, 6%) MS m / z: 383 [M+1] +1 H NMR (400MHz, CD3OD) δ8.41(dd,J=4.8,1.2Hz,1H),7.95(dd,J=8.4,1.2Hz,1H),7.86(d,J=2.5Hz,1H),7.51(d,J=9 .0Hz,1H),7.43(dd,J=8.4,4.8Hz,1H),7.20(dd,J=9.0,2.5Hz,1H),7.15-7.07(m,4H),5.57(s,2H),3.92(s,3H).

[0558] [Example 9] 4-(2-(8-methoxy-5H-pyrido[3,2-b]indol-5-yl)ethyl)benzenesulfonamide (Compound 9) Preparation

[0559]

[0560] Example 5 (Step 3) The prepared compound (25.0 mg, 0.13 mmol) and intermediate 5 (23.0 mg, 0.13 mmol) were dissolved in dimethyl sulfoxide (1.00 mL), and potassium hydroxide (14.0 mg, 0.25 mmol) was then added to the mixture and stirred at 110 ° C for 48 hours. After cooling to room temperature, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 3: 7 to 9: 1) to obtain the title compound in the form of a white solid. (6.70 mg, 14%) MS m / z: 382 [M+1] +1H NMR (400MHz, DMSO-d6) δppm: 8.40 (dd, J=4.6, 1.4Hz, 1H), 7.91 (dd, J=8.3, 1.4Hz, 1H), 7.70-7.61 (m, 4H), 7.42 (d, J=8.4Hz, 2H), 7.34(dd,J=8.3,4.6Hz,1H),7.26(s,2H),7.17(dd,J=8.9,2.6Hz,1H),4.64(t,J=7.4Hz,2H),3.87(s,3H),3.12(t,J=7.3Hz,2H).

[0561] [Example 10] Imino(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(methyl Preparation of 1-(2-(4-thio)-1,6-thiocanone (Compound 10)

[0562]

[0563] (Step 1) Preparation of 8-methoxy-5-(4-(methylthio)benzyl)-5H-pyrido[3,2-b]indole

[0564]

[0565] Example 5 (Step 3) The prepared compound (140 mg, 0.71 mmol) was dissolved in N, N-dimethylformamide (3.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (84.8 mg, 2.12 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 6 (184 mg, 0.85 mmol) dissolved in N, N-dimethylformamide (1 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to obtain the title compound in the form of a yellow solid. (95.0 mg, 40%) MSm / z: 335 [M+1] +

[0566] (Step 2) Preparation of imino(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(methyl)-16-thiocanone (Compound 10)

[0567]

[0568] The above (Step 1)The compound (95.0 mg, 0.28 mmol) obtained in the reaction mixture was dissolved in ethanol (1.00 mL), and then iodobenzene diacetate (265 mg, 0.82 mmol) and ammonium acetate (83.2 mg, 1.08 mmol) were added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. Compound 10 was purified (90.0 mg, 86%) by preparative high performance liquid chromatography (preparative HPLC, chiralpak (250 * 30 mm, 5 μm), hexane: methanol: ethanol = 40: 30: 30) to obtain 10a and 10b, which were white optical isomers, respectively. 3a:[α]D24+6°(c 0.14,CHCl3), 3b:[α]D24-6°(c 0.13,CHCl3). MS m / z:366[M+1] +1 H NMR (400MHz, CD3OD) δ8.69(d,J=4.9Hz,1H),8.47(d,J=8.3Hz,1H),7.96(d,J=8.0Hz,2H),7.89(s,1H),7. 73(d,J=8.3Hz,2H),7.45(d,J=8.0Hz,2H),7.34(d,J=9.1Hz,1H),5.97(s,2H),3.89(s,3H),3.53(s,3H).

[0569] [Example 11] Ethyl(imino)(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzene Preparation of 1-(2-(4-thio)-1,6-thiocanone (Compound 11)

[0570]

[0571] (Step 1) Preparation of 5-(4-(ethylthio)benzyl)-8-methoxy-5H-pyrido[3,2-b]indole

[0572]

[0573] Example 5 (Step 3)The prepared compound (30.0 mg, 0.15 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (9.10 mg, 0.23 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 7 (45.5 mg, 0.20 mmol) dissolved in N, N-dimethylformamide (1.00 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9 to 1: 1) to obtain the title compound in the form of a yellow solid. (16.3 mg, 31%) MS m / z: 349 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 8.54 (d, J = 4.6 Hz, 1H), 7.89 ( d, J = 2.6 Hz, 1H), 7.60 ( d, J = 9.8 Hz, 1H), 7.29 ( dd, J = 8.3, 4.6 Hz, 2H), 7.20 ( d,J=8.4Hz,2H),7.16(d,J=8.9Hz,1H),7.01(d,J=8.3Hz,2H),5.45(s,2H),3.95(s,3H),2.88(q,J=7.4Hz,2H),1.31-1.24(m,3H).

[0574] (Step 2) Preparation of ethyl(imino)(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)-16-thiocanone (Compound 11)

[0575]

[0576] The above (Step 1) The prepared compound (16.5 mg, 0.05 mmol) was dissolved in ethanol (2.00 mL), and then iodobenzene diacetate (43.7 mg, 0.14 mmol) and ammonium acetate (13.7 mg, 0.18 mmol) were added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (8.20 mg, 46%) MS m / z: 380 [M+1] +1H NMR (400MHz, DMSO-d6) δppm: 8.56 (d, J = 3.6Hz, 1H), 8.22 (d, J = 7.9Hz, 1H), 7.82 (d, J = 8.4Hz, 2H), 7.79 (d, J = 2.5Hz, 1H), 7.65 (d, J = 9.0Hz, 1H), 7.54 (dd,J=8.3,4.8Hz,1H),7.36(d,J=8.4Hz,2H),7.24(dd,J=8.9,2.6Hz,1H),5.87(s,2H),3.88(s,3H),3.29(q,J=7.2Hz,2H),1.04(t,J=7.3Hz,3H).

[0577] [Example 12] Benzyl(imino)(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzene Preparation of 1-(2-(4-thio)-1,6-thiocanone (Compound 12)

[0578]

[0579]

[0580] (Step 1) Preparation of 5-(4-(benzylthio)benzyl)-8-methoxy-5H-pyrido[3,2-b]indole

[0581]

[0582] Example 5 (Step 3) The prepared compound (30.0 mg, 0.15 mmol) was dissolved in N, N-dimethylformamide (1.0 mL), and then cooled to 0 ° C, and 60% sodium hydride (9.10 mg, 0.13 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 8 (57.7 mg, 0.20 mmol) dissolved in N, N-dimethylformamide (1.00 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9 to 1: 1) to obtain the title compound in the form of a yellow solid. (20.9 mg, 34%) MS m / z: 411 [M+1] +1H NMR (400MHz, CDCl3) δppm: 8.54 (dd, J=4.7, 1.4Hz, 1H), 7.90 (d, J=2.6Hz, 1H), 7.59 (dd, J=8.4, 1.5Hz, 1 H),7.33-7.25(m,5H),7.23-7.14(m,5H),6.98(d,J=8.4Hz,2H),5.43(s,2H),4.05(s,2H),3.95(s,3H).

[0583] (Step 2) Preparation of ethyl(imino)(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)-16-thiocanone (Compound 12)

[0584]

[0585] The compound (20.9 mg, 0.05 mmol) obtained above (step 1) was dissolved in ethanol (2.00 mL), and then iodobenzene diacetate (49.2 mg, 0.15 mmol) and ammonium acetate (15.7 mg, 0.20 mmol) were added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (8.10 mg, 36%) MS m / z: 442 [M+1] +1 H NMR (400MHz, DMSO-d6) δppm: 8.59 (s, 1H), 8.25 (s, 1H), 7.81 (s, 1H), 7.65-7.57 (m, 4H), 7.34-7. 19(m,4H),7.13(t,J=7.5Hz,2H),6.97(d,J=7.8Hz,2H),5.83(s,2H),4.52(s,2H),3.89(s,3H).

[0586] [Example 13] (4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)phosphonic acid (Compound 13) Preparation

[0587]

[0588] (Step 1) Preparation of 5-(4-bromobenzyl)-8-methoxy-5H-pyrido[3,2-b]indole

[0589]

[0590] Example 5 (Step 3)The prepared compound (40.0 mg, 0.20 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (9.60 mg, 0.24 mmol) was added to the mixture and stirred for 30 minutes. 1-Bromo-4-(bromomethyl)benzene (60.5 mg, 0.24 mmol) dissolved in N, N-dimethylformamide (1.00 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0: 10 to 3: 2) to obtain the title compound in the form of a yellow solid. (30.0 mg, 40%) MS m / z: 368 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 8.55 (dd, J=4.8, 1.4Hz, 1H), 7.89 (d, J=2.5Hz, 1H), 7.57 (dd, J=8.4, 1.4Hz, 1H), 7.43 -7.36(m,2H),7.33-7.26(m,2H),7.17(dd,J=8.9,2.5Hz,1H),6.97(d,J=8.8Hz,2H),5.44(s,2H),3.95(s,3H).

[0591] (Step 2) Preparation of diethyl (4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)phosphonate

[0592]

[0593] The above (Step 1) The prepared compound (36.0 mg, 0.10 mmol) and diethyl phosphite (14.0 μl, 0.11 mmol) were dissolved in toluene (2.00 mL), and then triethylamine (15.0 μl, 0.11 mmol) and tetrakis (triphenylphosphine) palladium (0) (11.3 mg, 0.01 mmol) were added to the mixture and stirred at 90 ° C for 3 hours. After cooling to room temperature, the precipitate was removed by filtration using diethyl ether, and the organic layer was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1 to 10: 0; methanol: dichloromethane = 1: 19) to obtain the title compound in the form of a yellow liquid. (32.0 mg, 77%) MS m / z: 425 [M+1] +1H NMR (400MHz, CDCl3) δppm: 8.56 (dd, J = 4.7, 1.3Hz, 1H), 7.93 (d, J = 2.6Hz, 1H), 7.69 (dd, J = 13.0, 8.4Hz, 2H), 7.59 (d, J = 8.4Hz, 1H), 7. 31(dd,J=8.3,4.7Hz,1H),7.28-7.26(m,1H),7.22-7.15(m,3H),5.53(s,2H),4.18-3.97(m,4H),3.95(s,3H),1.29(t,J=7.1Hz,6H).

[0594] (Step 3) Preparation of (4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)phosphonic acid (Compound 13)

[0595]

[0596] The above (Step 2) The prepared compound (32.0 mg, 0.08 mmol) was dissolved in dichloromethane (1.50 mL), and then bromotrimethylsilane (0.10 mL, 0.75 mmol) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (18.3 mg, 65%) MS m / z: 369 [M+1] +1 H NMR (400MHz, DMSO-d6) δppm: 8.63 (d, J = 5.0Hz, 1H), 8.39 (d, J = 8.4Hz, 1H), 7.84 (s, 1H), 7.75-7.63 (m, 2H), 7.55(dd,J=12.8,8.1Hz,2H),7.29(d,J=9.0Hz,1H),7.20(dd,J=8.1,3.4Hz,2H),5.81(s,2H),3.88(s,3H).

[0597] [Example 14] (4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid (Compound 14) Preparation

[0598]

[0599] (Step 1) Preparation of diethyl (4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate

[0600]

[0601] Example 5 (Step 3) The prepared compound (20.0 mg, 0.10 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (8.00 mg, 0.20 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 9 (35.6 mg, 0.11 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 3 hours at 80 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9 to 10: 0) to obtain the title compound in the form of a yellow solid. (12.0 mg, 27%) MS m / z: 439 [M+1] +

[0602] Step 2) Preparation of (4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid (Compound 14)

[0603]

[0604] The above (Step 1) The prepared compound (12.0 mg, 0.03 mmol) was dissolved in dichloromethane (1.00 mL), and then bromotrimethylsilane (36.0 μl, 0.27 mmol) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 15 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (3.00 mg, 28%) MS m / z: 383 [M+1] +1 H NMR (400MHz, CD3OD) δ8.72(d,J=8.4Hz,1H),8.66(d,J=5.6Hz,1H),7.92(dd,J=8.5,5.7Hz,1H),7.87(d,J=2.5Hz,1H),7.77(d,J=9.2Hz, 1H),7.47(dd,J=9.2,2.5Hz,1H),7.25(dd,J=8.1,2.3Hz,2H),7.16(d,J=8.1Hz,2H),5.79(s,2H),3.97(s,3H),3.08(s,1H),3.03(s,1H).

[0605] [Example 15] 3-Fluoro-4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Chemical Preparation of Compound 15)

[0606]

[0607] Example 5 (Step 3) The prepared compound (30.0 mg, 0.15 mmol) was dissolved in N, N-dimethylformamide (1.50 mL), and then cooled to 0 ° C, and 60% sodium hydride (12.1 mg, 0.30 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 10 (48.6 mg, 0.18 mmol) dissolved in N, N-dimethylformamide (1.50 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (3.50 mg, 6%) MS m / z: 386 [M+1] +1 H NMR(400MHz,DMSO-d6)δppm:8.54(s,1H),8.17(s,1H),7.78(s,1H),7.63(s, 1H),7.55-7.38(m,5H),7.24(s,1H),7.02(s,1H),5.84(s,2H),3.88(m,3H).

[0608] [Example 16] 3-Chloro-4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Chemical Preparation of Compound 16)

[0609]

[0610] Example 5 (Step 3) The prepared compound (30.0 mg, 0.15 mmol) was dissolved in N, N-dimethylformamide (1.50 mL), and then cooled to 0 ° C, and 60% sodium hydride (12.1 mg, 0.30 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 11 (51.6 mg, 0.18 mmol) dissolved in N, N-dimethylformamide (1.50 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile distilled water = 5:95 to 100:0) to obtain the title compound in the form of a yellow solid. (4.00 mg, 7%) MS m / z: 402 [M+1]+1 H NMR(400MHz,DMSO-d6)δppm:8.55(s,1H),8.08(s,1H),7.93(s,1H),7.80(s, 1H),7.53-7.41(m,5H),7.20(s,1H),6.58(s,1H),5.83(s,2H),3.88(m,3H).

[0611] [Example 17] (3-fluoro-4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl) (imido Preparation of (1-methyl)-16-thiocanone (Compound 17)

[0612]

[0613] (Step 1) Preparation of 5-(2-fluoro-4-(methylthio)benzyl)-8-methoxy-5H-pyrido[3,2-b]indole

[0614]

[0615] Example 5 (Step 3) The prepared compound (33.0 mg, 0.17 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (7.90 mg, 0.20 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 12 (50.9 mg, 0.22 mmol) dissolved in N, N-dimethylformamide (1.00 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9 to 1: 1) to obtain the title compound in the form of a yellow liquid. (24.0 mg, 41%) MS m / z: 353 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 8.55 (s, 1H), 7.89 (s, 1H), 7.66 (d, J = 8.0Hz, 1H), 7.35 (d, J = 7.9Hz, 2H), 7.18 (d, J =8.3Hz,1H),6.97(d,J=9.8Hz,1H),6.78(s,1H),6.69-6.68(m,1H),5.48(s,2H),3.95(s,3H),2.42(s,3H).

[0616] (Step 2) Preparation of (3-fluoro-4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(imino)(methyl)-16-thiocanone (Compound 17)

[0617]

[0618] The above (Step 1) The prepared compound (24.0 mg, 0.07 mmol) was dissolved in ethanol (2.00 mL), and then iodobenzene diacetate (63.6 mg, 0.20 mmol) and ammonium acetate (19.9 mg, 0.26 mmol) were added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (18.0 mg, 68%) MS m / z: 384 [M+1] +1 H NMR (400MHz, DMSO-d6) δppm: 8.61 (s, 1H), 8.30 (s, 1H), 7.86-7.74 (m, 2H), 7.67 (d, J = 10.4Hz, 1H), 7.61 (s, 2H), 7.27 (d, J = 7.4Hz, 1H), 7.08 (s, 1H), 5.90 (s, 2H), 3.88 (s, 3H), 3.14 (s, 3H).

[0619] [Example 18] Imido(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)-3-methylbenzene Preparation of (1-methyl)-16-thiocanone (Compound 18)

[0620]

[0621] (Step 1) Preparation of 8-methoxy-5-(2-methyl-4-(methylthio)benzyl)-5H-pyrido[3,2-b]indole

[0622]

[0623] Example 5 (Step 3) The prepared compound (40.0 mg, 0.20 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (12.0 mg, 0.30 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 14 (56.0 mg, 0.24 mmol) dissolved in N, N-dimethylformamide (1.00 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9 to 1: 1) to obtain the title compound in the form of a yellow solid. (33.5 mg, 48%) MS m / z: 349 [M+1]+1 H NMR (400MHz, CDCl3) δppm: 8.54 (dd, J=4.6, 1.4Hz, 1H), 7.91 (d, J=2.4Hz, 1H), 7.51 (dd, J=8.3, 1.4Hz, 1H), 7.27 (dd, J=8.3, 4.6Hz, 1H), 7.21 (d,J=8.9Hz,1H),7.19-7.10(m,2H),6.85(dd,J=8.2,2.2Hz,1H),6.44(d,J=8.0Hz,1H),5.41(s,2H),3.95(s,3H),2.42(s,3H),2.39(s,3H).

[0624] (Step 2) Preparation of imino(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)-3-methylphenyl)(methyl)-16-thiocanone (Compound 18)

[0625]

[0626] The above (Step 1) The prepared compound (33.5 mg, 0.096 mmol) was dissolved in ethanol (2.00 mL), and then iodobenzene diacetate (89.8 mg, 0.28 mmol) and ammonium acetate (28.2 mg, 0.36 mmol) were added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (36.1 mg, 98%) MS m / z: 380 [M+1] +1 H NMR (400MHz, DMSO-d6) δppm:8.61(dd,J=4.9,1.3Hz,1H),8.15(d,J=8.9Hz,1H),7.93(d,J=2.4Hz,1H),7.85(d,J=2.5Hz,1H) ,7.62-7.53(m,3H),7.26(dd,J=9.0,2.6Hz,1H),6.28(d,J=8.4Hz,1H),5.87(s,2H),3.90(s,3H),3.42(s,3H),2.60(s,3H).

[0627] [Example 19] Imido(3-methoxy-4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl) Preparation of (phenyl)(methyl)-16-thiocanone (Compound 19)

[0628]

[0629]

[0630] (Step 1) Preparation of 8-methoxy-5-(2-methoxy-4-(methylthio)benzyl)-5H-pyrido[3,2-b]indole

[0631]

[0632] Example 5 (Step 3) The prepared compound (30.0 mg, 0.15 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (9.00 mg, 0.23 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 13 (48.6 mg, 0.20 mmol) dissolved in N, N-dimethylformamide (1.00 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9 to 1: 1) to obtain the title compound in the form of a yellow solid. (20.0 mg, 36%) MS m / z: 365 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 8.53 (dd, J=4.6, 1.4Hz, 1H), 7.89 (d, J=2.6Hz, 1H), 7.65 (dd, J=8.4, 1.4Hz, 1H), 7.36-7.28 (m, 2H), 7.16 (dd, J=8. 9,2.5Hz,1H),6.82(d,J=1.8Hz,1H),6.60(dd,J=7.9,1.8Hz,1H),6.53(d,J=8.0Hz,1H),5.43(s,2H),3.95(s,3H),3.89(s,3H),2.42(s,3H).

[0633] (Step 2) Preparation of imino(3-methoxy-4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(methyl)-16-thiocanone (Compound 19)

[0634]

[0635] The above (Step 1)The prepared compound (20.0 mg, 0.06 mmol) was dissolved in ethanol (2.00 mL), and then iodobenzene diacetate (51.3 mg, 0.16 mmol) and ammonium acetate (16.1 mg, 0.21 mmol) were added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (20.9 mg, 95%) MS m / z: 396 [M+1] +1 H NMR (400MHz, DMSO-d6) δppm: 8.63 (d, J = 4.3Hz, 1H), 8.31 (d, J = 7.9Hz, 1H), 7.84 (d, J = 2.5Hz, 1H), 7.64 (dd, J = 8.7, 4.8Hz, 2H), 7.57 (d, J = 1.9 Hz,1H),7.40(dd,J=8.0,1.9Hz,1H),7.28(dd,J=9.0,2.6Hz,1H),6.87(d,J=7.9Hz,1H),5.77(s,2H),3.94(s,3H),3.88(s,3H),3.34(s,3H).

[0636] [Example 20] (2-fluoro-4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl) (imido Preparation of (1-(2-methyl)-1,6-thiocanone (Compound 20)

[0637]

[0638] (Step 1) Preparation of 5-(3-fluoro-4-(methylthio)benzyl)-8-methoxy-5H-pyrido[3,2-b]indole

[0639]

[0640] Example 5 (Step 3)The prepared compound (40.0 mg, 0.20 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (10.5 mg, 0.26 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 15 (61.7 mg, 0.26 mmol) dissolved in N, N-dimethylformamide (1.00 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9 to 1: 1) to obtain the title compound in the form of a yellow solid. (30.0 mg, 42%) MS m / z: 353 [M+1] +1 H NMR(400MHz, CDCl3)δppm:8.56(s,1H),7.90(s,1H),7.65-7.54(m,1H),7.35-7.2 7(m,2H),7.19-7.13(m,2H),6.81(m,2H),5.44(s,2H),3.95(s,3H),2.41(s,3H).

[0641] (Step 2) Preparation of (2-fluoro-4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(imino)(methyl)-16-thiocanone (Compound 20)

[0642]

[0643] The above (Step 1) The prepared compound (30.0 mg, 0.09 mmol) was dissolved in ethanol (2.00 mL), and then iodobenzene diacetate (79.5 mg, 0.25 mmol) and ammonium acetate (24.9 mg, 0.32 mmol) were added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (25.4 mg, 99%) MS m / z: 384 [M+1] +1H NMR(400MHz,DMSO-d6)δppm:8.60(s,1H),8.31(s,1H),7.81(s,1H),7.76(s,1H),7.69(s,1H),7.6 1(s,1H),7.30(s,1H),7.21(d,J=10.1Hz,1H),7.09(s,1H),5.85(s,2H),3.89(s,3H),3.15(s,3H).

[0644] [Example 21] Preparation of 4-((8-chloro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 21) preparation

[0645]

[0646] (Step 1) Preparation of tert-butyl 8-chloro-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0647]

[0648] 4-Chlorophenylhydrazine hydrochloride (500mg, 2.79mmol) was dissolved in toluene (22.0mL), and then tert-butyl 3-oxopiperidin-1-carboxylate (668mg, 3.35mmol) and propanephosphonic anhydride (0.34mL, 0.56mmol) were added to the mixture in sequence. The reaction mixture was stirred at 90°C and nitrogen for 4 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:9 to 1:8) to obtain the title compound in the form of a yellow solid. (350mg, 34%) MS m / z: 307 [M+1] +1 H NMR(400MHz, CDCl3)δ7.78(s,1H),7.64(s,1H),7.15-7.09(m,1H),7.07-7.03(m,1 H), 3.75 (dt, J = 7.8, 2.2Hz, 2H), 2.85-2.77 (m, 2H), 2.11-2.00 (m, 2H), 1.54 (s, 9H).

[0649] (Step 2) Preparation of 8-chloro-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0650]

[0651] The above (Step 1)The compound obtained in (350mg, 1.69mmol) was dissolved in dichloromethane (4.00mL), and then trifluoroacetic acid (8.00mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ether, and then n-hexane was added. The obtained solid was filtered, washed with a mixed solution of ether / n-hexane, and dried to obtain the title compound in the form of a red solid. (245mg, 70%) MS m / z: 207 [M+1] +

[0652] (Step 3) Preparation of 8-chloro-5H-pyrido[3,2-b]indole

[0653]

[0654] The above (Step 2) The obtained compound (245 mg, 1.18 mmol) was dissolved in dimethyl sulfoxide (5.00 mL) and then stirred at 90 ° C and nitrogen for 12 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added and extracted twice with ethyl acetate. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, acetonitrile: distilled water = 5:95 to 100:0) to obtain the title compound in the form of a yellow solid. (51.0 mg, 22%) MS m / z: 203 [M+1] +

[0655] (Step 4) Preparation of 4-((8-chloro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 21)

[0656]

[0657] The above (Step 3) The prepared compound (20.0 mg, 0.10 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (11.8 mg, 0.30 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (32.0 mg, 0.13 mmol) dissolved in N, N-dimethylformamide (1.00 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (3.60 mg, 10%) MS m / z: 372 [M+1]+1 H NMR (400MHz, CD3OD) δ8.66 (dd, J=5.3, 1.3Hz, 1H), 8.43 (dd, J=8.4, 1.2Hz, 1H), 8.39 (dd, J=1.9, 0.8Hz, 1H),7.85-7.80(m,2H),7.78(dd,J=8.5,5.3Hz,1H),7.74-7.65(m,2H),7.35-7.28(m,2H),5.87(s,2H).

[0658] [Example 22] 4-((8-(trifluoromethoxy)-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Chemical Preparation of Compound 22

[0659]

[0660]

[0661] (Step 1) Preparation of (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride

[0662]

[0663] 4-(Trifluoromethoxy)aniline (800mg, 4.52mmol) was dissolved in 6N HCl (9.00mL), and then sodium nitrite (467mg, 6.78mmol) dissolved in saturated saline solution (3.00mL) was slowly added to the mixture at -20°C. The reaction mixture was stirred at -20°C and nitrogen for 30 minutes, and then dihydrated tin (II) chloride (3.60g, 15.8mmol) dissolved in 2.00mL concentrated HCl was slowly added. After stirring at 0°C for 2 hours, a mixed solution of ethanol: ether = 3:7 was added to the reaction mixture and further stirred for 1 hour. The resulting solid was filtered, washed with ether, and then dried to obtain the title compound (800mg, 81%) in the form of a white solid. MS m / z: 193[M+1]+

[0664] (Step 2) Preparation of tert-butyl 8-(trifluoromethoxy)-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0665]

[0666] The above (Step 1)The prepared compound (400 mg, 2.08 mmol) was dissolved in toluene (8.00 mL), and then tert-butyl 3-oxopiperidine-1-carboxylate (456 mg, 2.30 mmol) and propanephosphonic anhydride (0.30 mL, 0.42 mmol) were added to the mixture in sequence. The reaction mixture was stirred at 90 ° C and nitrogen for 4 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9 to 1: 8) to obtain the title compound in the form of a yellow solid. (137 mg, 18%) MS m / z: 357 [M+1] +

[0667] (Step 3) Preparation of 8-(trifluoromethoxy)-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0668]

[0669] The above (Step 2) The compound obtained in (137mg, 0.38mmol) was dissolved in dichloromethane (3.00mL), and then trifluoroacetic acid (3.00mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ether, and then n-hexane was added. The obtained solid was filtered, washed with a mixed solution of ether / n-hexane, and dried to obtain the title compound in the form of a brown solid. (98.0mg, 99%) MS m / z: 257 [M+1] +

[0670] (Step 4) Preparation of 8-(trifluoromethoxy)-5H-pyrido[3,2-b]indole

[0671]

[0672] The above (Step 3) The obtained compound (98.0 mg, 0.38 mmol) was dissolved in dimethyl sulfoxide (2.00 mL) and then stirred at 90 ° C and nitrogen for 12 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added and extracted twice with ethyl acetate. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, acetonitrile: distilled water = 5:95 to 100:0) to obtain the title compound in the form of a yellow solid. (48.0 mg, 50%) MS m / z: 253 [M+1] +

[0673] (Step 5) Preparation of 4-((8-(trifluoromethoxy)-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 22)

[0674]

[0675] The above (Step 4) The prepared compound (10.0 mg, 0.04 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (5.00 mg, 0.12 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (14.5 mg, 0.06 mmol) dissolved in N, N-dimethylformamide (1.00 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (2.10 mg, 13%) MS m / z: 422 [M+1] +1 H NMR (400MHz, CD3OD) δ8.65 (s, 1H), 8.34 (d, J = 11.5Hz, 2H), 7.86-7.70 (m, 4H), 7.60 (d, J = 9.2Hz, 1H), 7.36-7.29 (m, 2H), 5.88 (d, J = 3.4Hz, 2H).

[0676] [Example 23] Imino(methyl)(4-((6-methyl-9H-pyrido[3,4-b]indol-9-yl)methyl)phenyl)- Preparation of 16-thiocanone (Compound 23)

[0677]

[0678] (Step 1) Preparation of tert-butyl 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0679]

[0680] 4-Methylphenylhydrazine hydrochloride (1.00g, 6.30mmol) was dissolved in toluene (30.0mL), and then tert-butyl 3-oxopiperidin-1-carboxylate (1.03g, 6.30mmol) and propanephosphonic anhydride (0.80mL, 1.26mmol) were added to the mixture in sequence. The reaction mixture was stirred at 90°C and nitrogen for 4 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:9 to 1:2) to obtain the title compound in the form of a yellow solid. (630mg, 35%) MS m / z: 287 [M+1] +1 H NMR (400MHz, CDCl3) δ7.58(s,1H),7.44(s,1H),7.10(t,J=10.4Hz,1H),6.93(d,J=8.2Hz,1 H), 3.79-3.71 (m, 2H), 2.80 (t, J = 6.7Hz, 2H), 2.43 (s, 3H), 2.11-2.00 (m, 2H), 1.54 (s, 9H).

[0681] (Step 2) Preparation of 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0682]

[0683] The above (Step 1) The compound obtained in (280mg, 0.98mmol) was dissolved in dichloromethane (4.00mL), and then trifluoroacetic acid (3.00mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ether, and then n-hexane was added. The obtained solid was filtered, washed with a mixed solution of ether / n-hexane, and dried to obtain the title compound in the form of a red solid. (130mg, 71%) MS m / z: 187 [M+1] +

[0684] (Step 3) Preparation of 8-methyl-5H-pyrido[3,2-b]indole

[0685]

[0686] The above (Step 2)The compound (130 mg, 0.70 mmol) obtained in the reaction mixture was dissolved in toluene (3.00 mL), and then Pd / C (50 wt%, 65.0 mg) was added to the mixture. The reaction mixture was stirred at 100 ° C for 15 hours. It was cooled to room temperature, and the precipitate was removed by filtration using diatomaceous earth, and the filtrate was then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a green solid. (100 mg, 79%) MS m / z: 183 [M + 1] +

[0687] (Step 4) Preparation of 8-methyl-5-(4-(methylthio)benzyl)-5H-pyrido[3,2-b]indole

[0688]

[0689] The above (Step 3) The prepared compound (27.0 mg, 0.15 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (17.8 mg, 0.45 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 6 (32.1 mg, 0.15 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 3 hours at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9 to 1: 3) to obtain the title compound in the form of a yellow solid. (30.0 mg, 64%) MS m / z: 319 [M+1] +

[0690] (Step 5) Preparation of Imino(methyl)(4-((8-methyl-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)-16-thiocanone (Compound 23)

[0691]

[0692] The above (Step 4)The prepared compound (30.0 mg, 0.09 mmol) was dissolved in ethanol (1.00 mL), and then iodobenzene diacetate (88.0 mg, 0.27 mmol) and ammonium acetate (28.3 mg, 0.37 mmol) were added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (15.0 mg, 46%) MS m / z: 350 [M+1] +1 H NMR (400MHz, CD3OD) δ8.69(d,J=5.5Hz,1H),8.65(d,J=8.4Hz,1H),8.24(s,1H),8.04(d,J=8.5Hz,2H), 7.91(dd,J=8.5,5.6Hz,1H),7.66(s,2H),7.51(d,J=8.4Hz,2H),6.00(s,2H),3.54(s,3H),2.59(s,3H).

[0693] [Example 24] (4-((8-ethoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(imino)(methyl Preparation of 1-(2-(4-thio)-1,6-thiocanone (Compound 24)

[0694]

[0695] (Step 1) Preparation of (4-ethoxyphenyl)hydrazine hydrochloride

[0696]

[0697] 4-Ethoxyaniline (840mg, 6.12mmol) was dissolved in 6N HCl (5.00mL), and then sodium nitrite (592mg, 8.57mmol) dissolved in 2.00mL saturated saline solution was slowly added to the mixture at -20°C. The reaction mixture was stirred at -20°C and nitrogen for 30 minutes, and then dihydrated tin (II) chloride (2.30g, 12.3mmol) dissolved in concentrated HCl (2.00mL) was slowly added. After stirring at 0°C for 1 hour, a mixed solution of ethanol: ether = 3:7 was added to the reaction mixture and further stirred for 1 hour. The resulting solid was filtered, washed with ether, and then dried to obtain the title compound (530mg, 57%) in the form of a light pink solid. MS m / z: 189[M+1]+

[0698] (Step 2) Preparation of tert-butyl 8-ethoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0699]

[0700] The above (Step 1) The compound obtained (500mg, 2.65mmol) was dissolved in toluene (10.0mL), and then tert-butyl 3-oxopiperidine-1-carboxylate (528mg, 2.65mmol) and propanephosphonic anhydride (0.33mL, 0.53mmol) were added to the mixture in sequence. The reaction mixture was stirred at 90°C and nitrogen for 4 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:9 to 1:8) to obtain the title compound in the form of a yellow solid. (101mg, 12%) MS m / z: 317 [M+1] +

[0701] (Step 3) Preparation of 8-ethoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0702]

[0703] The above (Step 2) The prepared compound (100 mg, 0.32 mmol) was dissolved in dichloromethane (2.00 mL), and then trifluoroacetic acid (1.00 mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ether, and then n-hexane was added. The obtained solid was filtered, washed with a mixed solution of ether / n-hexane, and dried to obtain the title compound in the form of a red solid. (68.5 mg) MS m / z: 217 [M+1] +

[0704] (Step 4) Preparation of 8-ethoxy-5H-pyrido[3,2-b]indole

[0705]

[0706] The above (Step 3)The compound (68.5mg, 0.32mmol) obtained in the reaction mixture was dissolved in toluene (2.00mL), and then Pd / C (50wt%, 34.0mg) was added to the mixture. The mixture was stirred at 100°C and nitrogen for 15 hours. It was cooled to room temperature, and the precipitate was removed by filtration using diatomaceous earth, and the filtrate was then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, acetonitrile: distilled water = 5:95 to 100:0) to obtain the title compound in the form of a green solid. (65.0mg, 97%) MS m / z: 213 [M+1] +

[0707] (Step 5) Preparation of 8-ethoxy-5-(4-(methylthio)benzyl)-5H-pyrido[3,2-b]indole

[0708]

[0709] The above (Step 4) The prepared compound (31.0 mg, 0.15 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (12.0 mg, 0.29 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 6 (31.7 mg, 0.15 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9 to 1: 8) to obtain the title compound in the form of a yellow solid. (13.0 mg, 26%) MS m / z: 349 [M+1] +

[0710] (Step 6) Preparation of (4-((8-ethoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(imino)(methyl)-16-thiocanone (Compound 24)

[0711]

[0712] The above (Step 5)The prepared compound (13.0 mg, 0.04 mmol) was dissolved in ethanol (1.00 mL), and then iodobenzene diacetate (34.8 mg, 0.11 mmol) and ammonium acetate (10.9 mg, 0.14 mmol) were added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (8.20 mg, 55%) MS m / z: 380 [M+1] +1 H NMR (400MHz, CD3OD) δ8.66(d,J=5.4Hz,1H),8.57(d,J=8.5Hz,1H),8.02(d,J=8.4Hz,2H),7.89(d,J=2.3Hz,1H),7.84(dd,J=8.6,5.4Hz,1H), 7.66(d,J=9.1Hz,1H),7.48(d,J=8.4Hz,2H),7.41(dd,J=9.1,2.5Hz,1H),5.97(s,2H),4.20(q,J=7.0Hz,2H),3.45(s,3H),1.51-1.43(m,3H).

[0713] [Example 25] 4-((6-fluoro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Chemical Preparation of Compound 25)

[0714]

[0715] (Step 1) Preparation of (2-fluoro-4-methoxyphenyl)hydrazine hydrochloride

[0716]

[0717] 2-Fluoro-4-methoxyaniline (1.00 g, 7.09 mmol) was dissolved in a 1:1 mixed solution (12.0 mL) of concentrated HCl: distilled water, and then sodium nitrite (538 mg, 7.79 mmol) dissolved in 5.00 mL of saturated saline solution was slowly added to the mixture at -20 ° C. The reaction mixture was stirred at -20 ° C and nitrogen for 30 minutes, and then tin (II) chloride dihydrate (3.18 g, 14.2 mmol) dissolved in 4.00 mL of concentrated HCl was slowly added. After stirring at 0 ° C for 1 hour, a mixed solution of ethanol: ether = 3: 7 was added to the reaction mixture and further stirred for 2 hours. The resulting solid was filtered, washed with ether, and then dried to obtain the title compound (582 mg, 53%) in the form of a gray solid. MS m / z: 157 [M+1] +

[0718] (Step 2) Preparation of tert-butyl 6-fluoro-8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0719]

[0720] The above (Step 1) The prepared compound (100 mg, 0.52 mmol) was dissolved in toluene (63.0 mL), and then tert-butyl 3-oxopiperidin-1-carboxylate (124 mg, 0.62 mmol) and propanephosphonic anhydride (53.0 μL, 0.10 mmol) were added to the mixture in sequence. The reaction mixture was stirred at 90 ° C and nitrogen for 6 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2) to obtain the title compound in the form of a yellow solid. (34.9 mg, 21%) MS m / z: 321 [M+1] +

[0721] (Step 3) Preparation of 6-fluoro-8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0722]

[0723] The above (Step 2)The compound obtained in (34.9 mg, 0.11 mmol) was dissolved in dichloromethane (1.10 mL), and then trifluoroacetic acid (0.50 mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ether, and then n-hexane was added. The obtained solid was filtered, washed with a mixed solution of ether / n-hexane, and dried to obtain the title compound in the form of a brown solid. (34.0 mg, 100%) MS m / z: 221 [M+1] +

[0724] (Step 4) Preparation of 6-fluoro-8-methoxy-5H-pyrido[3,2-b]indole

[0725]

[0726] The above (Step 3) The obtained compound (34.0 mg, 0.11 mmol) was dissolved in dimethyl sulfoxide (1.00 mL) and then stirred at 90 ° C and nitrogen for 12 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added and extracted twice with ethyl acetate. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, acetonitrile: distilled water = 5:95 to 100:0) to obtain the title compound in the form of a yellow solid. (10.6 mg, 45%) MS m / z: 217 [M+1] +

[0727] (Step 5) Preparation of 4-((6-fluoro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 25)

[0728]

[0729] The above (Step 4)The prepared compound (10.6 mg, 0.05 mmol) was dissolved in N, N-dimethylformamide (0.50 mL), and then cooled to 0 ° C, and 60% sodium hydride (3.9 mg, 0.10 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (14.7 mg, 0.06 mmol) dissolved in N, N-dimethylformamide (0.20 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (7.00 mg, 37%) MS m / z: 386 [M+1] +1 H NMR (400MHz, CD3OD) δ8.61(s,1H),8.38(d,J=8.3Hz,1H),7.80(d,J=7.6Hz,2H),7.72( d,J=9.5Hz,2H),7.31-7.23(m,2H),7.13(d,J=14.8Hz,1H),5.90(s,2H),3.94(s,3H).

[0730] [Example 26] 4-((6-methoxy-8-methyl-9H-pyrido[3,4-b]indol-9-yl)methyl)benzenesulfonamide Preparation of (Compound 26)

[0731]

[0732] (Step 1) Preparation of (4-methoxy-2-methylphenyl)hydrazine hydrochloride

[0733]

[0734] 4-methoxy-2-methylaniline (2.00 g, 14.6 mmol) was dissolved in a 1:1 mixed solution (20.0 mL) of concentrated HCl: distilled water, and then sodium nitrite (1.11 g, 16.0 mmol) dissolved in 5.00 mL of saturated saline solution was slowly added to the mixture at -20 ° C. The reaction mixture was stirred at -20 ° C and nitrogen for 30 minutes, and then tin (II) chloride dihydrate (6.58 g, 29.2 mmol) dissolved in 5.00 mL of concentrated HCl was slowly added. After stirring at 0 ° C for 1 hour, a mixed solution of ethanol: ether = 3: 7 was added to the reaction mixture and further stirred for 2 hours. The resulting solid was filtered, washed with ether, and then dried to obtain the title compound (1.85 g, 83%) in the form of a gray solid. MS m / z: 151 [M+1] +

[0735] (Step 2) Preparation of tert-butyl 8-methoxy-6-methyl-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0736]

[0737] The above (Step 1) The prepared compound (300 mg, 1.59 mmol) was dissolved in toluene (15.9 mL), and then tert-butyl 3-oxopiperidin-1-carboxylate (380 mg, 1.91 mmol) and propanephosphonic anhydride (202 mL, 0.32 mmol) were added to the mixture in sequence. The reaction mixture was stirred at 90 ° C and nitrogen for 6 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2) to obtain the title compound in the form of a yellow solid. (38.9 mg, 7%) MS m / z: 317 [M+1] +

[0738] (Step 3) Preparation of 8-methoxy-6-methyl-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0739]

[0740] The above (Step 2) The compound obtained in (38.9 mg, 0.123 mmol) was dissolved in dichloromethane (1.00 mL), and then trifluoroacetic acid (0.50 mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ether, and then n-hexane was added. The obtained solid was filtered, washed with a mixed solution of ether / n-hexane, and dried to obtain the title compound in the form of a brown solid. (38.7 mg, 100%) MS m / z: 217 [M+1] +

[0741] (Step 4) Preparation of 8-methoxy-6-methyl-5H-pyrido[3,2-b]indole

[0742]

[0743] The above (Step 3)The obtained compound (38.7 mg, 0.12 mmol) was dissolved in dimethyl sulfoxide (0.20 mL) and then stirred at 90 ° C and nitrogen for 12 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added and extracted twice with ethyl acetate. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, acetonitrile: distilled water = 5:95 to 100:0) to obtain the title compound in the form of a yellow solid. (13.5 mg, 52%) MS m / z: 213 [M+1] +

[0744] (Step 5) Preparation of 4-((8-methoxy-6-methyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 26)

[0745]

[0746] The above (Step 4) The compound (13.5 mg, 0.06 mmol) obtained in the reaction mixture was dissolved in N, N-dimethylformamide (0.60 mL), and then cooled to 0 ° C, and 60% sodium hydride (5.10 mg, 0.13 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (19.1 mg, 0.08 mmol) dissolved in N, N-dimethylformamide (0.10 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (3.9 mg, 16%) MS m / z: 382 [M+1] +1 H NMR (400MHz, CD3OD) δ8.53 (s, 1H), 8.20 (s, 1H), 7.80 (d, J = 7.6Hz, 2H), 7.75 (s ,1H),7.62(s,1H),7.11-7.09(m,3H),6.02(s,2H),3.92(s,3H),2.59(s,3H).

[0747] [Example 27] 4-((6-chloro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Chemical Preparation of Compound 27

[0748]

[0749]

[0750] (Step 1) Preparation of (2-chloro-4-methoxyphenyl)hydrazine hydrochloride

[0751]

[0752] (2-Chloro-4-methoxyphenyl) hydrazine (800mg, 5.08mmol) was dissolved in 6N HCl (9.00mL), and then sodium nitrite (525mg, 7.61mmol) dissolved in a saturated saline solution (3.00mL) was slowly added to the mixture at -20°C. The reaction mixture was stirred at -20°C and nitrogen for 30 minutes, and then tin (II) chloride dihydrate (4.00g, 17.8mmol) dissolved in 2.00mL concentrated HCl was slowly added. After stirring at 0°C for 1 hour, a mixed solution of ethanol: ether = 3:7 was added to the reaction mixture and further stirred for 1 hour. The resulting solid was filtered, washed with ether, and then dried to obtain the title compound (303mg, 35%) in the form of a white solid. MS m / z: 173[M+1]+

[0753] (Step 2) Preparation of tert-butyl 6-chloro-8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0754]

[0755] The above (Step 1) The prepared compound (300 mg, 1.74 mmol) was dissolved in toluene (7.00 mL), and then tert-butyl 3-oxopiperidine-1-carboxylate (492 mg, 2.09 mmol) and propanephosphonic anhydride (0.23 mL, 0.35 mmol) were added to the mixture in sequence. The reaction mixture was stirred at 90 ° C and nitrogen for 6 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9 to 1: 8) to obtain the title compound in the form of a yellow solid. (90.0 mg, 15%) MS m / z: 337 [M+1] +

[0756] (Step 3) Preparation of 6-chloro-8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0757]

[0758] The above (Step 2)The compound obtained in (90.0 mg, 0.27 mmol) was dissolved in dichloromethane (2.00 mL), and then trifluoroacetic acid (2.00 mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ether, and then n-hexane was added. The obtained solid was filtered, washed with a mixed solution of ether / n-hexane, and dried to obtain the title compound in the form of a brown solid. (51.0 mg, 80%) MS m / z: 237 [M+1] +

[0759] (Step 4) Preparation of 6-chloro-8-methoxy-5H-pyrido[3,2-b]indole

[0760]

[0761] The above (Step 3) The obtained compound (51.0 mg, 0.22 mmol) was dissolved in dimethyl sulfoxide (2.00 mL) and then stirred at 90 ° C and nitrogen for 12 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added thereto and extracted twice with ethyl acetate. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, acetonitrile: distilled water = 5:95 to 100:0) to obtain the title compound in the form of a yellow solid. (21.0 mg, 41%) MS m / z: 233 [M+1] +

[0762] (Step 5) Preparation of 4-((6-chloro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 27)

[0763]

[0764] The above (Step 4)The prepared compound (11.0 mg, 0.05 mmol) was dissolved in N, N-dimethylformamide (0.50 mL), and then cooled to 0 ° C, and 60% sodium hydride (6.00 mg, 0.14 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (17.7 mg, 0.07 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 2 hours at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added thereto, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (1.60 mg, 8%) MS m / z: 402 [M+1] +1 H NMR (400MHz, CD3OD) δ8.65 (s, 1H), 8.34 (d, J = 8.5Hz, 1H), 7.91 (s, 1H), 7.85-7.6 9(m,3H),7.35(s,1H),7.19(q,J=2.8Hz,2H),6.20(s,2H),3.96(t,J=2.4Hz,3H).

[0765] [Example 28] 4-((7,8-dimethoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (compound Preparation of Compound 28

[0766]

[0767] (Step 1) Preparation of (3,4-dimethoxyphenyl)hydrazine hydrochloride

[0768]

[0769] 3,4-dimethoxyaniline (1.00g, 6.52mmol) was dissolved in 9.00mL 6N HCl, and then sodium nitrite (675mg, 6.79mmol) dissolved in 2.00mL saturated saline solution was slowly added to the mixture at -20°C. The reaction mixture was stirred at -20°C and nitrogen for 30 minutes, and then dihydrated tin chloride (II) (4.42g, 19.6mmol) dissolved in 2.00mL concentrated HCl was slowly added. After stirring at 0°C for 1 hour, a mixed solution of ethanol: ether = 3:7 was added to the reaction mixture and further stirred for 1 hour. The resulting solid was filtered, washed with ether, and then dried to obtain the title compound (713mg, 53%) in the form of a white solid. MS m / z: 205[M+1] +1H NMR (400MHz, DMSO-d6) δ10.24(s,3H),7.02(d,J=8.6Hz,1H),6.98(s,1H),6.70(d,J=8.4Hz,1H),3.88(s,3H),3.84(s,3H)

[0770] (Step 2) Preparation of tert-butyl 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0771]

[0772] The above (Step 1) The compound obtained (713 mg, 3.48 mmol) was dissolved in toluene (10.0 mL), and then tert-butyl 3-oxopiperidin-1-carboxylate (833 mg, 4.18 mmol) and propanephosphonic anhydride (0.35 mL, 0.69 mmol) were added to the mixture in sequence. The reaction mixture was stirred at 90 ° C and nitrogen for 3 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 4: 6) to obtain the title compound in the form of a yellow solid. (492 mg, 42%) MS m / z: 333 [M+1] +1 H NMR (400MHz, CDCl3) δ7.47(s,1H),7.14(s,1H),6.77(s,1H),3.91(dd,J=14.2,2.4Hz, 6H), 3.75 (d, J = 5.3Hz, 2H), 2.80 (s, 2H), 2.04 (d, J = 2.6Hz, 2H), 1.53 (d, J = 2.1Hz, 9H).

[0773] (Step 3) Preparation of 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0774]

[0775] The above (Step 2)The compound obtained in (492mg, 1.48mmol) was dissolved in dichloromethane (5.00mL), and then trifluoroacetic acid (2.00mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ether, and then n-hexane was added. The obtained solid was filtered, washed with a mixed solution of ether / n-hexane, and dried to obtain the title compound in the form of a brown solid. (512mg, 100%) MS m / z: 233 [M+1] +

[0776] (Step 4) Preparation of 7,8-dimethoxy-5H-pyrido[3,2-b]indole

[0777]

[0778] The above (Step 3) The compound prepared in (512 mg, 1.48 mmol) was dissolved in dimethyl sulfoxide (1.00 mL), and the reaction mixture was then stirred at 80° C. under nitrogen for 24 hours. The reaction mixture was purified by preparative high performance liquid chromatography (preparative HPLC, acetonitrile: distilled water = 5:95 to 100:0) to obtain the title compound in the form of a yellow solid. (40.0 mg, 12%) MS m / z: .229 [M+1] +

[0779] (Step 5) Preparation of 4-((7,8-dimethoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 28)

[0780]

[0781] The above (Step 4) The compound obtained (40.0 mg, 0.17 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (14.0 mg, 0.35 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (65.0 mg, 0.26 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred at 0 ° C and nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (1.00 mg, 1%) MS m / z: 398 [M + 1] + 1H NMR (400 MHz, CD3OD) δ8.56 (s, 2H), 7.80 (m, 4H), 7.41-7.27 (m, 3H), 5.93 (d, J = 2.6 Hz, 2H), 4.13-3.76 (m, 6H)

[0782] [Example 29] 4-((7-fluoro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Chemical Preparation of Compound 29)

[0783]

[0784]

[0785] (Step 1) Preparation of (3-fluoro-4-methoxyphenyl)hydrazine hydrochloride

[0786]

[0787] 3-Fluoro-4-methoxyaniline (1.00 g, 7.08 mmol) was dissolved in 9.00 mL 6N HCl, and then sodium nitrite (733 mg, 10.6 mmol) dissolved in 2.00 mL saturated saline solution was slowly added to the mixture at -20 ° C. The reaction mixture was stirred at -20 ° C and nitrogen for 30 minutes, and then dihydrated tin chloride (II) (4.80 g, 21.3 mmol) dissolved in 2.00 mL concentrated HCl was slowly added. After stirring at 0 ° C for 1 hour, a mixed solution of ethanol: ether = 3: 7 was added to the reaction mixture and further stirred for 1 hour. The resulting solid was filtered, washed with ether, and then dried to obtain the title compound (1.20 g, 88%) in the form of a white solid. MS m / z: 193 [M+1] +1 H NMR (400MHz, DMSO-d6) δ 10.07 (s, 3H), 8.08 (s, 1H), 7.12 (td, J = 9.0, 5.3Hz, 1H), 6.95 (dd, J = 13.1, 2.7Hz, 1H), 6.79 (d, J = 9.4Hz, 1H), 3.78 (s, 3H).

[0788] (Step 2) Preparation of tert-butyl 7-fluoro-8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0789]

[0790] The above (Step 1)The compound obtained (1.20g, 6.22mmol) was dissolved in toluene (10.0mL), and then tert-butyl 3-oxopiperidin-1-carboxylate (1.49mg, 7.47mmol) and propanephosphonic anhydride (0.64mL, 1.24mmol) were added to the mixture in sequence. The reaction mixture was stirred at 90°C and nitrogen for 3 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2:8) to obtain the title compound in the form of a yellow solid. (760mg, 38%) MS m / z: 321 [M+1] +1 H NMR (400MHz, CDCl3) δ7.53(d,J=5.5Hz,1H),7.21(d,J=8.1Hz,1H),6.98(d,J=11.3Hz,1H ),3.93(s,3H),3.80-3.71(m,2H),2.81(t,J=6.7Hz,2H),2.11-1.99(m,2H),1.56(s,9H)

[0791] (Step 3) Preparation of 7-fluoro-8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0792]

[0793] The above (Step 2) The compound obtained in (760mg, 2.37mmol) was dissolved in dichloromethane (5.00mL), and then trifluoroacetic acid (2.00mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ether, and then n-hexane was added. The obtained solid was filtered, washed with a mixed solution of ether / n-hexane, and dried to obtain the title compound in the form of a brown solid. (792mg, 99%) MS m / z: 221 [M+1] +

[0794] (Step 4) Preparation of 7-fluoro-8-methoxy-5H-pyrido[3,2-b]indole

[0795]

[0796] The above (Step 3)The compound (392mg, 2.37mmol) obtained in the reaction mixture was dissolved in toluene (15.0mL), and then Pd / C (10wt%, 370mg) was added to the mixture. The reaction mixture was stirred at 120°C and nitrogen for 25 hours. The precipitate was removed by filtration using diatomaceous earth, and the filtrate was then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, acetonitrile: distilled water = 5:95 to 100:0) to obtain the title compound in the form of a yellow solid. (370mg, 72%) MS m / z: 217 [M+1] +1 H NMR(400MHz, CDCl3)δ8.55(d,J=4.4Hz,1H),8.34,(bs,1H),7.89(d,J=8.4Hz,1H),7. 72 (d, J = 8.0 Hz, 1H), 7.31 (dd, J = 4.8, 8.0 Hz, 1H), 7.22 (d, J = 11.2 Hz, 1H), 3.97 (s, 3H).

[0797] (Step 5) Preparation of 4-((7-fluoro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 29)

[0798]

[0799] The above (Step 4) The prepared compound (80.0 mg, 0.37 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (29.0 mg, 0.74 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (138 mg, 0.55 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (36.0 mg, 25%) MS m / z: 386 [M+1] +1H NMR (400MHz, CD3OD) δ8.65 (dd, J=5.5, 1.1Hz, 1H), 8.55 (dd, J=8.4, 1.1Hz, 1H), 8.03 (d, J=8.1H z,1H),7.85-7.79(m,3H),7.63(d,J=11.3Hz,1H),7.38-7.28(m,2H),5.86(s,2H),4.04(s,3H).

[0800] [Example 30] (4-((7-fluoro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl) (imido Preparation of (1-(2-methyl)-1,6-thiocanone (Compound 30)

[0801]

[0802] (Step 1) Preparation of 7-fluoro-8-methoxy-5-(4-(methylthio)benzyl)-5H-pyrido[3,2-b]indole

[0803]

[0804] Example 29 (Step 4) The prepared compound (50.0 mg, 0.23 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (18.0 mg, 0.46 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 6 (55.0 mg, 0.25 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3) to obtain the title compound in the form of a yellow solid. (50.0 mg, 60%) MS m / z: 353 [M+1] +1 H NMR (400MHz, CDCl3) δ8.54(dd,J=4.7,1.3Hz,1H),7.96(d,J=8.3Hz,1H),7.62(dd,J=8.3,1.4Hz,1H),7.3 0(dd,J=8.3,4.6Hz,1H),7.19-7.09(m,3H),7.01(d,J=8.6Hz,2H),5.40(s,2H),4.02(s,3H),2.43(s,3H).

[0805] (Step 2) Preparation of (4-((7-fluoro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(imino)(methyl)-16-thiocanone (Compound 30)

[0806]

[0807] The compound (50.0 mg, 0.14 mmol) prepared in the above (step 1) was dissolved in ethanol (1.00 mL), and then iodobenzene diacetate (132 mg, 0.41 mmol) and ammonium acetate (41.0 mg, 0.54 mmol) were added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. Compound 30 was purified (53.0 mg, 96%) by preparative high performance liquid chromatography (preparative HPLC, Chilapak IC (5 * 100 mm, 5 μm), hexane: methanol: ethanol = 40: 30: 30) to obtain 30a and 30b, which were white optical isomers, respectively.

[0808] 30a:[α]D23+3°(c 0.1,CHCl3), 30b:[α]D23-3°(c 0.1,CHCl3). MS m / z:384[M+1] +1 HNMR (400MHz, CD3OD) δ8.72(dd,J=5.6,1.1Hz,1H),8.66(dd,J=8.4,1.1Hz,1H),8.09(dt,J=8.4,2.0Hz,3H),7. 89(dd,J=8.5,5.6Hz,1H),7.62(d,J=11.1Hz,1H),7.54(d,J=8.8Hz,2H),6.01(s,2H),4.05(s,3H),3.70(s,3H).

[0809] [Example 31] (3-fluoro-4-((7-fluoro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl) Preparation of (Imino)(methyl)-16-thiocanone (Compound 31)

[0810]

[0811] (Step 1) Preparation of 7-fluoro-5-(2-fluoro-4-(methylthio)benzyl)-8-methoxy-5H-pyrido[3,2-b]indole

[0812]

[0813] Example 29 (Step 4)The prepared compound (50.0 mg, 0.23 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (18.0 mg, 0.46 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 12 (59.0 mg, 0.25 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2: 8) to obtain the title compound in the form of a yellow solid. (50.0 mg, 58%) MS m / z: 371 [M+1] +

[0814] (Step 2) Preparation of (3-fluoro-4-((7-fluoro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(imino)(methyl)-16-thiocanone (Compound 31)

[0815]

[0816] The above (Step 1) The compound (42.0 mg, 0.11 mmol) obtained in the reaction mixture was dissolved in ethanol (1.00 mL), and then iodobenzene diacetate (106 mg, 0.33 mmol) and ammonium acetate (33.0 mg, 0.43 mmol) were added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. Compound 31 was purified (45.0 mg, 99%) by preparative high performance liquid chromatography (preparative HPLC, Chilapak IC (5 * 100 mm, 5 μm), hexane: methanol: ethanol = 40: 30: 30) to obtain 31a and 31b, which were white optical isomers, respectively.

[0817] 31a:[α]D23+9°(c 0.12,CHCl3), 3b:[α]D23-7°(c 0.12,CHCl3). MS m / z:402[M+1] +1H NMR (400MHz, CD3OD) δ8.75-8.67(m,2H),8.07(d,J=8.1Hz,1H),7.98-7.88(m,2H),7.85-7.7 7(m,1H),7.68(d,J=11.1Hz,1H),7.37-7.28(m,1H),6.01(s,2H),4.04(s,3H),3.50(s,3H).

[0818] [Example 32] (4-((8-fluoro-7-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl) (imido Preparation of (1-(2-methyl)-1,6-thiocanone (Compound 32)

[0819]

[0820]

[0821] (Step 1) Preparation of (4-fluoro-3-methoxyphenyl)hydrazine hydrochloride

[0822]

[0823] 4-Fluoro-3-methoxyaniline (1.00 g, 7.08 mmol) was dissolved in 4.00 mL 6N HCl, and then sodium nitrite (733 mg, 10.6 mmol) dissolved in 2.00 mL saturated saline solution was slowly added to the mixture at -20 ° C. The reaction mixture was stirred at -20 ° C and nitrogen for 30 minutes, and then tin (II) chloride dihydrate (4.80 g, 21.3 mmol) dissolved in 2.00 mL concentrated HCl was slowly added. After stirring at 0 ° C for 1 hour, the solid produced in the reaction mixture was filtered, washed with concentrated hydrochloric acid, and then dried to obtain the title compound (1.10 g, 80%) in the form of a white solid. MS m / z: 193 [M+1] +1 HNMR (400MHz, DMSO-d6) δ9.99(s,2H),8.08(s,1H),7.15(dd,J=11.4,8.8Hz,1H),6.85(dd,J=7.4,2.7Hz,1H),6.49(dt,J=8.6,3.1Hz,1H),3.81(s,3H).

[0824] (Step 2) Preparation of tert-butyl 8-fluoro-7-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0825]

[0826] The above (Step 1)The compound obtained (200 mg, 1.03 mmol) was dissolved in toluene (5.00 mL), and then tert-butyl 3-oxopiperidine-1-carboxylate (248 mg, 1.24 mmol) and propanephosphonic anhydride (0.20 mL, 0.21 mmol) were added to the mixture in sequence. The reaction mixture was stirred at 90 ° C and nitrogen for 3 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 3: 7) to obtain the title compound in the form of a light yellow solid. (95.0 mg, 28%) MS m / z: 321 [M+1] +1 H NMR (400MHz, CDCl3) δ7.66 (s, 1H), 7.46-7.29 (m, 1H), 6.76 (d, J = 7.1Hz, 1H), 3.88 (s ,3H),3.79-3.70(m,2H),2.78(t,J=6.8Hz,2H),2.04(q,J=3.3Hz,2H),1.53(s,9H).

[0827] (Step 3) Preparation of 8-fluoro-7-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0828]

[0829] The above (Step 2) The compound obtained in (95.0 mg, 0.29 mmol) was dissolved in dichloromethane (1.00 mL), and then trifluoroacetic acid (1.00 mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ether, and then n-hexane was added. The resulting solid was filtered, washed with a mixed solution of ether / n-hexane, and dried to obtain the title compound in the form of a brown solid. (95.0 mg, 99%) MS m / z: 221 [M+1] +

[0830] (Step 4) Preparation of 8-fluoro-7-methoxy-5H-pyrido[3,2-b]indole

[0831]

[0832] The above (Step 3)The compound obtained (95.0 mg, 0.29 mmol) was dissolved in toluene (5.00 mL), and then Pd / C (10 wt%, 50.0 mg) was added to the mixture. The reaction mixture was stirred at 120 ° C and nitrogen for 18 hours. The precipitate was removed by filtration using diatomaceous earth, and the filtrate was then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (40.0 mg, 65%) MS m / z: 217 [M+1] +

[0833] (Step 5) Preparation of 8-fluoro-7-methoxy-5-(4-(methylthio)benzyl)-5H-pyrido[3,2-b]indole

[0834]

[0835] The above (Step 4) The prepared compound (40.0 mg, 0.18 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (15.0 mg, 0.37 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 6 (44.0 mg, 0.20 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2: 3) to obtain the title compound in the form of a light yellow solid. (25.0 mg, 39%) MS m / z: 353 [M+1] +1 H NMR (400MHz, CD3OD) δ8.39(dd,J=4.8,1.4Hz,1H),7.97(d,J=10.9Hz,1H),7.88(dd,J=8.3,1.4Hz,1H),7.37(dd,J=8. 3,4.8Hz,1H),7.23(d,J=6.9Hz,1H),7.21-7.14(m,2H),7.07(d,J=8.4Hz,2H),5.60(s,2H),3.95(s,3H),2.40(s,3H).

[0836] (Step 6) Preparation of (4-((8-fluoro-7-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(imino)(methyl)-16-thiocanone (Compound 32)

[0837]

[0838] The above (Step 5) The prepared compound (25.0 mg, 0.07 mmol) was dissolved in ethanol (1.00 mL), and then iodobenzene diacetate (56.0 mg, 0.20 mmol) and ammonium acetate (20.0 mg, 0.26 mmol) were added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (19.5 mg, 71%) MS m / z: 384 [M+1] +1 H NMR (400MHz, CD3OD) δ8.66(d,J=5.8Hz,1H),8.58(d,J=8.5Hz,1H),8.15-8.04(m,3H),7.83(dd,J= 8.4, 5.7Hz, 1H), 7.57-7.51 (m, 2H), 7.46 (d, J = 6.8Hz, 1H), 6.06 (s, 2H), 4.02 (s, 3H), 3.60 (s, 3H).

[0839] [Example 33] 4-((6-methoxy-3-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-9-yl)methyl Preparation of 2-(4-(4-(2-amino)benzenesulfonamide) (Compound 33)

[0840]

[0841]

[0842] (Step 1) Preparation of (E)-5-methoxy-3-(2-nitroprop-1-en-1-yl)-1H-indole

[0843]

[0844] Nitroethane (257mg, 3.42mmol) and ammonium acetate (329mg, 4.27mmol) were added to 5-methoxy-1H-indole-3-carboxaldehyde (500mg, 2.85mmol) in sequence. The reaction mixture was stirred at 90°C and nitrogen for 6 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1 to 3: 1) to obtain the title compound in the form of a white solid. (410mg, 75%) MS m / z: 233 [M+1] +1H NMR (400MHz, DMSO-d6) δ12.11(s,1H),8.50(s,1H),7.97(s,1H),7.47-7.33(m,2H),6.92-6.84(m,1H),3.85(s,3H),2.52(s,3H).

[0845] (Step 2): Preparation of 1-(5-methoxy-1H-indol-3-yl)propan-2-amine

[0846]

[0847] The above (Step 1) The compound obtained (410mg, 1.75mmol) was dissolved in tetrahydrofuran (3.00mL), and then lithium aluminum hydride (133mg, 3.52mmol) was added to the mixture. The reaction mixture was stirred at 80°C and nitrogen for 10 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 5: 1 to 9: 1) to obtain the title compound in the form of a white solid. (280mg, 55%) MS m / z: 205 [M+1] +1 HNMR(400MHz,DMSO-d6)δ8.51(s,1H),7.28-7.21(m,1H),7.05-6.95(m,1H),6.88-6.81(m,1H),3.84(s,3H),3.50(br s,2H),3.29(s,1H),2.91-2.63(m,2H),1.18(s,3H).

[0848] (Step 3) Preparation of 6-methoxy-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

[0849]

[0850] Formaldehyde (5.0 mL) was added to the above (Step 2) The obtained compound (100 mg, 0.49 mmol) was added. The reaction mixture was stirred at 80 ° C and nitrogen for 5 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 5: 1 to 7: 1) to obtain the title compound in the form of a white solid. (33.0 mg) MS m / z: 217 [M+1] +

[0851] (Step 4) Preparation of tert-butyl 6-methoxy-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate

[0852]

[0853] The above (Step 3) The prepared compound (33.0 mg, 0.15 mmol) was dissolved in dichloromethane (3.00 mL), and then N, N-diisopropylethylamine (53.0 μl, 0.30 mmol) and di-tert-butyl dicarbonate (36.1 mg, 0.16 mmol) were added to the mixture in sequence. The reaction mixture was stirred at room temperature and nitrogen for 8 hours. After the reaction was completed, distilled water and sodium bicarbonate aqueous solution were added, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 3: 1 to 5: 1) to obtain the title compound in the form of a white solid. (13.0 mg, 48%) MS m / z: 317 [M+1] +

[0854] (Step 5) Preparation of tert-butyl 6-methoxy-3-methyl-9-(4-sulfamoylbenzyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate

[0855]

[0856] The above (Step 4) The compound (13.0 mg, 0.04 mmol) obtained in the reaction mixture was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (2.00 mg, 0.08 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (12.1 mg, 0.05 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1 → 9: 1) to obtain the title compound in the form of a yellow solid. (8.50 mg, 43%) MS m / z: 486 [M + 1] +

[0857] (Step 6) Preparation of 4-((6-methoxy-3-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-9-yl)methyl)benzenesulfonamide (Compound 33)

[0858]

[0859] The above (Step 5) The compound obtained (8.00 mg, 0.02 mmol) was dissolved in dichloromethane (1.50 mL), and then trifluoroacetic acid (1.50 mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5:95 to 100:0) to obtain the title compound in the form of a yellow solid. (4.10 mg, 5%) MS m / z: 386 [M+1] +1 H NMR (400MHz, DMSO-d6) δ7.74(d,J=8.4Hz,2H),7.32(s,3H),7.17(d,J=8.4Hz,2H),7.02(s,1H),6.79-6. 72(m,1H),5.45(s,2H),3.76(s,3H),3.75-3.74(m,1H),3.01(s,2H),2.71(s,2H),1.43(d,J=6.4Hz,3H).

[0860] [Example 34] 4-((3-methoxy-5,6,7,8-tetrahydro-9H-pyrrolo[2,3-b:5,4-c']bipyridin-9-yl) Preparation of (Methyl)benzenesulfonamide (Compound 34)

[0861]

[0862]

[0863] (Step 1) Preparation of 5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde

[0864]

[0865] Phosphorus oxychloride (51.7 g, 337 mmol) and N, N-dimethylformamide (30.0 mL) were added to the mixture in sequence at 0 ° C, and then stirred for 30 minutes. 5-Methoxy-1H-pyrrolo[2,3-b]pyridine (5.00 g, 33.7 mmol) dissolved in N, N-dimethylformamide (30.0 mL) was slowly added to the reaction mixture, and then stirred at 80 ° C for 3 hours. After the reaction was completed, it was cooled to room temperature, and a 2M aqueous sodium hydroxide solution (pH = 9) was added. The reaction mixture was extracted 3 times with ethyl acetate. Ethyl acetate was added to the mixture, and the resulting solid was filtered and dried to obtain the title compound in the form of a yellow solid. (2.68 g, 45%) MS m / z: 304 [M + 1] +1H NMR (400MHz, DMSO-d6) δ 12.60 (br s, 1H), 9.89 (s, 1H), 8.40 (s, 1H), 8.11 (d, J = 2.9Hz, 1H), 7.91 (d, J = 2.9Hz, 1H), 3.86 (s, 3H).

[0866] (Step 2) Preparation of (E)-5-methoxy-3-(2-nitrovinyl)-1H-pyrrolo[2,3-b]pyridine

[0867]

[0868] The above (Step 1) The compound prepared in (1.68 g, 9.54 mmol) was dissolved in nitromethane (20.0 mL), and then ammonium acetate (2.83 g, 36.7 mmol) was added to the mixture. The mixture was stirred at 85 ° C and nitrogen for 1 hour. After the reaction was completed, distilled water was added and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The title compound was obtained as a brown solid without further purification. (1.80 g, 86%) MS m / z: 220 [M+1] +1 H NMR (400MHz, DMSO-d6) δ 8.37 (d, J = 13.5 Hz, 1H), 8.32 (s, 1H), 8.16 (d, J = 13.5 Hz, 1H), 8.08 (d, J = 2.6 Hz, 1H), 7.97 (d, J = 2.6 Hz, 1H), 3.91 (s, 3H).

[0869] (Step 3) Preparation of 2-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-amine

[0870]

[0871] The above (Step 2) The obtained compound (2.50 g, 11.4 mmol) was dissolved in tetrahydrofuran (20.0 mL), and then lithium aluminum hydride (2.60 g, 68.4 mmol) was slowly added to the mixture at 0 ° C. The reaction mixture was stirred at room temperature and nitrogen for 5 hours. After the reaction was completed, distilled water and 15% aqueous sodium hydroxide solution (2.6 mL) were added, and then extracted twice with a mixed solution of dichloromethane: methanol = 5: 1. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The title compound was obtained in the form of a brown oil without further purification. (2.00 g) MS m / z: 192 [M + 1] + 1H NMR (400MHz, DMSO-d6) δ11.66 (br s, 1H), 8.04 (br d, J = 2.5Hz, 3H), 7.86 (d, J = 2.4Hz, 1H), 7.41 (d, J = 2.3Hz, 1H), 3.87 (s, 3H), 3.12-2.97 (m, 4H).

[0872] (Step 4) Preparation of 3-methoxy-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:5,4-c']bipyridine

[0873]

[0874] The above (Step 3) The compound prepared in (200 mg, 1.04 mmol) was dissolved in acetic acid (4.00 mL) and methanol (0.40 mL), and then formaldehyde solution (452 ​​μl, 1.04 mmol) was added to the mixture. The reaction mixture was stirred at 65 ° C and nitrogen for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain the title compound in the form of a yellow solid without further purification. (75.0 mg, 53%) MS m / z: 204 [M+1] +

[0875] (Step 5) Preparation of tert-butyl 3-methoxy-5,6,8,9-tetrahydro-7H-pyrrolo[2,3-b:5,4-c']bipyridine-7-carboxylate

[0876]

[0877] The above (Step 4) The prepared compound (75.0 mg, 0.37 mmol) was dissolved in dichloromethane (2.00 mL), and then cooled to 0 ° C, and triethylamine (80.0 μl, 0.55 mmol) and di-tert-butyl dicarbonate (93.0 uL, 0.41 mmol) were added to the mixture and stirred for 1 hour at room temperature and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9 to 1: 8) to obtain the title compound in the form of a yellow solid. (30.0 mg, 26%) MS m / z: 304 [M+1] +

[0878] (Step 6) Preparation of tert-butyl 3-methoxy-9-(4-sulfamoylbenzyl)-5,6,8,9-tetrahydro-7H-pyrrolo[2,3-b:5,4-c′]bipyridine-7-carboxylate

[0879]

[0880] The above (Step 5) The prepared compound (30.0 mg, 0.10 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (11.9 mg, 0.30 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (27.2 mg, 0.11 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9 to 1: 3) to obtain the title compound in the form of a yellow solid. (25.0 mg, 53%) MS m / z: 473 [M+1] +

[0881] (Step 7) Preparation of 4-((3-methoxy-5,6,7,8-tetrahydro-9H-pyrrolo[2,3-b:5,4-c′]bipyridin-9-yl)methyl)benzenesulfonamide (Compound 34)

[0882]

[0883] The above (Step 6) The compound obtained (25.0 mg, 0.05 mmol) was dissolved in dichloromethane (0.50 mL), and then trifluoroacetic acid (0.50 mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5:95 to 100:0) to obtain the title compound in the form of a yellow solid. (2.30 mg, 12%) MSm / z: 373 [M+1] +1 H NMR (400MHz, CD3OD) δ8.04(s,1H),7.82(s,2H),7.60(s,1H),7.24(s,2H),5.55(s,2H),4.34(s,2H),3.90(s,3H),3.58(s,2H),3.10(s,2H).

[0884] [Example 35] 4-((7-methoxy-1,2,3,4-tetrahydro-5H-pyrido[4.3-b]indol-5-yl)methyl)benzenesulfonate Preparation of amide (Compound 35)

[0885]

[0886] (Step 1) Preparation of tert-butyl 7-methoxy-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0887]

[0888] (3-methoxyphenyl) hydrazine hydrochloride (2.00g, 11.5mmol) is dissolved in toluene (5.00mL), and then tert-butyl 4-oxopiperidin-1-carboxylate (2.70g, 13.8mmol) and propanephosphonic anhydride (2.50g, 17.2mmol) are added to the mixture in sequence. The reaction mixture is stirred at 90°C and nitrogen for 6 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution are added, and extracted twice with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:4 to 1:2) to obtain the title compound in the form of a yellow solid. (180mg) MS m / z: 303 [M+1] +

[0889] (Step 2) Preparation of tert-butyl 7-methoxy-5-(4-sulfamoylbenzyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0890]

[0891] The above (Step 1) The prepared compound (20.0 mg, 0.07 mmol) was dissolved in N, N-dimethylformamide (1.50 mL), and then cooled to 0 ° C, and 60% sodium hydride (3.20 mg, 0.13 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (19.5 mg, 0.08 mmol) dissolved in N, N-dimethylformamide (1.00 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 5: 95 → 10: 90) to obtain the title compound in the form of a yellow solid. (5.10 mg, 16%) MS m / z: 472 [M+1] +

[0892] (Step 3) Preparation of 4-((7-methoxy-1,2,3,4-tetrahydro-5H-pyrido[4.3-b]indol-5-yl)methyl)benzenesulfonamide (Compound 35)

[0893]

[0894] The above (Step 2) The compound obtained (5.00 mg, 0.01 mmol) was dissolved in dichloromethane (2.00 mL), and then trifluoroacetic acid (2.00 mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5:95 to 100:0) to obtain the title compound in the form of a yellow solid. (1.50 mg, 40%) MS m / z: 372 [M+1] +

[0895] [Example 36] 4-((8-methoxy-1,2,3,4-tetrahydro-5H-pyrido[4.3-b]indol-5-yl)methyl)benzenesulfonate Preparation of amide (Compound 36)

[0896]

[0897] (Step 1) Preparation of tert-butyl 8-methoxy-5-(4-sulfamoylbenzyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0898]

[0899] Example 4 (Step 1) The prepared compound (180 mg, 0.60 mmol) was dissolved in N, N-dimethylformamide (3.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (90.0 mg, 2.25 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (178 mg, 0.71 mmol) was slowly added to the reaction mixture, and then stirred for 2 hours at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2: 3 to 3: 2) to obtain the title compound in the form of a yellow solid. (128 mg, 46%) MS m / z: 472 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 7.81 (d, J = 8.0Hz, 2H), 7.08 (d, J = 8.0Hz, 2H), 7.04 (d, J = 8.9Hz, 1H), 6.95 (s, 1H), 6.79(d,J=8.6Hz,1H),5.28(s,2H),4.79(s,2H),4.65(s,2H),3.86-3.80(m,5H),2.68(s,2H),1.50(s,9H).

[0900] (Step 2) Preparation of 4-((8-methoxy-1,2,3,4-tetrahydro-5H-pyrido[4.3-b]indol-5-yl)methyl)benzenesulfonamide (Compound 36)

[0901]

[0902] The above (Step 1) The prepared compound (128 mg, 0.27 mmol) was dissolved in dichloromethane (1.00 mL), and then trifluoroacetic acid (1.00 mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (48.0 mg, 47%) MS m / z: 372 [M+1] +1 H NMR (400MHz, DMSO-d6) δppm: 9.03 (s, 1H), 7.75 (d, J = 8.0Hz, 2H), 7.45-7.30 (m, 3H), 7.20 (d, J = 8. 1Hz, 2H), 7.09 (s, 1H), 6.79 (d, J = 8.9Hz, 1H), 5.48 (s, 2H), 4.35 (s, 2H), 3.78 (s, 3H), 2.99 (s, 2H).

[0903] [Example 37] 4-((7-methoxy-1,2,3,4-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonate Preparation of amide (Compound 37)

[0904]

[0905] (Step 1) Preparation of tert-butyl 7-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0906]

[0907] Mix 1,3-dimethylurea (8.81 g, 100 mmol) and L-(+)-tartaric acid (4.50 g, 30.0 mmol), and then stir the reaction mixture at 80 ° C and nitrogen for 2 hours. (3-methoxyphenyl) hydrazine hydrochloride (1.87 g, 11.0 mmol) and tert-butyl 3-oxopiperidine-1-carboxylate (2.00 mg, 10.0 mmol) are added to the reaction mixture in sequence, and then stirred at 80 ° C for 2 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution are added, and extracted twice with dichloromethane. The organic layer is dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate: n-hexane = 0: 10 to 2: 8) to obtain the title compound in the form of a yellow solid. (471 mg, 15%) MS m / z: 303 [M+1] +1 H NMR (400MHz, CDCl3) δ7.56-7.48(m,2H),6.75(s,2H),3.86(s,3H),3.76-3.75(m,2H),2.81-2.78(m,2H),2.07-2.04(m,2H),1.52(s,9H)

[0908] (Step 2) Preparation of tert-butyl 7-methoxy-5-(4-sulfamoylbenzyl)-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0909]

[0910] The above (Step 1) The prepared compound (100 mg, 0.33 mmol) was dissolved in N, N-dimethylformamide (2.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (26.0 mg, 0.66 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (90.0 mg, 0.36 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred at 0 ° C and nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 3: 7) to obtain the title compound in the form of a yellow solid. (64.0 mg, 41%) MS m / z: 472 [M+1] +

[0911] (Step 3) Preparation of 4-((7-methoxy-1,2,3,4-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 37)

[0912]

[0913] The above (Step 2) The compound obtained (64.0 mg, 0.13 mmol) was dissolved in dichloromethane (2.00 mL), and then hydrogen chloride (4M 1,4-dioxane solution, 1.00 mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5:95 to 100:0) to obtain the title compound in the form of a yellow solid. (33.0 mg, 52%) MS m / z: 372 [M+1] +1 H NMR(400MHz,CD3OD)δ7.83(d,J=7.6Hz,2H),7.50-7.41(m,1H),7.19(d,J=8.4Hz,2H),6.94 (s,1H),6.86-6.82(m,1H),5.47(s,2H),3.77(s,3H).3.58(s,2H),2.83(s,2H),2.46(s,2H)

[0914] [Example 38] 4-((8-methoxy-1,2,3,4-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonate Preparation of amide (Compound 38)

[0915]

[0916]

[0917] (Step 1) Preparation of tert-butyl 8-methoxy-5-(4-sulfamoylbenzyl)-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0918]

[0919] Example 5 (Step 1)The prepared compound (200 mg, 0.66 mmol) was dissolved in N, N-dimethylformamide (2.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (52 mg, 1.32 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (330 mg, 1.32 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2: 8) to obtain the title compound in the form of a yellow solid. (22.0 mg, 7%) MSm / z: 472 [M+1] +

[0920] (Step 2) Preparation of 4-((8-methoxy-1,2,3,4-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 38)

[0921]

[0922] The above (Step 1) The compound obtained (11.0 mg, 0.02 mmol) was dissolved in dichloromethane (1.00 mL), and then 4N hydrogen chloride dioxane solution (1.00 mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5:95 to 100:0) to obtain the title compound in the form of a yellow solid. (6.00 mg, 68%) MS m / z: 372 [M+1] +1 H NMR(400MHz,CD3OD)δ7.78(d,J=7.4Hz,2H),7.10(d,J=7.7Hz,3H),7.00(s,1H),6.72 (s,1H),5.33(s,2H),3.82(d=J=1.62Hz,3H),3.23(s,2H),2.69(s,2H),2.02(s,2H).

[0923] [Example 39] 3-((8-methoxy-1,2,3,4-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonate Preparation of amide (Compound 39)

[0924]

[0925] (Step 1) Preparation of tert-butyl 8-methoxy-5-(3-sulfamoylbenzyl)-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0926]

[0927] Example 5 (Step 1) The prepared compound (50.0 mg, 0.17 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (19.8 mg, 0.50 mmol) was added thereto and stirred for 30 minutes. 3-(Bromomethyl)benzenesulfonamide (45.0 mg, 0.18 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred at 0 ° C and nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9 to 1: 8) to obtain the title compound in the form of a yellow solid. (22.0 mg, 28%) MS m / z: 472 [M+1] +

[0928] (Step 2) Preparation of 3-((8-methoxy-1,2,3,4-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 39)

[0929]

[0930] The above (Step 1) The compound obtained (22.0 mg, 0.05 mmol) was dissolved in dichloromethane (0.50 mL), and then trifluoroacetic acid (0.50 mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5:95 to 100:0) to obtain the title compound in the form of a yellow solid. (5.00 mg, 29%) MS m / z: 372 [M+1] +1H NMR(400MHz,CD3OD)δ7.64(d,J=8.8Hz,2H),7.40-7.34(m,1H),7.30(t,J=7.6Hz,1H),7.1 3(dd,J=9.2,2.6Hz,1H),6.84(d,J=2.6Hz,1H),6.74(d,J=9.2Hz,1H),4.14-3.95(m,2H),3 .69(s,3H),3.58(d,J=13.6Hz,1H),3.26(d,J=13.7Hz,1H),2.59(ddd,J=12.7,8.2,3.8Hz, 1H), 2.28 (tdd, J=16.9, 10.6, 6.3Hz, 1H), 2.06-1.92 (m, 1H), 1.83 (dt, J=13.2, 9.1Hz, 1H).

[0931] [Example 40] 4-((8-methyl-1,2,3,4-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonyl Preparation of amine (Compound 40)

[0932]

[0933] (Step 1) Preparation of tert-butyl 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0934]

[0935] p-Tolylhydrazine hydrochloride (400mg, 2.52mmol) was dissolved in toluene (25.0mL), and then tert-butyl 3-oxopiperidin-1-carboxylate (603mg, 3.03mmol) and propanephosphonic anhydride (0.30mL, 0.50mmol) were added to the mixture in sequence. The reaction mixture was stirred at 90°C and nitrogen for 6 hours. After cooling to room temperature, distilled water and sodium bicarbonate aqueous solution were added, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:2) to obtain the title compound in the form of a yellow solid. (320mg, 44%) MS m / z: 287 [M+1] +

[0936] (Step 2) Preparation of tert-butyl 8-methyl-5-(4-sulfamoylbenzyl)-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0937]

[0938] The above (Step 1)The prepared compound (50.0 mg, 0.18 mmol) was dissolved in N, N-dimethylformamide (2.40 mL), and then cooled to 0 ° C, and 60% sodium hydride (14.0 mg, 0.35 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (52.4 mg, 0.21 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3) to obtain the title compound in the form of a white solid. (17.1 mg, 21%) MS m / z: 456 [M+1] +

[0939] (Step 3) Preparation of 4-((8-methyl-1,2,3,4-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 40)

[0940]

[0941] The above (Step 2) The compound obtained (17.1 mg, 0.04 mmol) was dissolved in dichloromethane (0.80 mL), and then trifluoroacetic acid (0.40 mL) was added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5:95 to 100:0) to obtain the title compound in the form of a pink solid. (10.6 mg, 79%) MS m / z: 356 [M+1] +1 H NMR (400MHz, CD3OD) δ7.86-7.74(m,2H),7.35(s,1H),7.30(d,J=9.0Hz,1H),7.23-7.12(m,2H),7.08(d, J=9.1Hz,1H),5.48(s,2H),3.60(d,J=5.9Hz,2H),2.85(t,J=5.9Hz,2H),2.45(s,3H),2.36-2.16(m,2H).

[0942] [Example 41] 4-((8-methoxy-1-oxo-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl) Preparation of (Methyl)benzenesulfonamide (Compound 41)

[0943]

[0944]

[0945] (Step 1) Preparation of 4-(2-(4-methoxyphenyl)hydrazino)-5,6-dihydropyridin-2(1H)-one

[0946]

[0947] Piperidine-2,4-dione (6.48 g, 57.3 mmol) was dissolved in ethanol (80 mL), and then 4-methoxyhydrazine hydrochloride (10.0 g, 57.3 mmol) was added to the mixture. The reaction mixture was stirred at room temperature under nitrogen for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure. The title compound was obtained as a brown solid without further purification. (9.80 g) MS1 m / z: 234 [M+1] +

[0948] (Step 2) Preparation of 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one

[0949]

[0950] At 0°C, (Step 1) The prepared compound (8.80 g, 37.7 mmol) was slowly dissolved in a mixed solution (44.0 mL) of sulfuric acid: distilled water = 3: 1, and then stirred at room temperature for 3 hours. After the reaction was completed, distilled water and 2M sodium hydroxide aqueous solution (200 mL) were slowly added, and extracted twice with a mixed solution of dichloromethane: methanol = 10: 1. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 1 to 10: 1) to obtain the title compound in the form of a yellow solid. (1.06 g, 13%) MS m / z: 217 [M+1] +1 H NMR (400MHz, DMSO-d6) δ11.47(s,1H),7.35(d,J=2.5Hz,1H),7.25(d,J=8.7Hz,1H),6.96(br s, 1H), 6.72 (dd, J = 2.6, 8.8Hz, 1H), 3.74 (s, 3H), 3.43 (dt, J = 2.3, 6.9Hz, 2H), 2.92 (t, J = 6.9Hz, 2H).

[0951] (Step 3) Preparation of 4-((8-methoxy-1-oxo-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)methyl)benzenesulfonamide (Compound 41)

[0952]

[0953] The above (Step 2) The prepared compound (50.0 mg, 0.23 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (18.0 mg, 0.46 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (86.0 mg, 0.34 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (2.80 mg, 3%) MS m / z: 386 [M+1] +1 H NMR (400MHz, CD3OD) δ7.92(d,J=8.0Hz,1H),7.87(d,J=8.3Hz,1H),7.62(d,J=9.2Hz,2H),7.2 6(t,J=9.7Hz,2H),6.83(d,J=9.5Hz,1H),5.54(s,2H),3.87(s,3H),3.65(s,2H),3.03(s,2H)

[0954] [Example 42] 4-((7-methoxy-1-oxo-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl) Preparation of 2-(4-Methyl)benzenesulfonamide (Compound 42)

[0955]

[0956]

[0957] (Step 1) Preparation of 4-(2-(3-methoxyphenyl)hydrazino)-5,6-dihydropyridin-2(1H)-one

[0958]

[0959] Hexahydropyridine-2,4-dione (10.0 g, 88.4 mmol) was dissolved in ethanol (80 mL), and then 3-methoxyhydrazine hydrochloride (15.4 g, 88.4 mmol) was added to the mixture. The reaction mixture was stirred at room temperature under nitrogen for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure. The title compound was obtained as a yellow solid without further purification. (20.0 g) MS m / z: 234 [M+1] +

[0960] (Step 2) Preparation of 7-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one

[0961]

[0962] At 0°C, (Step 1) The prepared compound (10.0 g, 42.9 mmol) was slowly dissolved in a mixed solution (45.0 mL) of sulfuric acid: distilled water = 3: 1, and then stirred at room temperature for 3 hours. After the reaction was completed, distilled water and 2M sodium hydroxide aqueous solution (200 mL) were slowly added to the mixture, and extracted twice with a mixed solution of dichloromethane: methanol = 10: 1. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 1 to 10: 1) to obtain the title compound in the form of a yellow solid. (354 mg, 4%) MSm / z: 217 [M+1] +1 H NMR (400MHz, DMSO-d6) δ11.42 (s, 1H), 7.70 (d, J = 8.6Hz, 1H), 6.93 (br s, 1H), 6.88 (d, J = 2.1Hz, 1H), 6.73 (dd, J = 2.3, 8.6Hz, 1H), 3.76 (s, 3H), 3.44 (dt, J = 2.4, 6.9Hz, 2H), 2.91 (t, J = 6.9Hz, 2H).

[0963] (Step 3) Preparation of 4-((7-methoxy-1-oxo-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)methyl)benzenesulfonamide (Compound 42)

[0964]

[0965] The above (Step 2) The prepared compound (50.0 mg, 0.23 mmol) was dissolved in N, N-dimethylformamide (2.40 mL), and then cooled to 0 ° C, and 60% sodium hydride (18.5 mg, 0.46 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (69.4 mg, 0.28 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a white solid. (16.2 mg, 18%) MS m / z: 386 [M+1] +1H NMR(400MHz,CD3OD)δ7.96-7.73(m,3H),7.30-7.10(m,2H),6.92-6.75(m,2 H), 5.50 (s, 2H), 3.75 (s, 3H), 3.59 (t, J = 7.2Hz, 2H), 2.96 (t, J = 7.1Hz, 2H).

[0966] [Example 43] 4-((7-methoxy-1-oxo-1,2-dihydro-5H-pyrido[4,3-b]indol-5-yl)methyl Preparation of 2-(4-(2-amino)benzenesulfonamide (Compound 43)

[0967]

[0968] (Step 1) Preparation of 7-methoxy-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one

[0969]

[0970] (3-Methoxyphenyl)hydrazine hydrochloride (1.12 g, 8.10 mmol) was dissolved in diphenyl ether (50.0 mL), and then 2,4-dihydroxypyridine (300 mg, 2.70 mmol) was added to the mixture in sequence. Under nitrogen, the reaction mixture was stirred at 180 ° C for 1 hour and then at 240 ° C for 3 hours. After the reaction was completed, it was cooled to room temperature, and the residue was then purified by silica gel column chromatography (ethyl acetate: n-hexane = 0: 10 to methanol: dichloromethane = 1: 9) to obtain the title compound in the form of a yellow solid. (196 mg, 34%) MS m / z: .215 [M+1] +1 H NMR (400MHz, CD3OD) δ 8.08 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 7.01 (s, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 4.5 Hz, 1H), 3.86 (s, 3H).

[0971] (Step 2) Preparation of 4-((7-methoxy-1-oxo-1,2-dihydro-5H-pyrido[4,3-b]indol-5-yl)methyl)benzenesulfonamide (Compound 43)

[0972]

[0973] The above (Step 1)The compound (52.0 mg, 0.24 mmol) obtained in the reaction mixture was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (19.0 mg, 0.48 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (72.0 mg, 0.29 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (3.70 mg, 3%) MS m / z: 384 [M+1] +1 H NMR(400MHz,CD3OD)δ8.06(s,1H),7.87(s,2H),7.58(s,1H),7.45(s,2H),7.02(s,1H),6.90(s,1H),6.72(s,1H),5.41(s,2H),3.88(s,3H)

[0974] [Example 44] 4-((8-methoxy-1-oxo-1,2-dihydro-5H-pyridazine[4,5-b]indol-5-yl)methyl Preparation of 2-(4-(2-amino)benzenesulfonamide (Compound 44)

[0975]

[0976] (Step 1) Preparation of 2,2,2-trifluoro-1-(5-methoxy-1H-indol-3-yl)ethan-1-one

[0977]

[0978] 5-Methoxyindole (3.00 g, 20.4 mmol) was dissolved in N,N-dimethylformamide (15.0 mL), and then trifluoroacetic anhydride (TFAA, 1.60 mL, 30.6 mmol) was added to the mixture at 0°C. The reaction mixture was stirred at room temperature under nitrogen for 16 hours. After the reaction was completed, distilled water was added to the mixture, and the resulting solid was filtered and dried to obtain the title compound in the form of a white solid. (6.40 g, 129%) MS m / z: 244 [M+1] +1 H NMR (400MHz, DMSO-d6) δppm: 12.60 (s, 1H), 8.40 (s, 1H), 7.68 (s, 1H), 7.49 (d, J = 8.9Hz, 1H), 6.97 (d, J = 8.8Hz, 1H), 3.81 (s, 3H).

[0979] (Step 2) Preparation of 5-methoxy-1H-indole-3-carboxylic acid

[0980]

[0981] The above (Step 1) The obtained compound (6.40 g) was dissolved in 5N sodium hydroxide aqueous solution (20.0 mL), and then tetrahydrofuran (5.00 mL) was added to the mixture. The reaction mixture was stirred at 90 ° C and nitrogen for 16 hours. The reaction mixture was concentrated under reduced pressure. After cooling to room temperature, distilled water was slowly added and extracted twice with ethyl acetate. The water layer was adjusted to pH 2 or less by adding 1N hydrogen chloride aqueous solution thereto, and the obtained solid was filtered and dried to obtain the title compound in the form of a white solid. (2.90 g, 76%) MS m / z: 192 [M+1] +1 H NMR (400MHz, DMSO-d6) δppm: 11.66 (s, 1H), 7.92 (d, J = 2.5Hz, 1H), 7.49 (d, J = 2.6Hz, 1H), 7.35 (d, J = 8.8Hz, 1H), 6.82 (dd, J = 8.8, 2.5Hz, 1H), 3.78 (s, 3H).

[0982] (Step 3) Preparation of ethyl 5-methoxy-1H-indole-3-carboxylate

[0983]

[0984] The above (Step 2) The prepared compound (1.30 g, 6.80 mmol) was dissolved in methanol: distilled water (10.0 mL, 9: 1), and then cesium carbonate (2.10 g, 6.46 mmol) was added to the mixture and stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure, and iodoethane (0.49 mL, 6.12 mmol) was added and stirred for another 16 hours. Distilled water was slowly added to the reaction mixture and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0: 10 to 2: 3) to obtain the title compound in the form of a white solid. (1.10 g, 74%) MS m / z: 220 [M+1] +1H NMR (400MHz, DMSO-d6) δppm: 11.78 (s, 1H), 7.98 (d, J = 2.9Hz, 1H), 7.48 (d, J = 2.6Hz, 1H), 7.35 (d, J = 8.9Hz, 1H), 6.82 (dd, J = 8.8, 2.6Hz, 1H), 4.24 (q, J = 7.1Hz, 2H), 3.78 (s, 3H), 1.31 (t, J = 7.1Hz, 3H).

[0985] (Step 4) Preparation of ethyl 2-formyl-5-methoxy-1H-indole-3-carboxylate

[0986]

[0987] Phosphorus oxychloride (0.39 mL, 4.20 mmol) and N,N-dimethylformamide (0.28 mL, 3.65 mmol) were sequentially added thereto at 0°C under nitrogen, and then stirred for 1 minute. The reaction mixture was dissolved in dichloromethane (5.00 mL), and the above (Step 3) The compound obtained (400mg, 1.82mmol) was slowly added to the mixture, and then stirred at room temperature for 16 hours. After completing the reaction, it was concentrated under reduced pressure, and 10mL of saturated sodium acetate aqueous solution was added and stirred for another 12 hours. The reaction mixture was extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0: 10 to 2: 3) to obtain the title compound in the form of a white solid. (80.0mg, 18%) MS m / z: 248 [M+1] +1 H NMR (400MHz, DMSO-d6) δppm: 12.07 (s, 1H), 10.66 (s, 1H), 8.09 (d, J = 3.4Hz, 1H), 7.66 (dd, J = 8 .9, 3.4Hz, 1H), 7.10 (d, J = 9.0Hz, 1H), 4.05-4.00 (m, 2H), 3.85 (s, 3H), 1.16 (t, J = 4.8Hz, 3H).

[0988] (Step 5) Preparation of ethyl 2-formyl-5-methoxy-1-(4-sulfamoylbenzyl)-1H-indole-3-carboxylate

[0989]

[0990] The above (Step 4)The prepared compound (25.0 mg, 0.10 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (4.90 mg, 0.12 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (30.3 mg, 0.12 mmol) was slowly added to the reaction mixture, and then stirred for 2 hours at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4 to 9: 1) to obtain the title compound in the form of a yellow solid. (23.0 mg, 55%) MS m / z: 417 [M+1] +1 H NMR (400MHz, CD3OD) δppm: 10.77 (s, 1H), 8.19 (s, 1H), 7.86 (d, J = 8.0Hz, 2H), 7.60 (d, J = 9.2Hz, 1H), 7.34 (d, J=8.1Hz,2H),7.10(d,J=9.1Hz,1H),5.60(s,2H),4.32(q,J=6.7Hz,2H),3.92(s,3H),1.37(t,J=7.1Hz,3H).

[0991] (Step 6) Preparation of 4-((8-methoxy-1-oxo-1,2-dihydro-5H-pyridazin[4,5-b]indol-5-yl)methyl)benzenesulfonamide (Compound 44)

[0992]

[0993] The compound (23.0 mg, 0.055 mmol) obtained above (step 5) was dissolved in acetic acid (0.50 mL) and ethanol (0.50 mL), and then hydrazine monohydrate (8.00 μl, 0.17 mmol) was added to the mixture. The reaction mixture was stirred at 90 ° C and nitrogen for 3 hours. After the reaction was completed, it was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (4.70 mg, 17%) MS m / z: 499 [M + 1] +1 H NMR (400MHz, DMSO-d6) δppm: 10.18 (s, 1H), 8.07 (s, 1H), 7.77 (d, J = 7.6Hz, 2H), 7 .63(s,1H),7.47-7.27(m,5H),6.93(d,J=8.7Hz,1H),5.50(s,2H),3.81(s,3H).

[0994] [Example 45] 4-((7-methoxy-1-oxo-1,2-dihydro-5H-pyridazine[4,5-b]indol-5-yl)methyl Preparation of 2-(4-(2-amino)benzenesulfonamide (Compound 45)

[0995]

[0996] (Step 1) Preparation of 2,2,2-trifluoro-1-(6-methoxy-1H-indol-3-yl)ethan-1-one

[0997]

[0998] 6-Methoxyindole (3.00 g, 20.38 mmol) was dissolved in N,N-dimethylformamide (15.0 mL), and then trifluoroacetic anhydride (TFAA, 1.60 mL, 30.6 mmol) was added to the mixture at 0°C. The reaction mixture was stirred at room temperature under nitrogen for 16 hours. After the reaction was completed, distilled water was added to the mixture, and the resulting solid was filtered and dried to obtain the title compound in the form of a white solid. (7.00 g, 141%) MS m / z: 244 [M+1] +1 H NMR (400MHz, DMSO-d6) δppm: 12.50 (s, 1H), 8.36 (s, 1H), 8.02 (d, J = 8.7Hz, 1H), 7.06 (s, 1H), 6.95 (d, J = 8.6Hz, 1H), 3.81 (s, 3H).

[0999] (Step 2) Preparation of 6-methoxy-1H-indole-3-carboxylic acid

[1000]

[1001] The above (Step 1) The prepared compound (7.00 g) was dissolved in 5N sodium hydroxide aqueous solution (20.0 mL), and then tetrahydrofuran (5.00 mL) was added to the mixture. The reaction mixture was stirred at 90 ° C and nitrogen for 16 hours. The reaction mixture was concentrated under reduced pressure. After cooling to room temperature, distilled water was slowly added and extracted twice with ethyl acetate. The water layer was adjusted to pH 2 or less by adding 1N hydrogen chloride aqueous solution, and the resulting solid was filtered and dried to obtain the title compound in the form of a white solid. (3.50 g, 90%) MS m / z: 192 [M+1] +1 H NMR (400MHz, DMSO-d6) δppm: 11.84 (br, 1H), 11.57 (s, 1H), 7.90-7.72 (m, 2H), 6.92 (s, 1H), 6.78 (d, J = 8.7, 1H), 3.76 (s, 3H).

[1002] (Step 3) Preparation of ethyl 6-methoxy-1H-indole-3-carboxylate

[1003]

[1004] The above (Step 2) The prepared compound (500mg, 2.61mmol) was dissolved in methanol: distilled water (10.0mL, 9:1), and then cesium carbonate (810mg, 2.48mmol) was added to the mixture and stirred at room temperature for 1 hour. After completing the reaction, it was concentrated under reduced pressure, and iodoethane (0.19mL, 2.35mmol) was added and stirred for another 16 hours. Distilled water was slowly added to the reaction mixture and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0:10 to 2:3) to obtain the title compound in the form of a white solid. (372mg, 64%) MS m / z: 220 [M+1] +1 H NMR (400MHz, CDCl3) δppm: 8.37 (br, 1H), 8.06 (d, J = 8.8Hz, 1H), 7.83 (s, 1H), 7.01 -6.93(m,1H),6.90(s,1H),4.49-4.29(m,2H),3.88(s,3H),1.44(t,J=7.2Hz,3H).

[1005] (Step 4) Preparation of ethyl 2-formyl-6-methoxy-1H-indole-3-carboxylate

[1006]

[1007] Phosphorus oxychloride (0.39 mL, 4.20 mmol) and N,N-dimethylformamide (0.28 mL, 3.65 mmol) were sequentially added to the mixture at 0°C under nitrogen, and then stirred for 1 minute. The above solution dissolved in dichloromethane (5.20 mL) was added to the mixture. (step Step 3) The compound obtained (400mg, 1.82mmol) was slowly added to the reaction mixture, and then stirred at room temperature for 16 hours. After completing the reaction, it was concentrated under reduced pressure, and 10.0mL of saturated sodium acetate aqueous solution was added and stirred for another 12 hours. The reaction mixture was extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9 to 2: 3) to obtain the title compound in the form of a white solid. (330mg, 37%) MS m / z: 248 [M+1] +

[1008] (Step 5) Preparation of ethyl 2-formyl-6-methoxy-1-(4-sulfamoylbenzyl)-1H-indole-3-carboxylate

[1009]

[1010] The above (Step 4) The prepared compound (50.0 mg, 0.20 mmol) was dissolved in N, N-dimethylformamide (2.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (16.1 mg, 0.40 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (60.7 mg, 0.24 mmol) dissolved in N, N-dimethylformamide (0.30 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 8 to 1: 2) to obtain the title compound in the form of a yellow solid. (35.0 mg, 42%) MS m / z: 417 [M+1] +

[1011] (Step 6) Preparation of 4-((7-methoxy-1-oxo-1,2-dihydro-5H-pyridazin[4,5-b]indol-5-yl)methyl)benzenesulfonamide (Compound 45)

[1012]

[1013] The compound (35.0 mg, 0.08 mmol) obtained above (step 5) was dissolved in acetic anhydride (0.40 mL), and then hydrazine monohydrate (12.0 μl, 0.25 mmol) was added to the mixture. The reaction mixture was stirred at 80 ° C and nitrogen for 3 hours. After the reaction was completed, it was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (4.60 mg, 14%) MS m / z: 385 [M + 1] +1 H NMR (400MHz, CD3OD) δ8.53 (s, 1H), 8.22 (d, J = 9.3Hz, 1H), 7.94-7.73 (m, 2H), 7.3 3(d,J=5.4Hz,2H),7.17(s,1H),7.07(d,J=8.6Hz,1H),5.86(s,2H),3.88(s,3H).

[1014] [Example 46] 7-methoxy-5-(4-(S-methylsulfonimidoyl)benzyl)-2,5-dihydro-1H-pyridazin[4,5- b] Preparation of indole-1-one (Compound 46)

[1015]

[1016] (Step 1) Preparation of ethyl 2-formyl-6-methoxy-1-(4-(methylthio)benzyl)-1H-indole-3-carboxylate

[1017]

[1018] Example 45 (Step 4) The prepared compound (50.0 mg, 0.20 mmol) was dissolved in N, N-dimethylformamide (2.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (16.2 mg, 0.40 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 6 (87.8 mg, 0.40 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added thereto, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 8 to 1: 4) to obtain the title compound in the form of a yellow solid. (75.0 mg, 97%) MS m / z: 384 [M+1] +

[1019] (Step 2) Preparation of 7-methoxy-5-(4-(methylthio)benzyl)-2,5-dihydro-1H-pyridazin[4,5-b]indol-1-one

[1020]

[1021] The compound (75.0 mg, 0.20 mmol) obtained above (step 1) was dissolved in acetic anhydride (2.00 mL), and then hydrazine monohydrate (0.03 mL, 0.59 mmol) was added to the mixture. The reaction mixture was stirred at 80 ° C and nitrogen for 3 hours. After the reaction was completed, it was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (38.0 mg, 55%) MS m / z: 352 [M + 1] +

[1022] (Step 3) Preparation of 7-methoxy-5-(4-(S-methylsulfonimidoyl)benzyl)-2,5-dihydro-1H-pyridazin[4,5-b]indol-1-one (Compound 46)

[1023]

[1024] The above (Step 2) The prepared compound (20.0 mg, 0.06 mmol) was dissolved in ethanol (1.70 mL), and then iodobenzene diacetate (53.2 mg, 0.17 mmol) and ammonium acetate (16.7 mg, 0.22 mmol) were added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 16 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a white solid. (4.60 mg, 21%) MS m / z: 383 [M+1] +1 H NMR (400MHz, CD3OD) δ8.49(s,1H),8.22(d,J=7.6Hz,1H),8.10(d,J=5.6Hz,2H),7.52(d, J=3.6Hz,2H),7.12(s,1H),7.07(d,J=7.2Hz,1H),5.95(s,2H),3.86(s,3H),2.03(s,3H).

[1025] [Example 47] 4-((7-methoxy-5H-pyridazin[4,5-b]indol-5-yl)methyl)benzenesulfonamide (Compound Preparation of 47)

[1026]

[1027] (Step 1) Preparation of 7-methoxy-2,5-dihydro-1H-pyridazin[4,5-b]indol-1-one

[1028]

[1029] Example 45 (Step 4) The prepared compound (75.0 mg, 0.30 mmol) was dissolved in acetic anhydride (3.00 mL), and then hydrazine monohydrate (44.0 mL, 0.91 mmol) was added to the mixture. The reaction mixture was stirred at 80 ° C and nitrogen for 3 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (12.1 mg, 19%) MS m / z: 216 [M+1] +

[1030] (Step 2) Preparation of 1-chloro-7-methoxy-2,5-dihydro-1H-pyridazin[4,5-b]indole

[1031]

[1032] The above (Step 1) The prepared compound (12.1 mg, 0.06 mmol) was dissolved in trichlorophosphoric acid (1.00 mL) and then stirred at 60 ° C and nitrogen for 3 hours. After the reaction was completed, it was cooled to room temperature, and then distilled water was slowly added to the mixture and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The title compound was obtained as a white solid without further purification. (13.1 mg, 99%) MS m / z: 244 [M+1] +

[1033] (Step 3) Preparation of 7-methoxy-5H-pyridazin[4,5-b]indole

[1034]

[1035] The above (Step 2) The compound obtained in (13.1 mg, 0.06 mmol) was dissolved in methanol (1.10 mL), and then ammonium formate (14.0 mg, 0.22 mmol) and 10% Pd / C (5.00 mg) were added to the mixture. The reaction mixture was stirred at room temperature and nitrogen for 12 hours. The precipitate was removed by filtration using diatomaceous earth, and the filtrate was then concentrated under reduced pressure. The title compound was obtained as a white solid without further purification. (11.2 mg, 100%) MS m / z: 200 [M+1] +

[1036] (Step 4) Preparation of 4-((7-methoxy-5H-pyridazin[4,5-b]indol-5-yl)methyl)benzenesulfonamide (Compound 47)

[1037]

[1038] The above (Step 3)The compound (11.2 mg, 0.06 mmol) obtained in the reaction mixture was dissolved in N, N-dimethylformamide (0.60 mL), and then cooled to 0 ° C, and 60% sodium hydride (4.50 mg, 0.11 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (21.1 mg, 0.08 mmol) dissolved in N, N-dimethylformamide (0.30 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (1.70 mg, 8%) MS m / z: 369 [M+1] +1 H NMR (400MHz, CD3OD) δ9.99 (s, 1H), 9.64 (s, 1H), 8.34 (d, J = 5.2Hz, 1H), 7.86 (d, J = 4. 4Hz, 2H), 7.38 (s, 2H), 7.30 (s, 1H), 7.21 (d, J = 6.4Hz, 1H), 6.06 (s, 2H), 3.99 (s, 3H).

[1039] [Example 48] 4-((7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)methyl)benzenesulfonamide (Compound Preparation of 48)

[1040]

[1041] (Step 1) Preparation of 7-methoxy-9H-pyrimido[4,5-b]indole

[1042]

[1043] 4-Amino-5-bromopyrimidine (500 mg, 2.87 mmol) was dissolved in 1,4-dioxane (6.00 mL), and then [1,1-bis(diphenylphosphino)phenanthroline (ferrosine)]dichloropalladium (165 mg, 0.29 mmol), xantphos (166 mg, 0.29 mmol) and sodium tert-butoxide (828 mg, 8.62 mmol) were added to the mixture in sequence and stirred at 110 ° C for 24 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to obtain the title compound in the form of a light yellow solid. (220 mg, 38%) MS m / z: .200 [M+1] +1H NMR (400MHz, CDCl3) δ9.74 (s, 1H), 9.21 (d, J = 5.3Hz, 1H), 8.99 (d, J = 5.6Hz, 1H), 7.99 (s, 1H), 7.11-6.84 (m, 2H), 3.93 (d, J = 1.3Hz, 3H).

[1044] (Step 2) Preparation of 4-((7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)methyl)benzenesulfonamide (Compound 48)

[1045]

[1046] The above (Step 1) The prepared compound (50.0 mg, 0.25 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (20.0 mg, 0.50 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (95.0 mg, 0.38 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (49.0 mg, 51%) MS m / z: 369 [M+1] +1 H NMR (400MHz, CD3OD) δ9.58-9.43(m,1H),9.30-9.12(m,1H),8.38-8.21(m,1H),7.91-7.77(m,2H), 7.63-7.43(m,2H),7.34-7.24(m,1H),7.24-7.13(m,1H),6.02-5.86(m,2H),3.91(t,J=3.2Hz,3H).

[1047] [Example 49] 4-((6-methoxy-9H-pyrido[2,3-b]indol-9-yl)methyl)benzenesulfonamide (Compound Preparation of 49)

[1048]

[1049] (Step 1) Preparation of 3-chloro-N-(4-methoxyphenyl)pyridin-2-amine

[1050]

[1051] Compound 4-methoxyaniline (500mg, 4.05mmol) and 2,3-dichloropyridine (500mg, 3.34mmol) were dissolved in toluene (10.0mL), and then palladium acetate (75.8mg, 0.34mmol), BINAP (421mg, 0.68mmol) and potassium carbonate (1.60g, 11.8mol) were added to the mixture and stirred at 100°C and nitrogen for 18 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:9 to 10:0) to obtain the title compound in the form of a yellow solid. (540mg, 68%). MS m / z:235[M+1]+1H NMR (400MHz, CDCl3) δ8.07 (dd, J=4.9, 1.4Hz, 1H), 7.57-7.51 (m, 1H), 7.51-7.45 ( m, 2H), 6.93-6.88 (m, 2H), 6.80 (s, 1H), 6.69-6.63 (m, 1H), 3.81 (d, J = 0.8Hz, 3H).

[1052] (Step 2) Preparation of 6-methoxy-9H-pyrido[2,3-b]indole

[1053]

[1054] The compound (35.0 mg, 0.15 mmol) prepared in the above (step 1) was dissolved in N, N-dimethylformamide (1.0 mL), and then palladium acetate (3.30 mg, 0.01 mmol) and potassium carbonate (31.0 mg, 0.22 mmol) were added to the mixture and stirred at 135 ° C and nitrogen for 18 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9 to 10: 0) to obtain the title compound in the form of a yellow solid. (5.0 mg, 17%). MS m / z:199[M+1]+1H NMR(400MHz, CDCl3) δ9.08(s,1H),8.45(dd,J=5.0,1.6Hz,1H),8.30(dd,J=7.8,1.6Hz,1H),7 .54(d,J=2.6Hz,1H),7.42(d,J=8.8Hz,1H),7.15(ddd,J=13.9,8.3,3.8Hz,2H),3.93(s,3H).

[1055] (Step 3) Preparation of 4-((6-methoxy-9H-pyrido[2,3-b]indol-9-yl)methyl)benzenesulfonamide (Compound 49)

[1056]

[1057] The above (Step 2) The prepared compound (19.0 mg, 0.096 mmol) was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (7.80 mg, 0.11 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (28.8 mg, 0.12 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 2 hours at 0 ° C and nitrogen. After completing the reaction, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4 to 10: 0) to obtain the title compound in the form of a yellow solid. (2.9 mg, 8%). MS m / z:368[M+1]+1H NMR (400MHz, CD3OD) δ8.62(dd,J=7.8,1.5Hz,1H),8.45(d,J=5.3Hz,1H),7.82(d,J=8.4Hz,2H),7.78(d,J=2.9Hz,1H) ,7.40(d,J=9.0Hz,1H),7.34(dd,J=7.8,5.1Hz,3H),7.15(dd,J=8.9,2.6Hz,1H),5.81(s,2H),3.93(d,J=1.0Hz,3H).

[1058] [Example 50] 4-((8-methoxy-5H-pyridazin[4,5-b]indol-5-yl)methyl)benzenesulfonamide (Compound Preparation of 50)

[1059]

[1060] (Step 1) Preparation of dimethyl 5-methoxy-1H-indole-2,3-dicarboxylate

[1061]

[1062] 2-iodo-4-methoxyaniline (5.0g, 20.1mmol) and dimethyl acetylene dicarboxylate (3.14g, 22.1mmol) were dissolved in dimethyl sulfoxide (50.0mL), and then tris(dibenzylideneacetone)dipalladium (0) (919mg, 1.00mmol) and triethylamine (8.38mL, 60.2mmol) were added to the mixture and stirred at 90°C and nitrogen for 16 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: ether = 1: 100 to 2: 5) to obtain the title compound in the form of a yellow solid. (960mg, 18%). MS m / z:264[M+1]+1H NMR(400MHz, CDCl3)δ9.19(br s,1H),7.49(d,J=2.4Hz,1H),7.33(d,J=9.2Hz,1H),7.05(dd,J=9.2,2.4Hz,1H),3.99(s,3H),3.99(s,3H),3.89(s,3H).

[1063] (Step 2) Preparation of 8-methoxy-2,3-dihydro-1H-pyridazin[4,5-b]indole-1,4(5H)-dione

[1064]

[1065] The compound prepared above (step 1) (960 mg, 3.65 mmol) was dissolved in ethanol (5.7 mL), and then hydrazine monohydrate (5.82 g, 114 mmol, 98% pure) was slowly added to the mixture. The mixture was stirred at 80 ° C and nitrogen for 16 hours. After the reaction was completed, it was concentrated under reduced pressure. The title compound was obtained as a yellow solid without further purification. (970 mg). MS m / z: 232 [M+1] + 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.04 (dd, J = 8.8, 2.4 Hz, 1H), 3.82 (s, 3H).

[1066] (Step 3) Preparation of 1,4-dichloro-8-methoxy-5H-pyridazino[4,5-b]indole

[1067]

[1068] The compound (970 mg, 4.20 mmol) prepared above (step 2) was cooled to 0 ° C, and then phosphoryl chloride (5.00 mL) was slowly added to the mixture. The mixture was stirred at 110 ° C and nitrogen for 16 hours. The reaction was completed by slowly adding an aqueous sodium carbonate solution, and then the resulting solid was filtered to obtain the title compound in the form of a brown solid. (870 mg, 77%). MS m / z: 268 [M+1] + 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H) 7.42 (dd, J = 8.8, 2.4 Hz, 1H), 3.91 (s, 3H).

[1069] (Step 4) Preparation of 8-methoxy-5H-pyridazino[4,5-b]indole

[1070]

[1071] The compound (870mg, 3.25mmol) prepared in the above (step 3) is dissolved in methanol (30.0mL), and then Pd / C (300mg, 10% pure, 50% wet) is added to the mixture. The mixture is stirred for 2 hours at room temperature and nitrogen. After completing the reaction, it is filtered through a diatomaceous earth pad to remove impurities, and then the solvent is removed from the filtrate under reduced pressure. The residue is purified by silica gel column chromatography (methanol: dichloromethane=1:10) to obtain the title compound in the form of a brown solid. (403mg, 62%). MS m / z:200[M+1]+1H NMR(400MHz,DMSO-d6)δ12.44-13.76(m,1H),10.21(s,1H),9.64(s,1H),8.05( d,J=2.4Hz,1H),7.79(d,J=8.8Hz,1H),7.40(dd,J=8.8,2.4Hz,1H),3.90(s,3H)

[1072] (Step 5) Preparation of 4-((6-methoxy-9H-pyrido[2,3-b]indol-9-yl)methyl)benzenesulfonamide (Compound 49)

[1073]

[1074] The compound (50.0 mg, 0.251 mmol) obtained above (step 4) was dissolved in N, N-dimethylformamide (2.50 mL), and then cooled to 0 ° C, and 60% sodium hydride (20.1 mg, 0.50 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (75.3 mg, 0.30 mmol) dissolved in N, N-dimethylformamide (0.50 mL) was slowly added to the reaction mixture, and then stirred for 2 hours at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (5.6 mg, 6%). MS m / z:369[M+1]+1H NMR (400MHz, CD3OD) δ10.21(s,1H),10.01(s,1H),8.00-7.95(m,3H),7.84(d,J=9.2 Hz,1H),7.73(d,J=8.0Hz,2H),7.57(dd,J=2.2,9.0Hz,1H),6.14(s,2H),3.98(s,3H)

[1075] [Example 51] 4-((8-methoxy-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzenesulfonamide (Compound Preparation of 51)

[1076]

[1077]

[1078] (Step 1) Preparation of 5-methoxy-1H-indole-3-carbonyl azide

[1079]

[1080] 5-Methoxyindole-3-carboxylic acid (1.00 g, 5.23 mmol) was dissolved in tetrahydrofuran (17.0 mL), and then diphenylphosphoryl azide (1.18 mL, 5.49 mmol) and triethylamine (0.77 mL, 5.49 mmol) were added to the mixture and stirred at room temperature for 24 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2: 3) to obtain the title compound in the form of a white solid. (870 mg, 77%). MS m / z:217[M+1]+1H NMR (400MHz, CDCl3) δppm: 12.11 (s, 1H), 8.12 (s, 1H), 7.53 (d, J = 2.6Hz, 1H), 7.42 (d, J = 8.9Hz, 1H), 6.89 (dd, J = 8.9, 2.6Hz, 1H), 3.80 (s, 3H)

[1081] (Step 2) Preparation of tert-butyl (5-methoxy-1H-indol-3-yl)carbamate

[1082]

[1083] The compound (870 mg, 4.02 mmol) prepared above (step 1) was dissolved in tert-butyl alcohol (30.0 mL), and the reaction mixture was then stirred at 80 ° C and nitrogen for 16 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0: 10 to 1: 3) to obtain the title compound in the form of a green solid. (589 mg, 56%). MS m / z: 263 [M + 1] + 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.49 (s, 1H), 8.99 (s, 1H), 7.34 (d, J = 16.4 Hz, 2H), 7.17 (d, J = 8.8 Hz, 1H), 6.69 (dd, J = 8.8, 2.5 Hz, 1H), 3.73 (s, 3H), 1.49 (s, 9H).

[1084] (Step 3) Preparation of 5-methoxy-1H-indol-3-amine

[1085]

[1086] The compound prepared in the above (step 2) (100 mg, 0.38 mmol) was dissolved in dichloromethane (1.50 mL), and then trifluoroacetic acid (0.14 mL, 1.91 mmol) was added to the mixture and stirred for 2 hours at room temperature and nitrogen. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the solvent, and a brown mixture (140 mg) was obtained without further purification. MS m / z: 163 [M+1] +

[1087] (Step 4) Preparation of N'-(2-formyl-5-methoxy-1H-indol-3-yl)-N,N-dimethylformamidine

[1088]

[1089] Phosphoryl chloride (0.18mL, 1.96mmol) was dissolved in dichloromethane (1.00mL) at 0°C and nitrogen, and then N,N-dimethylformamide (0.15mL, 1.96mmol) was added to the mixture and stirred for 30 minutes. The compound (140mg) prepared in dichloromethane (3.00mL) was slowly added above (step 3), and then stirred at room temperature for 24 hours. After the reaction was completed, the reaction mixture was placed in an Erlenmeyer flask filled with ice, and sodium bicarbonate aqueous solution was added, and then extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5:95 to 100:0) to obtain the title compound in the form of a yellow solid. (7.5mg). MS m / z: 246[M+1]+

[1090] (Step 5) Preparation of 8-methoxy-5H-pyrimido[5,4-b]indole

[1091]

[1092] The compound (7.50 mg, 0.03 mmol) prepared above (step 4) was dissolved in ethanol (0.50 mL), and then aqueous ammonia solution (0.30 mL) was added to the mixture. The reaction mixture was stirred at 80 ° C and nitrogen for 2 hours. After the reaction was completed, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 19) to obtain the title compound in the form of a yellow solid. (4.8 mg). MS m / z: 200 [M + 1] + 1H NMR (400 MHz, DMSO-d6) δ ppm: 11.70 (s, 1H), 9.08 (s, 1H), 9.01 (s, 1H), 7.71 (d, J = 2.9 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.33 (dd, J = 8.6, 2.2 Hz, 1H), 3.89 (s, 3H).

[1093] (Step 6) Preparation of 4-((8-methoxy-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzenesulfonamide (Compound 51)

[1094]

[1095] The compound (4.80 mg, 0.024 mmol) obtained above (step 5) was dissolved in N, N-dimethylformamide (0.40 mL), and then cooled to 0 ° C, and 60% sodium hydride (1.70 mg, 0.043 mmol) was added to the mixture and stirred for 10 minutes. Intermediate 1 (15.1 mg, 0.06 mmol) dissolved in N, N-dimethylformamide (0.40 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After completing the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (preparative HPLC, 0.1% TFA acetonitrile: distilled water = 5: 95 to 100: 0) to obtain the title compound in the form of a yellow solid. (3.4 mg, 38%). MS m / z:369[M+1]+1H NMR (400MHz, DMSO-d6) δppm: 9.28 (s, 1H), 9.06 (s, 1H), 7.78 (d, J = 2.5Hz, 1H), 7.74 (d, J = 3. 4Hz, 1H), 7.71 (d, J = 4.1Hz, 2H), 7.40-7.32 (m, 3H), 7.28 (s, 2H), 5.86 (s, 2H), 3.89 (s, 3H).

[1096] [Example 52] 4-((7-methoxy-5H-pyrido[4.3-b]indol-5-yl)methyl)benzenesulfonamide (Compound Preparation of 52)

[1097]

[1098] (Step 1) Preparation of 3-(2-chloro-4-methoxyphenyl)pyridin-4-amine

[1099]

[1100] (2-Chloro-4-methoxyphenyl)boric acid (2.0g, 11.6mmol) and 4-bromopyridine-4-amine (2.59g, 13.0mmol) are dissolved in a mixed solution of toluene (30.0mL), ethanol (20.0mL) and water (10.0mL), and then sodium carbonate (7.35g, 69.4mmol) and tetrakis (triphenylphosphine) palladium (0) (1.34g, 1.16mmol) are added to the mixture. The reaction mixture is stirred at 100°C and nitrogen for 6 hours. After completing the reaction, the reaction mixture is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate: ether = 1: 100 to 1: 3) to obtain the title compound in the form of a yellow solid. (1.1g, 40%). MS m / z:234.7[M+1]+1H NMR(400MHz, DMSO-d6)δppm:8.23(d,J=5.6Hz,1H),8.10(s,1H),7.23(d,J=8.4Hz,1H),7.08( d, J=2.4Hz, 1H), 6.92 (dd, J=8.4, 2.5Hz, 1H), 6.63 (d, J=5.6Hz, 1H), 4.15 (s, 2H), 3.86 (s, 3H).

[1101] (Step 2) Preparation of 7-methoxy-5H-pyrido[4.3-b]indole

[1102]

[1103] The compound (1.0 g, 4.26 mmol) prepared in the above (step 1) was dissolved in dimethyl sulfoxide (10.0 mL), and then potassium tert-butoxide (1.43 g, 12.8 mmol) was added to the mixture. The reaction mixture was stirred at 130 ° C and nitrogen for 4 hours. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 100 to 1: 20) to obtain the title compound in the form of a light brown solid. (893 mg, 52%). MS m / z:199.0[M+1]+1H NMR(400MHz, CDCl3)δppm:9.54(br s,1H),9.24(s,1H),8.47(d,J=5.6Hz,1H),8.01(d,J=8.4Hz,1H),7.33(d,J=6.0Hz,1H),6.92-6.99(m,2H),3.90(s,3H).

[1104] (Step 3) Preparation of 4-((7-methoxy-5H-pyrido[4.3-b]indol-5-yl)methyl)benzenesulfonamide (Compound 52)

[1105]

[1106] The above (Step 2)The compound (50.0 mg, 0.25 mmol) obtained in the reaction mixture was dissolved in N, N-dimethylformamide (1.00 mL), and then cooled to 0 ° C, and 60% sodium hydride (15.0 mg, 0.38 mmol) was added to the mixture and stirred for 30 minutes. Intermediate 1 (126.2 mg, 0.50 mmol) dissolved in N, N-dimethylformamide (1.00 mL) was slowly added to the reaction mixture, and then stirred for 1 hour at 0 ° C and nitrogen. After the reaction was completed, distilled water was slowly added and extracted twice with ethyl acetate. The organic layer was dried over anhydr...

Claims

1. A compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof, in Each R 1 are independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide; A is aryl, heteroaryl or heterocyclic; Y is CH, CR 1 or N; R 2 is aralkyl, heteroaralkyl, heterocyclylalkyl or cycloalkylalkyl; and n is 0, 1, 2, 3 or 4.

2. The compound according to claim 1, wherein A is heteroaryl (eg pyridyl, pyrimidinyl or pyridazinyl, preferably pyridinyl).

3. The compound according to claim 1, wherein A is a heterocyclic group (eg, piperidinyl, piperidonyl, tetrahydropyridazinonyl).

4. The compound according to claim 1, wherein the compound has a structure represented by Formula Ia, or a pharmaceutically acceptable salt thereof: in, X 1 CR 3 or N; X 2 CR 4 or N; X 3 CR 5 or N; X 4 CR 6 or N; and R 3 , R 4 , R 5 and R 6 Each is independently selected from H, alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl and sulfonamide.

5. The compound according to claim 4, wherein X 1 is N.

6. The compound according to claim 4, wherein X 1 CR 3 .

7. The compound according to claim 6, wherein R 3 For H.

8. The compound according to any one of claims 4 to 7, wherein X 2 is N.

9. The compound according to any one of claims 4 to 7, wherein X 2 CR 4 .

10. The compound according to claim 9, wherein R 4 For H.

11. The compound according to any one of claims 4 to 10, wherein X 3 is N.

12. The compound according to any one of claims 4 to 10, wherein X 3 CR 7 .

13. The compound according to claim 12, wherein R 5 For H.

14. The compound according to any one of claims 4 to 13, wherein X 4 is N.

15. The compound according to any one of claims 4 to 13, wherein X 4 CR 6 .

16. The compound according to claim 15, wherein R 6 For H.

17. The compound according to any one of claims 1 to 12, wherein n is 1.

18. The compound according to any one of claims 1 to 12, wherein n is 2.

19. The compound according to any one of claims 1 to 16, wherein Y is CH.

20. The compound of any one of claims 1 to 16, wherein Y is N.

21. The compound according to any one of claims 1 to 17 and 19, wherein the compound has a structure represented by Formula Ib, or a pharmaceutically acceptable salt thereof:

22. The compound according to any one of claims 1 to 17 and 19, wherein the compound has a structure represented by Formula Ic, or a pharmaceutically acceptable salt thereof:

23. The compound according to any one of claims 1 to 16, 18 and 19, wherein the compound has a structure represented by Formula Id, or a pharmaceutically acceptable salt thereof: in, R 7 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide.

24. The compound according to any one of claims 1 to 16, 18 and 19, wherein the compound has a structure represented by Formula Ie, or a pharmaceutically acceptable salt thereof: in, R 7 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide.

25. The compound according to any one of claims 1 to 16, 18 and 19, wherein the compound has a structure represented by Formula If, or a pharmaceutically acceptable salt thereof: in, R 7 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide.

26. The compound according to any one of claims 1 to 25, wherein R 2 is an aralkyl group (eg, a phenylalkyl group such as phenylmethylene or phenylethylene, preferably phenylmethylene).

27. The compound according to any one of claims 1 to 25, wherein R 2 is heterocyclylalkyl (eg piperidinylmethylene).

28. The compound according to any one of claims 1 to 17 and 19, wherein the compound has a structure represented by Formula IIa, or a pharmaceutically acceptable salt thereof: in, Each R 8 are independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide; R 9 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, phosphoramidite, phosphoramidite, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl, sulfonamide, imidothioanone or aminosulfonamide; and y is 1, 2, 3, or 4.

29. The compound according to any one of claims 1 to 17 and 19, wherein the compound has a structure represented by Formula IIb, or a pharmaceutically acceptable salt thereof: in, Each R 8 are independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide; R 9 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, phosphoramidite, phosphoramidite, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl, sulfonamide, imidothioanone or aminosulfonamide; and y is 1, 2, 3, or 4.

30. The compound according to any one of claims 1 to 16, 18 and 19, wherein the compound has a structure represented by Formula IIc, or a pharmaceutically acceptable salt thereof: in, R 7 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide; Each R 8 are independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide; R 9 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, phosphoramidite, phosphoramidite, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl, sulfonamide, imidothioanone or aminosulfonamide; and y is 1, 2, 3, or 4.

31. The compound according to any one of claims 1 to 16, 18 and 19, wherein the compound has a structure represented by Formula IId, or a pharmaceutically acceptable salt thereof: in, R 7 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide; Each R 8 are independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide; R 9 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, phosphoramidite, phosphoramidite, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl, sulfonamide, imidothioanone or aminosulfonamide; and y is 1, 2, 3, or 4.

32. The compound according to any one of claims 1 to 16, 18 and 19, wherein the compound has a structure represented by Formula IIe, or a pharmaceutically acceptable salt thereof: in, R 7 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide; Each R 8 are independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl or sulfonamide; R 9 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, carboxyl, acyl, ester, thioester, phosphoryl, phosphoramidite, phosphoramidite, amino, amide, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxide, alkylsulfonyl, sulfonamide, imidothioanone or aminosulfonamide; and y is 0, 1, 2, 3, or 4.

33. A compound according to any one of claims 1 to 32, wherein R 1 is an alkyl group (eg, methyl).

34. A compound according to any one of claims 1 to 32, wherein R 1 is an alkoxy group (eg, methoxy, trifluoromethoxy or ethoxy, preferably methoxy).

35. A compound according to any one of claims 1 to 32, wherein R 1 is a halogen group (eg, fluorine or chlorine).

36. A compound according to any one of claims 23 to 35, wherein R 7 is an alkyl group (eg, methyl).

37. A compound according to any one of claims 23 to 35, wherein R 7 is an alkoxy group (eg, a methoxy group).

38. A compound according to any one of claims 23 to 35, wherein R 7 is a halogen group (eg, fluorine or chlorine).

39. The compound of any one of claims 28 to 38, wherein y is 0.

40. The compound of any one of claims 28 to 38, wherein y is 1.

41. The compound according to any one of claims 28 to 40, wherein R 8 is a halogen group (eg, fluorine or chlorine).

42. The compound according to any one of claims 28 to 40, wherein R 8 is an alkyl group (eg, methyl or trifluoromethyl).

43. A compound according to any one of claims 28 to 40, wherein R 10 is an alkoxy group (eg, a methoxy group).

44. The compound according to any one of claims 28 to 43, wherein R 9 It is a sulfonylamide group (eg, a methylsulfonylamide group).

45. The compound according to any one of claims 28 to 43, wherein R 9 It is an iminothiolanone group (for example, an (imino)(methyl)iminothiolanone group, an (imino)(ethyl)iminothiolanone group, an (imino)(benzyl)iminothiolanone group or an (imino)(cyclopropyl)iminothiolanone group).

46. ​​A compound according to any one of claims 28 to 43, wherein R 9 It is an aminosulfonylamide group (for example, an (imino)(methyl)iminothiolato group).

47. A compound according to any one of claims 28 to 43, wherein R 9 It is a phosphoryl group.

48. A compound according to any one of claims 28 to 43, wherein R 9 is an alkyl group (eg, phosphorylmethyl or phosphoryldifluoromethyl).

49. The compound according to any one of claims 28 to 43, wherein R 9 It is a phosphoramidite group.

50. The compound according to any one of claims 28 to 43, wherein R 9 It is a phosphoramide group.

51. The compound according to claim 1, wherein the compound is selected from or a pharmaceutically acceptable salt thereof.

52. A compound represented by the following formula 1, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof, [Formula 1] in, A1 is a substituted or unsubstituted C3-30 cycloalkyl ring, a substituted or unsubstituted C2-30 heterocycloalkyl ring, a substituted or unsubstituted C6-30 aryl ring, or a substituted or unsubstituted C3-30 heteroaryl ring, which is fused to an adjacent ring; A2 is a substituted or unsubstituted C3-20 cycloalkylene group, a substituted or unsubstituted C2-20 heterocycloalkylene group, a substituted or unsubstituted C6-30 arylene group, or a substituted or unsubstituted C3-30 heteroarylene group; X1 to X4 are each independently CR or N; R is hydrogen, hydroxyl, halogen, C1-10 alkyl, C1-10 alkoxy, C6-20 aryl, C3-20 heteroaryl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, amino, nitro, amide, carboxylic acid, nitrile, urea or sulfonamide; L1 is C1-10 alkylene or C2-10 alkenylene; Z represent; R1 is O or NR5; R2 is hydrogen, hydroxyl, cyano, C1-C10 alkyl, C1-10 alkoxy, C6-C12 aryl, C3-C10 cycloalkyl, C2-C12 heterocycloalkyl, -C(=O)OR6 or -NR8R9; L 21 , L 22 and L3 are each independently a single bond, a substituted or unsubstituted C1-C5 alkylene group or -NR7-; R3 to R7 are each independently hydrogen or C1-C5 alkyl; R8 and R9 are each independently hydrogen, -C(=O)R 10 (The condition is R 10 is C1-C5 alkyl) or -Boc(tert-butoxycarbonyl); and * is a point connected to A2 in Formula 1.

53. The compound according to claim 52, its hydrate, its solvate, its isomer or its pharmaceutically acceptable salt, wherein A1 in Formula 1 is represented by the following Formula 2 or Formula 3: [Formula 2] in, Y 11 To Y 14 Each independently is CR a or N; R a is hydrogen, hydroxyl, halogen, C1-10 alkyl, C1-10 alkoxy, C6-20 aryl, C3-20 heteroaryl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, amino, nitro, amide, carboxylic acid, nitrile, urea or sulfonamide; and * is the point of attachment to each of the two adjacent carbon atoms on the fused ring to which A1 is attached, and [Formula 3] in, Y 21 To Y 24 Each independently is CR b R c , -C(=O)- or NR d ; R b to R d are each independently hydrogen, hydroxyl, halogen, C1-10 alkyl, C1-10 alkoxy, C6-20 aryl, C3-20 heteroaryl, C3-10 cycloalkyl or C3-10 heterocycloalkyl, amino, nitro, amide, carboxylic acid, nitrile, urea or sulfonamide; and * is the point of attachment to each of the two adjacent carbon atoms on the fused ring to which A1 is attached.

54. The compound according to claim 52, its hydrate, its solvate, its isomer or its pharmaceutically acceptable salt, in, A1 in Formula 1 is a substituted or unsubstituted C3-10 cycloalkyl ring, a substituted or unsubstituted C2-10 heterocycloalkyl ring, a substituted or unsubstituted C6-10 aryl ring, or a substituted or unsubstituted C3-10 heteroaryl ring, which is fused to an adjacent ring; A2 is a substituted or unsubstituted C3-10 cycloalkylene group, a substituted or unsubstituted C2-10 heterocycloalkylene group, a substituted or unsubstituted C6-10 arylene group, or a substituted or unsubstituted C3-10 heteroarylene group; X1 to X4 are each independently CR or N; R is hydrogen, hydroxyl, halogen, C1-10 alkyl, C1-10 alkoxy, C6-10 aryl, C3-10 heteroaryl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, amino, nitro, amide, carboxylic acid, nitrile, urea or sulfonamide; and L1 is a C1-10 alkylene group.

55. The compound according to claim 52, its hydrate, its solvate, its isomer or its pharmaceutically acceptable salt, in, A1 in Formula 1 is a substituted or unsubstituted C5 heterocycloalkyl ring, a substituted or unsubstituted C6 aryl ring, or a substituted or unsubstituted C4-5 heteroaryl ring, which is fused to an adjacent ring; A2 is substituted or unsubstituted C5 heterocycloalkylene, substituted or unsubstituted C6 arylene, or substituted or unsubstituted C5 heteroarylene; X1 to X4 are each independently CR or N; R is hydrogen, a halogen group, a C1-2 alkyl group or a C1-2 alkoxy group; and L1 is a C1-2 alkylene group.

56. The compound according to claim 53, its hydrate, its solvate, its isomer or its pharmaceutically acceptable salt, wherein: Y11 to Y14 are each independently CRa or N; and R a It is hydrogen, hydroxy, C1-10 alkyl or C1-10 alkoxy.

57. The compound according to claim 53, its hydrate, its solvate, its isomer or its pharmaceutically acceptable salt, wherein: Y 21 To Y 24 Each independently is CR b R c , -C(=O)- or NR d ;and R b to R d Each is independently hydrogen, hydroxy, C1-10 alkyl or C1-10 alkoxy.

58. The compound according to claim 53, its hydrate, its solvate, its isomer or its pharmaceutically acceptable salt, wherein: Z is (Provision is made that * is a point connected to A2 in Formula 1).

59. The compound according to claim 52, its hydrate, its solvate, its isomer or its pharmaceutically acceptable salt, wherein the compound is selected from compounds having the following structures:

60. The compound according to claim 52, its hydrate, its solvate, its isomer or its pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt is a salt with an inorganic or organic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

61. A pharmaceutical composition comprising a compound according to any one of claims 1 to 60 and a pharmaceutically acceptable excipient.

62. A method of treating cancer in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof.

63. The method of claim 62, wherein the cancer is gastric cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenosis, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, hematological malignancies (e.g., leukemia, multiple myeloma, and myelodysplastic syndrome), lymphoma (e.g., Hodgkin's lymphoma or non-Hodgkin's lymphoma), or fibroadenoma.

64. The method of claim 62 or 63, wherein the method further comprises co-administering another therapeutic agent (eg, a cancer agent).

65. A method of treating a disease or disorder characterized by ENPP-1 in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof.

66. A pharmaceutical composition for preventing, alleviating or treating cancer, comprising the compound according to any one of claims 1 to 60, its hydrate, its solvate, its isomer or its pharmaceutically acceptable salt as an active ingredient.

67. An ENPP-1 inhibitor composition comprising the compound according to any one of claims 1 to 60, its hydrate, its solvate, its isomer or its pharmaceutically acceptable salt as an active ingredient.

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