Ectonucleotide pyrophosphatase-phosphodiesterase-1 inhibitors and pharmaceutical compositions containing the same

Abstract

The present invention relates to compounds, or pharmaceutically acceptable salts thereof, for inhibiting ectonucleotide pyrophosphatase / phosphodiesterase-1 (ENPP-1).

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of priority to Korean Patent Application No. 10-2022-0072041, filed on June 14, 2022, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Ectonucleotide pyrophosphatase / phosphodiesterase-1 (or ENPP-1) is a type II transmembrane glycoprotein with pyrophosphatase and phosphodiesterase activities that is highly expressed in bone and cartilage.

[0003] ATP is a substrate for ENPP-1 and is hydrolyzed to AMP and PPi, which is converted to adenosine and inorganic phosphate (Pi) by CD73. ENPP-1 hydrolysis of nucleotide pyrophosphate bonds (e.g., in ATP) and phosphodiester bonds (e.g., in oligonucleotides) as part of functions mediated by nucleotide pyrophosphatases / phosphodiesterases (NPPs) is required for a wide range of cellular processes, including nucleotide pyrophosphate recycling, purinergic receptor signaling, and ATP-mediated apoptosis.

[0004] Recently, ENPP-1 has been found to play an important role in immunological responses to various stimuli via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Damage-associated molecular patterns (DAMPs) and 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). 2,3'-cGAMP then initiates an inflammatory response via the TANK-binding kinase 1 (TBK1)-interferon regulatory factor (IRF) 3 pathway, producing type 1 interferons (IFNs) and other cytokines. A link between the cGAS-STING pathway and ENPP-1 has emerged, whereby cGAMP hydrolysis by ENPP-1 attenuates cGAS-STING signaling. ENPP-1 plays a regulatory role in immune cells, such as neutrophils, macrophages, dendritic cells, natural killer cells, and B lymphocytes. In the presence of cancer, ENPP-1 expression is increased in M2 macrophages, promoting tumor growth and spread. The role of ENPP-1 in cancer is exemplified by the observation that overexpression of ENPP-1 promotes tumor metastasis from breast cancer to bone.

[0005] Recent reports suggest that cyclic dinucleotides, substrates of ENPP-1, stimulate innate immunity through STING-dependent activation of interferon genes. ENPP-1 inhibition of STING pathway activation is important for tumor management, as is checkpoint inhibitors, such as anti-PD-1 or anti-PD-L1, which are promising immunotherapeutic agents for various cancers.

[0006] Since STING activation is a promising therapeutic strategy for treating cancer, many compounds that activate the STING pathway have been reported. ENPP-1 is a highly potent cGAMP-degrading enzyme, and ENPP-1 inhibitors have been applied in antitumor therapy.

[0007] ADP-ribosylation is a conserved post-translational modification of proteins that plays a role in all major cellular processes, particularly DNA repair, transcription, translation, stress response, and cell death. Poly ADP-ribosylation (PARylation), mediated by poly ADP-ribose polymerase (PARP), plays an important role in DNA damage repair. Inhibition of poly ADP-ribosylation by PARP inhibitors inhibits DNA damage repair and induces 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.

[0008] However, recent studies suggest that depolyADP-ribosylation (dePAR) also plays an important role in DNA damage repair. Instead of antagonizing polyADP-ribosylation, depolyADP-ribosylation functions as a downstream step of polyADP-ribosylation in DNA damage repair. Protein polyADP-ribosylation can be reversed by macrodomains, including the proteins PARG, TARG1, MacroD1, MacroD2, and ENPP-1. Recently, ENPP-1 has been shown to play a role in the depolyADP-ribosylation process by hydrolyzing the ester bond known to link proteins to ADP-ribose. DepolyADP-ribosylation inhibitors represent a new class of inhibitors that offer an alternative to PARP inhibition and may overcome the anticancer drug resistance of PARPi. Therefore, ENPP-1 inhibitors may play an important role in the DNA damage repair process. Summary of the Invention [Problem to be solved by the invention]

[0009] Based on the above principles, there is an urgent and growing need for a class of antitumor compounds that can inhibit ENPP-1 and treat various types of cancer. [Means for solving the problem]

[0010] The present invention relates to inhibitors of ectonucleotide pyrophosphatase / phosphodiesterase-1 (ENPP-1) and pharmaceutically acceptable salts thereof.

[0011] In certain aspects, the present invention provides compounds having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof:

[0012] [ka] (In the formula, Each R 1 is independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, amino, amido, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, or sulfonamido; A is aryl, heteroaryl, or heterocyclyl; Y is CH, CR 1 , or N, R 2 is aralkyl, heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl; n is 0, 1, 2, 3, or 4.

[0013] In certain aspects, the present invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0014] In certain aspects, the present invention provides 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 disclosed herein, or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description of the Invention The present invention will be described in further detail below.

[0016] The compounds according to the present invention are novel and exhibit high inhibitory activity against ENPP-1, while at the same time activating the STING pathway, and therefore may be effectively used in the treatment, prevention and alleviation of diseases caused by abnormal cell proliferation mediated by ENPP-1, such as cancer.

[0017] In certain aspects, the present invention provides compounds having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof:

[0018] [ka] (In the formula, Each R 1 is independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, amino, amido, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, or sulfonamido; A is aryl, heteroaryl, or heterocyclyl; Y is CH, CR 1 , or N, R 2 is aralkyl, heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl; n is 0, 1, 2, 3, or 4.

[0019] 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).

[0020] In certain preferred embodiments, Y is CH. In other embodiments, Y is N.

[0021] In certain embodiments, the compound has a structure represented by Formula Ia, or a pharmaceutically acceptable salt thereof:

[0022] [ka] (In the formula, X 1 is CR 3 or N, X 2 is CR 4 or N, X 3 is CR 5 or N, X 4 is CR 6 or N, R 3 , R 4 , R 5 , and R 6 are each independently selected from H, alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, amino, amido, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, and sulfonamido.

[0023] In certain preferred embodiments, X 1 is N. In other embodiments, X 1 is CR 3 is.

[0024] In certain embodiments, X 1 is N. In other embodiments, X 1 is CR 3 is.

[0025] In certain embodiments, X 2 is N. In other embodiments, X2 is CR 4 is.

[0026] In certain embodiments, X 3 is N. In other embodiments, X 3 is CR 5 is.

[0027] In certain embodiments, X 4 is N. In other embodiments, X 4 is CR 6 is.

[0028] In certain embodiments, R 3 is H.

[0029] In certain preferred embodiments, R 4 is H.

[0030] In certain preferred embodiments, R 5 is H.

[0031] In certain preferred embodiments, R 6 is H.

[0032] In certain embodiments, n is 1. In other embodiments, n is 2.

[0033] In certain embodiments, the compound has a structure represented by Formula Ib, or a pharmaceutically acceptable salt thereof:

[0034] [ka]

[0035] In certain embodiments, the compound has a structure represented by Formula Ic, or a pharmaceutically acceptable salt thereof.

[0036] [ka]

[0037] In certain embodiments, the compound has a structure represented by Formula Id, or a pharmaceutically acceptable salt thereof.

[0038] [ka] (In the formula, R 7 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, amino, amido, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, or sulfonamido.

[0039] In certain embodiments, the compound has a structure represented by formula Ie, or a pharmaceutically acceptable salt thereof:

[0040] [ka] (In the formula, R 7 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, amino, amido, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, or sulfonamido.

[0041] In certain embodiments, the compound has a structure represented by formula If, or a pharmaceutically acceptable salt thereof.

[0042] [ka] (In the formula, R 7is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, amino, amido, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, or sulfonamido.

[0043] In certain preferred embodiments, R 2 is benzyl, preferably substituted by iminosulfanonyl (e.g., (imino)(methyl)sulfanonyl).

[0044] In certain embodiments, the compound has a structure represented by Formula IIa, or a pharmaceutically acceptable salt thereof:

[0045] [ka] (In the formula, Each R 8 is independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, amino, amido, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, or sulfonamido; R 9 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, phosphoramidityl, phosphoramidatyl, amino, amido, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, sulfonamido, iminosulfanonyl, or sulfamidyl; y is 1, 2, 3, or 4.

[0046] In certain embodiments, the compound has a structure represented by Formula IIb, or a pharmaceutically acceptable salt thereof:

[0047] [ka] (In the formula, Each R 8 is independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, amino, amido, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, or sulfonamido; R 9 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, phosphoramidityl, phosphoramidatyl, amino, amido, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, sulfonamido, iminosulfanonyl, or sulfamidyl; y is 1, 2, 3, or 4.

[0048] In certain embodiments, the compound has a structure represented by Formula IIc, or a pharmaceutically acceptable salt thereof:

[0049] [ka] (In the formula, R 7 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, amino, amido, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, or sulfonamido; Each R 8 is independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, amino, amido, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, or sulfonamido; R 9 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, phosphoramidityl, phosphoramidatyl, amino, amido, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, sulfonamido, iminosulfanonyl, or sulfamidyl; y is 1, 2, 3, or 4.

[0050] In certain embodiments, the compound has a structure represented by Formula IId, or a pharmaceutically acceptable salt thereof:

[0051] [ka] (In the formula, R 7 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, amino, amido, cyano, nitro, azido, cycloalkyl, heterocycle, alkylsulfoxidyl, alkylsulfonyl, or sulfonamido; Each R 8is independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, amino, amido, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, or sulfonamido; R 9 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, phosphoramidityl, phosphoramidatyl, amino, amido, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, sulfonamido, iminosulfanonyl, or sulfamidyl; y is 1, 2, 3, or 4.

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

[0053] [ka] (In the formula, R 7 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, amino, amido, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, or sulfonamido; Each R 8is independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, amino, amido, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, or sulfonamido; R 9 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, phosphoramidityl, phosphoramidatyl, amino, amido, cyano, nitro, azido, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, sulfonamido, iminosulfanonyl, or sulfamidyl; y is 0, 1, 2, 3, or 4.

[0054] In certain embodiments, R 1 is alkyl (e.g., methyl). In certain preferred embodiments, R 1 is alkoxy (e.g., methoxy, trifluoromethoxy, or ethoxy, preferably methoxy). In certain embodiments, R 1 is halo (eg, fluoro or chloro).

[0055] In certain embodiments, R 7 is alkyl (e.g., methyl). In certain embodiments, R 7 is alkoxy (e.g., methoxy). In certain embodiments, R 7 is halo (eg, fluoro or chloro).

[0056] In certain embodiments, y is 0. In other embodiments, y is 1.

[0057] In certain embodiments, R 8 is halo (e.g., fluoro or chloro). In certain embodiments, R8 is alkyl (e.g., methyl or trifluoromethyl). In certain embodiments, R 8 is alkoxy (e.g., methoxy).

[0058] In certain preferred embodiments, R 9 is iminosulfanonyl (e.g., (imino)(methyl)sulfanonyl, (imino)(ethyl)sulfanonyl, (imino)(benzyl)sulfanonyl, or (imino)(cyclopropyl)sulfanonyl). In other embodiments, R 9 is a sulfonamide (e.g., methylsulfonamide). In yet other embodiments, R 9 is phosphoryl. In yet another embodiment, R 9 is alkyl (e.g., phosphorylalkyl, such as phosphorylmethyl or phosphoryldifluoromethyl). In yet other embodiments, R 9 is phosphoramidityl. In yet another embodiment, R 9 is phosphoramidatyl.

[0059] In certain embodiments, R 11 teeth,

[0060] [ka] is.

[0061] In certain embodiments, the compound is

[0062] [ka] TIFF2025525335000016.tif222159TIFF2025525335000017.tif246158TIFF2025525335000018.tif224158TIFF2025525335000019.tif238158TIFF2025525335000020.tif195158, or a pharmaceutically acceptable salt thereof.

[0063] Many of the compounds useful in the methods and compositions of the invention, such as those described above, have at least one stereocenter in their structure (e.g., due to the presence of an unshared electron pair on a sulfur atom). This stereocenter may exist in the R or S configuration, and the R and S designations are used according to the rules set forth in Pure Appl. Chem. (1976), 45, 11-30. The invention contemplates all stereoisomers, e.g., enantiomeric and diastereomeric forms of the compounds, their salts, prodrugs, or mixtures, including all possible mixtures of stereoisomers. See, e.g., WO 01 / 062726.

[0064] In another embodiment, 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:

[0065] [ka] (In the formula, 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 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 each independently represent CR or N; R is hydrogen, a hydroxy group, a halogen group, a C1-10 alkyl group, a C1-10 alkoxy group, a C6-20 aryl group, a C3-20 heteroaryl group, a C3-10 cycloalkyl group, a C3-10 heterocycloalkyl group, an amino group, a nitro group, an amide group, a carboxylic acid group, a nitrile group, a urea group, or a sulfonamide group; L1 is a C1-10 alkylene group or a C2-10 alkenylene group, Z is

[0066] [ka] is represented by R1 is O or NR5; R2 is hydrogen, a hydroxy group, a cyano group, a C1-C10 alkyl group, a C1-10 alkoxy group, a C6-C12 aryl group, a C3-C10 cycloalkyl group, a C2-C12 heterocycloalkyl group, -C(=O)OR6, or -NR8R9; L 21 , L 22 and L3 each independently represent a single bond, a substituted or unsubstituted C1 to C5 alkylene group, or -NR7-; R3 to R7 are each independently hydrogen or a C1 to C5 alkyl group; R8 and R9 are each independently hydrogen, -C(=O)R 10 (However, R 10 is a C1-C5 alkyl group), or -Boc (tert-butoxycarbonyl), * is the point of attachment to A2 in Formula 1.)

[0067] In certain embodiments, the compounds represented by formula 1 according to the present invention exhibit very high inhibitory activity against ENPP-1 and simultaneously activate the STING pathway, and thus can be used for the treatment, prevention and alleviation of cancer caused by abnormal cell proliferation mediated by ENPP-1.

[0068] In a compound according to one embodiment of the present invention, A1 in the above formula 1 may be represented by the following formula 2 or formula 3:

[0069] [ka] (In the formula, Y 11 From Y 14 are each independently CR a or N, R arepresents hydrogen, a hydroxy group, a halogen group, a C1-10 alkyl group, a C1-10 alkoxy group, a C6-20 aryl group, a C3-20 heteroaryl group, a C3-10 cycloalkyl group, a C3-10 heterocycloalkyl group, an amino group, a nitro group, an amide group, a carboxylic acid group, a nitrile group, a urea group, or a sulfonamide group; * denotes the points where A1 is attached to each of the two adjacent carbon atoms on the fused ring to which A1 is attached.) and

[0070] [ka] (In the formula, Y 21 From Y 24 are each independently CR b R c , —C(═O)—, or NR d and R b From R d each independently represents a hydrogen atom, a hydroxy group, a halogen group, a C1-10 alkyl group, a C1-10 alkoxy group, a C6-20 aryl group, a C3-20 heteroaryl group, a C3-10 cycloalkyl group, a C3-10 heterocycloalkyl group, an amino group, a nitro group, an amide group, a carboxylic acid group, a nitrile group, a urea group, or a sulfonamide group; * indicates the points where A1 is attached to each of the two adjacent carbon atoms on the fused ring to which it is attached.)

[0071] In a compound according to one embodiment of the present invention, A1 in Formula 1 can 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; 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; X1 to X4 can each independently be CR or N; R may be hydrogen, a hydroxy group, a halogen group, a C1-10 alkyl group, a C1-10 alkoxy group, a C6-10 aryl group, a C3-10 heteroaryl group, a C3-10 cycloalkyl group, a C3-10 heterocycloalkyl group, an amino group, a nitro group, an amide group, a carboxylic acid group, a nitrile group, a urea group, or a sulfonamide group; L1 can be a C1-10 alkylene group.

[0072] In a compound according to one embodiment of the present invention, A1 in Formula 1 can 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; 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; X1 to X4 can each independently be CR or N; R can be hydrogen, a halogen group, a C1-2 alkyl group, or a C1-2 alkoxy group; L1 can be a C1-2 alkylene group.

[0073] In the compound according to one embodiment of the present invention, preferably, Y in formula 2 above is 11 From Y 14 are each independently CR a or N, R a can be hydrogen, a hydroxy group, a C1-10 alkyl group, or a C1-10 alkoxy group.

[0074] In the compound according to one embodiment of the present invention, preferably, Y in formula 3 above is 21 From Y 24 are each independently CR b R c , —C(═O)—, or NR d R b From R dmay each independently be hydrogen, a hydroxy group, a C1-10 alkyl group, or a C1-10 alkoxy group.

[0075] In a compound according to one embodiment of the present invention, A1 in the compound represented by the above formula 1 may be selected from the following structures:

[0076] [ka] (However, * and ** in the above structure respectively indicate the points of attachment to the two adjacent carbon atoms on the fused ring to which A1 is attached in the compound represented by formula 1.)

[0077] In a compound according to one embodiment of the present invention, A2 in the compound represented by the above formula 1 may be selected from the following structures:

[0078] [ka] (However, * and ** in the above structure indicate the points of attachment to L1 and Z in the compound represented by formula 1, respectively.)

[0079] In a compound according to one embodiment of the present invention, Z in the compound represented by formula 1 above may be selected from the following structures:

[0080] [ka] TIFF2025525335000028.tif30162 (where * denotes the point of attachment to A2 in Formula 1.)

[0081] Representative compounds of Formula 1 according to the present invention may include, but are not limited to, the following compounds:

[0082] [ka] TIFF2025525335000030.tif248160TIFF2025525335000031.tif223161TIFF20255253350 00032.tif233161TIFF2025525335000033.tif228161TIFF2025525335000034.tif107160

[0083] Salts, e.g., pharmaceutically acceptable salts, of the compounds referred to herein are provided. The invention also includes some or all of the stereochemical forms, including any enantiomeric or diastereomeric forms and any tautomeric or other forms, of the compounds described.

[0084] In certain embodiments, the compounds presented herein may exist as salts even if the salt is not shown, and may include all salts and solvates of the compounds presented, as well as non-salt and non-solvate forms of the compounds.

[0085] Where tautomeric forms may exist for any compound described herein, each and every tautomeric form, even if explicitly shown, is intended to be one or some of those tautomeric forms. A specifically shown tautomeric form may or may not be the form that predominates in solution when used in accordance with the methods described herein.

[0086] The novel compounds according to one embodiment of the present invention may have asymmetric carbon centers and may exist in the form of racemates or individual optical isomers. Of course, any form of isomers, including these optical isomers, may belong to the category of the compound according to one embodiment. As used herein, the term "isomer" may collectively refer to various compounds having the same molecular formula, and "optical isomer" may collectively refer to all stereoisomers, including the same geometric isomer, that may exist in a compound according to one embodiment.

[0087] It will be understood that in a compound represented by Formula 1 according to one embodiment of the present invention, each substituent may be bonded to a chiral center of a carbon atom. Furthermore, any asymmetric carbon atom on a compound according to one embodiment may be present in any of the (R)-, (S)-, or (R,S)-configurations, and each may suitably be present in either the (R)- or (S)-configuration in its separate forms. Furthermore, a compound according to one embodiment may exist in any of its possible isomeric or mixture forms, such as its pure geometric isomers, diastereomers, optical isomers, racemates, or mixtures. Furthermore, when a compound according to one embodiment contains a double bond, each substituent bonded to the double bond may be in the E- or Z-configuration. Furthermore, when a compound according to one embodiment contains a disubstituted cycloalkyl, each substituent on the cycloalkyl may have a cis- or trans-configuration.

[0088] Solvates and / or polymorphs of the compounds provided herein or pharmaceutically acceptable salts thereof are also contemplated. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are often formed during the crystallization process. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include various crystal packing arrangements of compounds with 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. Various factors, such as the recrystallization solvent, the rate of crystallization, and the storage temperature, may result in the predominance of a single crystalline form.

[0089] In another aspect, the present invention provides a pharmaceutical composition for preventing, alleviating, or treating cancer, comprising a compound represented by formula 1 according to the present invention, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0090] The pharmaceutical composition according to the present invention can be used to inhibit the activity of ENPP-1 in the body. Therefore, the pharmaceutical composition according to the present invention can be used for the purpose of treating, preventing, and alleviating cancer diseases, including, but 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, etc. Any cancer disease caused by abnormal cell proliferation can be prevented, treated, or alleviated by treatment with the pharmaceutical composition according to the present invention.

[0091] In another aspect, the present invention provides an ENPP-1 inhibitor comprising a compound represented by formula 1 according to the present invention, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0092] 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 can be appropriately adjusted by a person skilled in the art depending on the mode and method of using the pharmaceutical composition according to the present invention.

[0093] For example, the pharmaceutical composition according to the present invention contains 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 entire composition.

[0094] The compound represented by the above formula 1, its hydrate, its solvate, its isomer or its pharmaceutically acceptable salt may be contained alone in the pharmaceutical composition, or may be contained in combination with other pharmacologically acceptable carriers, excipients, diluents or auxiliary ingredients.

[0095] Examples of the pharmacologically acceptable carrier, excipient, or diluent may be one or more selected from the group consisting of, but not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, crystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, propylhydroxybenzoate, 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. Additionally, the pharmaceutical composition may further include conventional fillers, extenders, binders, disintegrants, anticoagulants, lubricants, humectants, pH adjusters, nutrients, vitamins, electrolytes, alginic acid and its salts, pectinic acid and its salts, protective colloids, glycerin, flavorings, emulsifiers, preservatives, etc.

[0096] The compound represented by formula 1 according to the present invention, its hydrate, solvate, isomer or pharmaceutically acceptable salt thereof may be administered together with other anticancer agents for treating cancer or tumors to enhance the therapeutic effect of the anticancer agent.

[0097] The pharmaceutical composition may be administered orally or parenterally, and may be administered via various routes, including, for example, oral, transdermal, subcutaneous, intravenous, or intramuscular routes. Furthermore, the formulation of the composition may vary depending on the method of use and may be formulated using methods well known in the art to provide immediate, sustained, or delayed release of the active ingredient after administration to a mammal. Solid formulations for oral administration generally include tablets, troches, soft or hard capsules, pills, powders, granules, etc., and such formulations may be prepared by mixing one or more excipients, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to basic excipients, lubricants, such as magnesium stearate and talc, may also be used. Liquid formulations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and may contain various excipients, such as wetting agents, sweeteners, flavorings, preservatives, etc., in addition to commonly used basic diluents, such as water and liquid paraffin. Forms for parenteral administration may be in the form of creams, lotions, ointments, plasters, external solutions and solutions, aerosols, liquid extracts, elixirs, infusions, sachets, patches, injections, etc., and in the case of injection preparations, they may preferably be in the form of an isotonic aqueous solution or suspension.

[0098] Moreover, the pharmaceutical compositions may further contain adjuvants, such as bactericides, preservatives, stabilizers, wetting or emulsifying agents, salts and / or buffers to control osmotic pressure, and other therapeutically valuable substances, and may be formulated according to conventional mixing, granulating or coating methods, or may be formulated using any suitable method known in the art.

[0099] Additionally, the present invention provides a method for preparing the compounds represented by formula 1 above.

[0100] Pharmaceutical Composition The compositions and methods of the present invention can be used to treat individuals in need of treatment. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or compound is preferably administered as a pharmaceutical composition, e.g., comprising a compound of the present invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include aqueous solutions, such as water or physiologically buffered saline, or other solvents or vehicles, such as glycols, glycerol, oils, e.g., olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are intended for administration to humans, particularly for invasive administration routes (i.e., routes such as injections or implants that avoid transport or diffusion across epithelial barriers), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to affect delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical compositions can be in dosage unit form, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilic compounds for reconstitution, powders, liquids, syrups, suppositories, injections, etc. The compositions can also be present in transdermal delivery systems, such as skin patches. The compositions can also be present in liquids suitable for topical administration, such as lotions, creams, or ointments.

[0101] Pharmaceutically acceptable carriers can contain physiologically acceptable agents that act to stabilize, increase the solubility, or enhance the absorption of compounds such as the compounds of the present invention. Such physiologically acceptable agents include carbohydrates such as glucose, sucrose, or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low-molecular-weight proteins, or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier containing a physiologically acceptable agent depends, for example, on the route of administration of the composition. The pharmaceutical or pharmaceutical composition can be a self-emulsifying or self-microemulsifying drug delivery system. The pharmaceutical composition (pharmaceutical) can also be, for example, a liposome or other polymer matrix into which the compounds of the present invention can be incorporated. Liposomes, for example, containing phospholipids or other lipids, are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively simple to prepare and administer.

[0102] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0103] As used herein, the phrase "pharmaceutically acceptable carrier" refers to 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 non-toxic to the patient. Some examples of materials that can function 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, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol, (11) polyols such as glycerin, 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) ethyl alcohol, (20) phosphate buffer, and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0104] Pharmaceutical compositions (formulations) can be administered to a subject by any of a number of routes of administration, including, for example, oral (e.g., solutions or suspensions such as aqueous or non-aqueous solutions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue), absorption through the oral mucosa (e.g., sublingually), subcutaneous, transdermal (e.g., as a patch applied to the skin), and topical (e.g., as a cream, ointment, or spray applied to the skin). The compounds may also be formulated for inhalation. In certain embodiments, the compounds may simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in 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 the patents cited therein.

[0105] The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending on the host treated and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of compound which produces a therapeutic effect. Generally, this amount will range from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%, of one hundred percent.

[0106] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the present invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0107] Formulations of the present invention suitable for oral administration may be presented in the form of capsules (including sprinkle capsules and gelatin capsules), cashews, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophilic compounds, 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 lozenges (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, etc., each containing a predetermined amount of a compound of the present invention as an active ingredient. The composition or compound may also be administered as a bolus, electuary, or paste.

[0108] To prepare solid dosage forms for oral administration (such as capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient may be mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) sorbents, such as agar, calcium carbonate, potato starch, or the like; The pharmaceutical composition may be mixed with any of the following: (1) disintegrating agents such as starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (2) dissolution retarders such as paraffin; (3) absorption accelerators such as quaternary ammonium compounds; (4) wetting agents such as cetyl alcohol and glycerol monostearate; (5) absorbents such as kaolin and bentonite clay; (6) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; (7) complexing agents such as modified and unmodified cyclodextrins; and (8) coloring agents. For capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical composition may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0109] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0110] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, may optionally be scored and may be provided with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to provide sustained or controlled release of the active ingredient(s), for example, using hydroxypropyl methylcellulose in various proportions to impart the desired release characteristics, other polymer matrices, liposomes, and / or microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be composed to release the active ingredient(s) only, or preferentially, in a certain part of the gastrointestinal tract, or in some case, delayed release. Examples of implantable compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0111] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophilic compounds 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 art, such as water or other solvents, cyclodextrin and its derivatives, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof.

[0112] 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.

[0113] Suspensions may contain, in addition to the active compound, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0114] 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, as may be required.

[0115] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicon, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0116] Powders and sprays can 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 can also contain commonly used propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0117] Transdermal patches have the additional advantage of controlled delivery of the compounds of the present invention to the body. Such dosage forms 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 across the skin. The rate of such flux can be controlled by either providing a rate-limiting membrane or dispersing the compound in a polymer matrix or gel.

[0118] As used herein, the phrases "parenteral administration" and "parenterally administered" refer to modes of administration other than enteral administration and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intradural, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intrathecal, and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration contain one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted with a sterile injectable solution or dispersion immediately before use, and may contain antioxidants, buffers, bacteriostats, solutes or suspending agents or thickeners that render the formulation isotonic with the blood of the intended recipient.

[0119] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0120] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like, in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.

[0121] In some cases, to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of drug absorption also depends on the rate of dissolution, which may in turn depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0122] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0123] For use in the methods of the present invention, the active compound may be provided per se or as a pharmaceutical composition comprising, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0124] Delivery methods can also be provided by rechargeable or biodegradable devices. A variety of sustained-release polymeric devices, including proteinaceous biopharmaceuticals, have been developed and recently tested in vivo for controlled drug delivery. A wide variety of biocompatible polymers, including hydrogels, including both biodegradable and non-degradable polymers, can be used to form implants for the sustained release of compounds at specific target sites.

[0125] Actual dosage levels of the active ingredient in the pharmaceutical compositions may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response in a particular patient, composition, and method of administration without toxicity to the patient.

[0126] The selected dosage level will depend on a wide variety of factors, including the activity of the particular compound or combination of compounds or their esters, salts, or amides used, the route of administration, the time of administration, the rate of excretion of the particular compound(s) used, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound(s) used, the age, sex, weight, condition, general health, and medical history of the patient being treated, as well as factors well known in the medical arts.

[0127] A physician or veterinarian skilled in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start with a lower dose of the pharmaceutical composition or compound than is necessary to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. A "therapeutically effective amount" refers to a concentration of the compound sufficient to induce the desired therapeutic effect. It is generally understood that the effective amount of a compound varies depending on the subject's weight, sex, age, and medical history. Other factors that affect the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if necessary, other therapeutic agents administered together with the compound of the present invention. Multiple drug administrations can deliver a larger total dose. 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 ed., pp. 1814-1882, incorporated herein by reference).

[0128] Generally, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective amount will generally depend upon the factors described above.

[0129] If necessary, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate time intervals throughout the day, optionally in unit dosage forms. In certain embodiments of the invention, the active compound may be administered two or three times a day. In a preferred embodiment, the active compound is administered once a day.

[0130] Patients for this treatment may be any animal in need of treatment, including primates, particularly humans, as well as other mammals such as horses, cows, pigs, sheep, cats and dogs, poultry, and pets in general.

[0131] In certain embodiments, the compounds of the present invention may be used alone or may be administered together with other types of therapeutic agents.

[0132] The present invention encompasses 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, contemplated salts of the present invention include, but are not limited to, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, or tetraalkylammonium salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, L-arginine, benethamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.In certain embodiments, contemplated salts of the present invention include 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), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-gluconic acid, methylparaben ... These include, but are not limited to, salts of heptonic 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.

[0133] Pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates can also be prepared. The source of such solvates can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0134] Wetting agents, emulsifying agents, 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 composition.

[0135] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0136] definition Unless otherwise defined herein, scientific and technical terms used in this application have the meanings commonly understood by those of ordinary skill in the art. Generally, the nomenclature used in connection with and techniques of chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are those well known and commonly used in the art.

[0137] The methods and techniques of the present invention are generally carried out according to conventional methods known in the art and as described in various general and more specific references cited and discussed throughout this specification, unless otherwise indicated. See, e.g., "Principles of Neural Science," McGraw-Hill Medical, New York, NY (2000); Motulsky, "Intuitive Biostatistics," Oxford University Press (1995); Lodish et al., "Molecular Cell Biology, 4th ed.," W.H. Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th ed.," W.H. Freeman & Co., NY (1999); and Gilbert et al., "Developmental Biology, 6th ed.," Sinauer Associates, Inc., Sunderland, MA (2000).

[0138] Chemical terms used herein, unless otherwise defined herein, are used in accordance with conventional usage in the art, as exemplified in "The McGraw-Hill Dictionary of Chemical Terms," Parker S., ed., McGraw-Hill, San Francisco, CA (1985).

[0139] All of the above, and any other publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, the present specification, including specific definitions, will control.

[0140] The term "agent" is used herein to refer to a chemical compound (e.g., an organic or inorganic compound, a mixture of compounds), a biological macromolecule (e.g., a nucleic acid, an antibody, a portion thereof, including humanized, chimeric, and human antibodies, and monoclonal antibodies, a protein or portion thereof, such as a peptide, lipid, carbohydrate, etc.), or an extract made from biological material such as a bacterial, plant, fungal, or animal (e.g., mammalian) cell or tissue. Agents include, for example, agents with known structure and agents with unknown structure. The ability of such agents to inhibit AR or promote AR degradation may make them suitable as "therapeutic agents" in the methods and compositions of the invention.

[0141] The terms "patient," "subject," or "individual" are used interchangeably and refer to either a human or non-human animal. These terms include humans, mammals such as primates, livestock animals (including cows, pigs, etc.), companion animals (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats).

[0142] "Treating" a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, attenuation of the extent of the disease, stabilization (i.e., not worsening) of the disease state, prevention of the spread of the disease, delay or slowing of the progression of the disease, improvement or remission of the disease state, and sedation (whether partial or total). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0143] The term "preventing," when used in connection with a condition, e.g., local recurrence (e.g., pain), a disease such as cancer, a complex syndrome such as heart failure, or any other medical condition, is art-recognized and well understood in the art and includes administration of a composition that reduces the frequency of symptoms of, or delays the onset of, a medical condition in a subject compared to subjects who do not receive the composition. Thus, preventing cancer includes reducing the number of detectable cancerous growths in a population of patients receiving prophylactic treatment, e.g., compared 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.

[0144] "Administering" a substance, compound, or agent to a subject, or "administering" a substance, compound, or agent to a subject, can be carried out using one of a wide variety of methods known to those of skill in the art. For example, the compound or agent may be administered intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intrathecally, intracerebrally, and transdermally (e.g., by absorption through the skin tract). The compound or agent may also be suitably introduced by rechargeable or biodegradable polymeric or other devices, such as patches and pumps, or formulations that provide sustained, sustained, or controlled release of the compound or agent. Administration may also be carried out, for example, once, multiple times, and / or over one or more extended periods of time.

[0145] Suitable methods for administering a substance, compound, or agent to a subject also depend, for example, on the age and / or physical condition of the subject and the chemical and biological properties (e.g., solubility, digestibility, bioavailability, stability, and toxicity) of the compound or agent. In certain embodiments, the compound or agent is administered to the subject orally, e.g., by ingestion. In certain embodiments, the orally administered compound or agent is in a sustained- or extended-release formulation or is administered using such a sustained- or extended-release device.

[0146] As used herein, the phrase "administering together" refers to any form of administration of two or more different therapeutic agents, such as when a second agent is administered while a previously administered therapeutic agent is still effective in the body (e.g., two agents are effective in a patient simultaneously, potentially involving a synergistic effect of the two agents). For example, different therapeutic compounds can be administered simultaneously or sequentially, either in the same formulation or in separate formulations. Thus, an individual undergoing such treatment can benefit from the combined effect of the different therapeutic agents.

[0147] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or agent is an amount of the drug or agent that has the desired therapeutic effect when administered to a subject. The full therapeutic effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount required for a subject will depend, for example, on the subject's size, health, and age, and the nature and extent of the condition, such as cancer or MDS, being treated. A skilled worker can readily determine the effective amount for a given situation by routine experimentation.

[0148] As used herein, the term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances in which the event or circumstance does not occur as well as instances in which the event or circumstance does occur. For example, "optionally substituted alkyl" refers to alkyl that is unsubstituted as well as alkyl that is substituted.

[0149] It is understood that the substituents and substitution patterns in the compounds of the present invention can be selected by one skilled in the art to result in chemically stable compounds that can be readily synthesized from readily available starting materials using techniques known in the art and the methods described below. When a substituent is itself substituted with multiple groups, it is understood that these multiple groups may be located on the same carbon or on different carbons, as long as a stable structure results.

[0150] As used herein, the term "optionally substituted" refers to the replacement of 1 to 6 hydrogen radicals in a given structure with a specified substituent group, including, but not limited to, hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH-O-alkyl, -OP(O)(O-alkyl) or -CH-OP(O)(O-alkyl). Preferably, "optionally substituted" refers to the replacement of 1 to 4 hydrogen radicals in a given structure with the aforementioned substituents. More preferably, 1 to 3 hydrogen radicals are replaced by the aforementioned substituents. It is understood that the substituents may be further substituted.

[0151] As used herein, "alkyl" refers to a straight-chain or branched-chain aliphatic saturated hydrocarbon group, preferably an alkyl having 1 to 6 carbon atoms, more preferably an alkyl having 1 to 4 carbon atoms. Examples of such alkyls 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. An "alkyl" group can be optionally substituted. Furthermore, as used throughout the specification, examples, and claims, the term "alkyl" is intended to include both unsubstituted and substituted alkyl groups, the latter referring to alkyl moieties having substituents replacing a hydrogen on one or more carbon atoms of the hydrocarbon backbone, including haloalkyl groups, such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0152] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0153] 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 hydrocarbylC(O)NH-.

[0154] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0155] The term "alkoxy" refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0156] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and can be represented by the general formula alkyl-O-alkyl.

[0157] The term “C x~y " or "C x ~C y " when used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups containing x to y carbons in the chain. CO alkyl refers to hydrogen when the group is in a terminal position and to a bond when it is internal. For example, C 1~6 Alkyl groups contain 1 to 6 carbon atoms in the chain.

[0158] The term "alkylamino," as used herein, refers to an amino group substituted with at least one alkyl group.

[0159] 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-.

[0160] The term "amide," as used herein, refers to the following group:

[0161] [ka] (In the formula, R 9 and R 10 each independently represents hydrogen or a hydrocarbyl group, or R 9 and R 10 Together with the N atom to which they are attached, complete a heterocycle having 4 to 8 atoms in the ring structure.

[0162] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, such as a moiety that can be represented by:

[0163] [ka] (In the formula, R 9 , R 10 , and R 10' each independently represent hydrogen or a hydrocarbyl group, or R 9 and R 10 Together with the N atom to which they are attached, complete a heterocycle having 4 to 8 atoms in the ring structure.

[0164] The term "aminoalkyl," as used herein, refers to an alkyl group substituted with an amino group.

[0165] As used herein, "aryl" refers to a carbocyclic aromatic group that can be further fused with a second 5- or 6-membered carbocyclic group, which can be aromatic, saturated, or unsaturated. Examples of aryl include, but are not limited to, phenyl, indanyl, 1-naphthyl, 2-naphthyl, tetrahydronaphthyl, and the like. The aryl can be bonded to other groups at any suitable position on the aromatic ring. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0166] The term "carbamate" is art-recognized and refers to the following group:

[0167] [ka] (In the formula, R 9 and R 10 each independently represents hydrogen or a hydrocarbyl group.

[0168] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocyclic group.

[0169] The term "carbocycle" includes 5- to 7-membered monocyclic rings and 8- to 12-membered bicyclic rings. Each ring in a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. Carbocycles include bicyclic rings in which one, two, or three or more atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each ring shares two adjacent atoms with the other ring. Each ring in a fused carbocycle can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. All combinations of saturated, unsaturated, and aromatic bicyclic rings, valence permitting, are included in the definition of carbocycle. Representative "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. Representative fused carbocycles include decalin, 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. A "carbocycle" can be substituted at any one or more positions that can have a hydrogen atom.

[0170] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocyclic group.

[0171] The term "carbonate" is art-recognized and refers to the group -OCO2-.

[0172] The term "carboxy," as used herein, refers to a group represented by the formula --CO.sub.2H.

[0173] The term "cycloalkyl" includes substituted or unsubstituted non-aromatic single ring structures, preferably 4-8 membered rings, more preferably 4-6 membered rings. The term "cycloalkyl" also includes polycyclic ring systems having two or more cyclic rings, in which two or more carbons are common to two adjacent rings (wherein at least one of the rings is cycloalkyl and no substituents (e.g., R 100 ) is attached to a cycloalkyl ring, e.g., the other cyclic ring can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, benzodioxane, tetrahydroquinoline, and the like.

[0174] The term "ester," as used herein, refers to a group -C(O)OR 9 (wherein R 9 represents a hydrocarbyl group).

[0175] The term "ether," as used herein, refers to a hydrocarbyl group linked to another hydrocarbyl group via an oxygen atom. Thus, an ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers can be either symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which can be represented by the general formula alkyl-O-alkyl.

[0176] As used herein, the terms "halo" and "halogen" mean halogen and include chloro, fluoro, bromo, and iodo.

[0177] The terms "hetarylalkyl" and "heteroaralkyl," as used herein, refer to an alkyl group substituted with a hetaryl group.

[0178] As used herein, "heteroaryl," unless otherwise specified, refers to a heteroaromatic compound containing at least one heteroatom selected from the group consisting of N, O, and S; preferably, heteroaryl groups may include, but are not limited to, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, imidazole, triazole, indole, oxadiazole, thiadiazole, quinoline, isoquinoline, isoxazole, oxazole, thiazole, and pyrrole groups. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings, in which two or more carbons are common to two adjacent rings (wherein at least one of the rings is heteroaromatic, e.g., the other cyclic ring may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl). Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

[0179] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0180] The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with a heterocycle group.

[0181] As used herein, the term "heterocycle" refers to an aromatic or non-aromatic ring containing a heteroatom other than carbon atoms selected from nitrogen, sulfur, and oxygen atoms as a ring member, and preferably includes a 4- to 10-membered, more preferably a 5- to 9-membered, aromatic or non-aromatic ring containing 1 to 4 of the above heteroatoms. Examples of such aromatic rings include thienyl, furyl, 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. Further examples of such non-aromatic rings include tetrahydrothienyl, 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 azepinyl. The terms "heterocyclyl" and "heterocycle" also include polycyclic ring systems having two or more cyclic rings, in which two or more carbons are common to two adjacent rings (wherein at least one of the rings is a heterocycle, e.g., the other cyclic ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl).

[0182] As used herein, "arylene" and "heteroarylene" refer to divalent radicals of aromatic and heteroaromatic rings.

[0183] The term "hydrocarbyl," as used herein, refers to a group that does not have =0 or =5 substituents, typically has at least one carbon-hydrogen bond, and a primarily carbon backbone, but may optionally contain heteroatoms, bonded through carbon atoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbyl for purposes of this application, while substituents such as acetyl (which has an =0 substituent on the bonded carbon) and ethoxy (which is bonded through an oxygen rather than a carbon) are not. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, alkynyl, and combinations thereof.

[0184] The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with a hydroxy group.

[0185] The term "lower," when used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups having 10 or fewer, preferably 6 or fewer atoms in the substituent. "Lower alkyl," for example, refers to alkyl groups containing 10 or fewer, preferably 6 or fewer, carbon atoms. In certain embodiments, an acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituent defined herein, whether occurring alone or in combination with other substituents such as the recited hydroxyalkyl and aralkyl (in which case, for example, atoms in an aryl group are not counted when counting carbon atoms in an alkyl substituent), is lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively.

[0186] The term "phosphoryl" is art-recognized and refers to a group that may be represented by the general formula:

[0187] [ka] (In the formula, R9 and R 10 each independently represents a negative charge, hydrogen, or hydrocarbyl.

[0188] The term "phosphoramidityl" is art-recognized and refers to a group that may be represented by the general formula:

[0189] [ka] (In the formula, R 9 represents a negative charge, hydrogen, or hydrocarbyl, and each R 10 independently represent hydrogen or hydrocarbyl.

[0190] The term "phosphoramidatyl" is art-recognized and refers to a group that may be represented by the general formula:

[0191] [ka] (In the formula, each R 9 and R 10 independently represent hydrogen or hydrocarbyl.

[0192] The terms "polycyclyl," "polycycle," 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 of the rings of a polycycle can be substituted or unsubstituted. In certain embodiments, each ring of a polycycle contains 3 to 10, preferably 5 to 7, atoms in the ring.

[0193] The term "sulfate" is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0194] The term "sulfonamide" is art-recognized and refers to a group that may be represented by the general formula:

[0195] [ka] (In the formula, each R 9 and R 10 independently represent hydrogen or hydrocarbyl.

[0196] The term "sulfoxide" is art-recognized and refers to the group --S(O)--.

[0197] The term "sulfonate" is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

[0198] The term "sulfone" is art-recognized and refers to the group -S(O)2-.

[0199] The term "iminosulfanonyl" is art-recognized and refers to a group that may be represented by the general formula:

[0200] [ka] (In the formula, R 9 and R 10 each independently represents hydrogen or hydrocarbyl.

[0201] 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 thiocarbamoyl groups, substituted or unsubstituted sulfamoyl groups, substituted or unsubstituted hydroxy groups, substituted or unsubstituted sulfonyl (SH) groups, and substituted or unsubstituted silyl groups.

[0202] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more backbone carbons. It is understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the allowed valencies of the substituted atom and substituent, and that the substitution results in a stable compound that does not spontaneously undergo transformation, e.g., by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituent of organic compounds described herein that satisfy the valence of the heteroatom. Substituents can include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

[0203] The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group.

[0204] The term "thioester," as used herein, refers to the group -C(O)SR 9 or -SC(O)R 9 (wherein R 9 represents hydrocarbyl).

[0205] The term "thioether," as used herein, is equivalent to an ether, where the oxygen is replaced with a sulfur.

[0206] The term "urea" is art recognized and may be represented by the general formula:

[0207] [ka] (In the formula, R 9 and R 10 each independently represents hydrogen or hydrocarbyl.

[0208] As used herein, the term "modulate" includes inhibiting or suppressing a function or activity (eg, cell proliferation) as well as enhancing a function or activity.

[0209] As used herein, the term "pharmaceutically acceptable salt" according to the present invention may collectively refer to salts that equally retain the biological effects and properties of the compounds disclosed herein according to one embodiment and are preferable in terms of pharmaceutical, biological, or other properties. Non-limiting examples of these salts may be salts in which an inorganic or organic base is added to the compounds disclosed herein, or acid addition salts. Examples of organic acids that can form such acid addition salts may 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, etc., and examples of inorganic acids may be hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.

[0210] As used herein, the term "pharmaceutically acceptable acid addition salt" refers to any non-toxic organic or inorganic salt of any base compound represented by Formula I. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as metal salts such as sodium hydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include monocarboxylic, dicarboxylic, 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. Either mono- or di-acid salts can be formed, and such salts may exist in either hydrated, solvated, or substantially anhydrous form. Generally, acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base forms. The selection of an appropriate salt is known to those skilled in the art. Other pharmaceutically unacceptable salts, such as oxalates, may be used, for example, for laboratory use or in the isolation of compounds of formula I for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0211] As used herein, the term "pharmaceutically acceptable base addition salt" refers to any non-toxic organic or inorganic base addition salt of any acid compound represented by Formula I, or any of their intermediates. Exemplary inorganic bases which form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide. Exemplary organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine, and picoline, or ammonia. The selection of appropriate salts is within the skill of the art.

[0212] A "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 present invention (e.g., a compound of Formula I). Typical examples of prodrugs include compounds that have a biologically labile or cleavable (protecting) group at a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to generate the active compound. Examples of prodrugs that use esters or phosphoramidates as the biologically labile or cleavable (protecting) group are described in U.S. Pat. Nos. 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of the present invention are metabolized to generate a compound 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", H. Bundgaard (ed.), Elsevier, 1985.

[0213] 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, useful in formulating a drug for pharmaceutical or therapeutic use.

[0214] As used herein, the terms "logarithm of solubility," "LogS," or "logS" are used in the art to quantify the aqueous solubility of a compound. The aqueous solubility of a compound greatly affects its absorption and distribution characteristics. Low solubility is often associated with poor absorption. The LogS value is the unit-removed logarithm (base 10) of the solubility measured in mol / liter. [Example]

[0215] The invention will now be generally described, but by reference to the following examples it will be more readily understood that these are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0216] [Example 1] Synthesis of intermediates [Preparation Example 1] Preparation of 4-(bromomethyl)benzenesulfonamide (intermediate 1)

[0217] [ka] (Step 1) Preparation of 4-(bromomethyl)benzenesulfonyl chloride

[0218] [ka] 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 α,α'-azobis(isobutyronitrile) (4.70 g, 28.8 mmol) were added to the mixture in sequence. The reaction mixture was stirred at 100°C under nitrogen for 12 hours. After cooling to room temperature, distilled water was added and the mixture was 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 as a white solid. (5.12 g, 72%) MS m / z: 267 [M+1] + (Step 2) Preparation of 4-(bromomethyl)benzenesulfonamide (intermediate 1)

[0219] [ka] The compound prepared above (Step 1) (3.30 g, 12.2 mmol) was dissolved in tetrahydrofuran (34.0 mL) and then cooled to 0°C. 28-30% aqueous ammonia solution (4.80 mL) was slowly added to the mixture. The reaction mixture was stirred under nitrogen at room temperature for 2 hours. After the reaction was completed, distilled water was added and the mixture was extracted twice with ethyl acetate. The organic layer was washed with distilled water and saturated brine 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 (400 MHz, CDCl3) δ ppm: 7.81 (d, J= 8.4 Hz, 2H), 7.63 (d, J= 8.4 Hz, 2H), 7.39 (s, 2H), 4.76 (s, 2H).

[0220] [Preparation Example 2] Preparation of tert-butyl ((4-(bromomethyl)piperidin-1-yl)sulfonyl)carbamate (Intermediate 2)

[0221] [ka] TIFF2025525335000048.tif25161 (Step 1) Preparation of tert-butyl ((4-(hydroxymethyl)piperidin-1-yl)sulfonyl)carbamate

[0222] [ka] 1-(tert-Butoxycarbonylsulfamoyl)piperidine-4-carboxylic acid (200 mg, 0.65 mmol) was dissolved in tetrahydrofuran (2.00 mL) and cooled to 0°C. Lithium aluminum hydride (36.9 mg, 0.97 mmol) was added to the mixture. This was stirred at 0°C under nitrogen for 2 hours. After the reaction was completed, a mixed solvent of methanol, 15% sodium carbonate solution, and distilled water in a ratio of 1:1:3 was added, followed by extraction 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 give the title compound as a colorless oil. (95.0 mg, 50%) MS m / z: 295 [M+1] + (Step 2) Preparation of tert-butyl ((4-(bromomethyl)piperidin-1-yl)sulfonyl)carbamate (Intermediate 2)

[0223] [ka] The compound prepared above (Step 1) (95.0 mg, 0.32 mmol) was dissolved in methylene chloride (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 under nitrogen at room temperature for 5 hours. After the reaction was completed, distilled water was slowly added to it, and the mixture was extracted twice with ethyl acetate. The organic layer was collected, washed with distilled water and saturated brine 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 as a white solid. (56.0 mg, 49%) MS m / z: 358 [M+1] + 1H NMR (400 MHz, CDCl3) δ 6.93 (s, 1H), 3.91 (d, J = 12.6 Hz, 2H), 3.31 (d, J = 6.3 Hz, 2H), 2.93 (t, J = 12.5 Hz, 2H), 1.93 (d, J = 13.2 Hz, 2H), 1.63 - 1.45 (m, 11H).

[0224] [Preparation Example 3] Preparation of tert-butyl((4-(bromomethyl)phenyl)sulfonyl)(methyl)carbamate (Intermediate 3)

[0225] [ka] (Step 1) Preparation of N,4-dimethylbenzenesulfonamide

[0226] [ka] p-Toluenesulfonyl chloride (1.50 g, 7.87 mmol) was dissolved in methylene chloride (8.00 mL) and then cooled to 0 °C. An aqueous solution of methylamine (40 wt% in HO, 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 were added, followed by extraction twice with methylene chloride. 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 give the title compound as a white solid. (1.40 g, 97%) MS m / z: 186 [M+1] + 1H NMR (400 MHz, CDCl3) δ ppm: 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). (Step 2) Preparation of tert-butyl methyl (tosyl)carbamate

[0227] [ka] The compound prepared above (Step 1) (600 mg, 3.24 mmol) was dissolved in methylene chloride (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 added slowly to the mixture, successively. The reaction mixture was stirred at room temperature under nitrogen for 16 hours. After the reaction was completed, saturated aqueous ammonium chloride solution was added, and the mixture was extracted twice with methylene chloride. 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 as a colorless liquid. (922 mg, 99%) MS m / z: 286 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 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). (Step 3) Preparation of tert-butyl((4-(bromomethyl)phenyl)sulfonyl)(methyl)carbamate (Intermediate 3)

[0228] [ka] The compound prepared above (Step 2) (920 mg, 3.22 mmol) was dissolved in carbon tetrachloride (5.00 mL), and then N-bromosuccinimide (545.1 mg, 3.06 mmol) and α,α'-azobis(isobutyronitrile) (37.1 mg, 0.23 mmol) were added to the mixture sequentially. The reaction mixture was stirred at 80°C under nitrogen for 3 hours. After cooling to room temperature, it was concentrated under reduced pressure, distilled water was added, and then extracted twice with ethyl acetate. The organic layer was washed with distilled water, 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 give the title compound as a colorless liquid. (662 mg, 56%) MS m / z: 365 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 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).

[0229] [Preparation Example 4] Preparation of tert-butyl (4-(bromomethyl)phenyl)carbamate (Intermediate 4)

[0230] [ka] (Step 1) Preparation of tert-butyl (4-(hydroxymethyl)phenyl)carbamate

[0231] [ka] 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 added slowly to the mixture, successively. The reaction mixture was stirred at room temperature under nitrogen for 24 hours. After the reaction was completed, 2N HCl (10.0 mL) was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with distilled water and saturated brine solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The title compound was obtained as a yellow liquid without further purification. (542 mg, 99%) MS m / z: 224 [M+1] + 1 H NMR (400 MHz, CDCl3) δ 7.43 - 7.15 (m, 4H), 6.48 (s, 1H), 4.63 (d, J = 2.3 Hz, 2H), 1.57 - 1.42 (m, 9H). (Step 2) Preparation of tert-butyl (4-(bromomethyl)phenyl)carbamate (Intermediate 4)

[0232] [ka] The compound prepared above (Step 1) (300 mg, 1.34 mmol) was dissolved in methylene chloride (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 under nitrogen for 5 hours. After the reaction was completed, distilled water was added and the mixture was extracted twice with ethyl acetate. The organic layer was washed with distilled water and saturated brine 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 (400 MHz, CDCl3) δ 7.36 - 7.27 (m, 4H), 6.56 (d, J = 15.4 Hz, 1H), 4.47 (s, 2H), 1.51 (s, 9H).

[0233] [Preparation Example 5] Preparation of 4-vinylbenzenesulfonamide (intermediate 5)

[0234] [ka] (Step 1) Preparation of 4-(2-bromoethyl)benzenesulfonyl chloride

[0235] [ka] (2-Bromoethyl)benzene (2.00 g, 10.8 mmol) was dissolved in anhydrous methylene chloride (10.8 mL) and then cooled to 0° C. Chlorosulfonic acid (2.20 mL, 32.4 mmol) was slowly added to the mixture. The reaction mixture was stirred under nitrogen at room temperature for 3 hours. After the reaction was completed, the reaction mixture was slowly added dropwise to ice water and then extracted twice with methylene chloride. The organic layer was collected, washed with distilled water and saturated brine 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 H NMR (400 MHz, CDCl3) δ ppm: 7.89 (d, J = 5.6 Hz, 2H), 7.36 (s, 2H), 3.55 (s, 2H), 3.21 (s, 2H). (Step 2) Preparation of 4-(2-bromoethyl)benzenesulfonamide

[0236] [ka] The compound (2.10 g) prepared above (Step 1) was dissolved in tetrahydrofuran (6.00 mL) and cooled to 0°C. 28-30% aqueous ammonia (2.00 mL) was slowly added to the mixture. The reaction mixture was stirred at room temperature under nitrogen for 2 hours. The mixture was dissolved in distilled water, and the resulting solid was filtered and dried to give the title compound as a white solid. (1.06 g, 55%) MS m / z: 265 [M+1] + 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.76 (d, J = 5.5 Hz, 2H), 7.56-7.40 (m, 2H), 7.31 (s, 2H), 3.78 (s, 2H), 3.21 (s, 2H). (Step 3) Preparation of 4-vinylbenzenesulfonamide (intermediate 5)

[0237] [ka] The compound prepared above (Step 2) (300 mg, 1.14 mmol) was dissolved in tetrahydrofuran (5.00 mL) and cooled to 0°C. Potassium tert-butoxide (1.0 M tetrahydrofuran solution, 3.3 mL, 3.40 mmol) was slowly added. The reaction mixture was stirred under nitrogen at 60°C for 3 hours. After the reaction was completed, distilled water was slowly added and the mixture was extracted twice with ethyl acetate. The organic layer was washed with distilled water and saturated brine 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 H NMR (400 MHz, CDCl3) δ ppm: 7.87 (d, J = 9.1 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H), 6.79-6.68 (m, 1H), 5.87 (d, J = 17.5 Hz, 1H), 5.43 (d, J = 9.1 Hz, 1H), 4.77 (s, 2H).

[0238] [Preparation Example 6] Preparation of 4-(bromomethyl)phenyl)(methyl)sulfane (Intermediate 6)

[0239] [ka] (4-Methylsulfanylphenyl)methanol (5.00 g, 32.4 mmol) was dissolved in methylene chloride (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 under nitrogen for 16 hours. After the reaction was completed, distilled water was slowly added, and the mixture was extracted twice with methylene chloride. 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 as a white solid. (5.40 g, 77%) MS m / z: 218 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 7.30 (d, J = 8.4 Hz, 2H), 7.2 (d, J = 8.5 Hz, 2H), 4.48 (s, 2H), 2.48 (s, 3H).

[0240] [Preparation Example 7] Preparation of (4-(bromomethyl)phenyl)(ethyl)sulfane (Intermediate 7)

[0241] [ka] (4-Ethylsulfanylphenyl)methanol (0.50 g, 2.97 mmol) was dissolved in methylene chloride (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 under nitrogen for 16 hours. After the reaction was completed, distilled water was added and the mixture was 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 as a colorless liquid. (232 mg, 34%) MS m / z: 232 [M+1] + 1H NMR (400 MHz, CDCl3) δ ppm: 7.29 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 4.47 (s, 2H), 2.95 (q, J = 7.4 Hz, 2H), 1.33 (t, J = 7.4 Hz, 3H).

[0242] [Preparation Example 8] Preparation of benzyl(4-(bromomethyl)phenyl)sulfane (intermediate 8)

[0243] [ka] (Step 1) Preparation of 4-(benzylthio)benzaldehyde

[0244] [ka] 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 under nitrogen at 100°C for 4 hours. After the reaction was completed, distilled water was slowly added and the mixture was 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 as a green solid. (1.10 g, 59%) MS m / z: 229 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 9.92 (s, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.39-7.36 (m, 4H), 7.31 (t, J = 7.2 Hz, 2H), 7.27 (d, J = 7.0 Hz, 1H), 4.24 (s, 2H). (Step 2) Preparation of (4-(benzylthio)phenyl)methanol

[0245] [ka] The compound prepared above (Step 1) (1.10 g, 4.77 mmol) was dissolved in methanol (7.00 mL) and then cooled to 0°C. 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 the mixture was 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 (400 MHz, CDCl3) δ ppm: 7.31-7.24 (m, 9H), 4.64 (d, J = 5.9 Hz, 2H), 4.11 (s, 2H). (Step 3) Preparation of benzyl(4-(bromomethyl)phenyl)sulfane (intermediate 8)

[0246] [ka] The compound prepared above (Step 2) (0.50 g, 2.17 mmol) was dissolved in methylene chloride (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 under nitrogen for 16 hours. After the reaction was completed, distilled water was added and the mixture was 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 give the title compound as a white solid. (468 mg, 74%) MS m / z: 294 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 7.36-7.20 (m, 9H), 4.45 (s, 2H), 4.13 (s, 2H).

[0247] [Preparation Example 9] Preparation of diethyl (4-(bromomethyl)benzyl)phosphonate (intermediate 9)

[0248] [ka] 1,4-Bis(bromomethyl)benzene (396 mg, 1.50 mmol) was dissolved in N,N-dimethylformamide (0.80 mL), and then triethyl phosphite (128 μl, 0.75 mmol) 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 it was 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 give the title compound as a white oil. (130 mg, 54%) MS m / z: 322 [M+1] + 1 H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.1 Hz, 2H), 7.30 - 7.26 (m, 2H), 4.48 (s, 2H), 4.08 - 3.96 (m, 4H), 3.16 (d, J = 7.2 Hz, 1H), 3.11 (d, J = 5.8 Hz, 1H), 1.29 - 1.17 (m, 6H).

[0249] [Preparation Example 10] Preparation of 4-(bromomethyl)-3-fluorobenzenesulfonamide (intermediate 10)

[0250] [ka] (Step 1) Preparation of 3-fluoro-4-methylbenzenesulfonamide

[0251] [ka] 3-Fluoro-4-methyl-benzenesulfonyl chloride (500 mg, 2.40 mmol) was dissolved in 28% aqueous ammonia (10.0 mL) and then stirred at room temperature under nitrogen for 4 hours. After the reaction was completed, distilled water was added and the mixture was 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] + (Step 2) Preparation of 4-(bromomethyl)-3-fluorobenzenesulfonamide (intermediate 10)

[0252] [ka] 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 α,α'-azobis(isobutyronitrile) (33.6 mg, 0.20 mmol) were added to the mixture sequentially. The reaction mixture was stirred at 90°C under nitrogen for 8 hours. After cooling to room temperature, distilled water was added and the mixture was extracted twice with ethyl acetate. The organic layer was washed with distilled water and saturated brine 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 as a white solid. (491 mg, 90%) MS m / z: 269 [M+1] +

[0253] [Preparation Example 11] Preparation of 4-(bromomethyl)-3-chlorobenzenesulfonamide (intermediate 11)

[0254] [ka] (Step 1) Preparation of 3-chloro-4-methylbenzenesulfonamide

[0255] [ka] 3-Chloro-4-methyl-benzenesulfonyl chloride (1.00 g, 4.44 mmol) was dissolved in 28% aqueous ammonia (20.0 mL) and then stirred at room temperature under nitrogen for 4 hours. 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] + (Step 2) Preparation of 4-(bromomethyl)-3-chlorobenzenesulfonamide (intermediate 11)

[0256] [ka] 3-Chloro-4-methyl-benzenesulfonamide (500 mg, 2.43 mmol) was dissolved in chloroform (16.0 mL), and then N-bromosuccinimide (649 mg, 3.64 mmol) and α,α'-azobis(isobutyronitrile) (39.9 mg, 0.24 mmol) were added to the mixture sequentially. The reaction mixture was stirred at 90°C under nitrogen for 8 hours. After cooling to room temperature, distilled water was added and the mixture was extracted twice with ethyl acetate. The organic layer was washed with distilled water and saturated brine 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 give the title compound as a white solid. (499 mg, 72%) MS m / z: 285 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 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).

[0257] [Preparation Example 12] Preparation of (4-(bromomethyl)-3-fluorophenyl)(methyl)sulfane (Intermediate 12)

[0258] [ka] (Step 1) Preparation of 2-fluoro-4-(methylthio)benzaldehyde

[0259] [ka] 1-Bromo-2-fluoro-4-methylsulfanylbenzene (1.00 g, 4.52 mmol) was dissolved in anhydrous tetrahydrofuran (11.0 mL) and cooled to 0°C. Isopropylmagnesium chloride (2.0 M tetrahydrofuran solution, 2.60 mL, 5.20 mmol) was added and stirred for 30 minutes. Anhydrous N,N-dimethylformamide (0.50 mL, 6.78 mmol) was added to the reaction mixture at 0°C, and the reaction mixture was stirred at room temperature under nitrogen for 1 hour. After the reaction was completed, 1N aqueous hydrogen chloride solution was slowly added at 0°C, and the mixture was 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 give the title compound as a white solid. (483 mg, 63%) MS m / z: 171 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 10.25 (s, 1H), 7.78-7.74 (m, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 11.3 Hz, 1H), 2.53 (s, 3H). (Step 2) Preparation of (2-fluoro-4-(methylthio)phenyl)methanol

[0260] [ka] The compound prepared above (Step 1) (483 mg, 2.84 mmol) was dissolved in methanol (7.00 mL) and then cooled to 0°C. 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 the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the title compound as a colorless liquid. (473 mg, 97%) MS m / z: 173 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 7.34-7.29 (m, 1H), 7.01 (d, J = 9.7 Hz, 1H), 7.92 (d, J = 10.7 Hz 1H), 4.70 (s, 2H), 2.48 (s, 3H). (Step 3) Preparation of (4-(bromomethyl)-3-fluorophenyl)(methyl)sulfane (Intermediate 12)

[0261] [ka] The compound prepared above (Step 2) (473 mg, 2.75 mmol) was dissolved in methylene chloride (5.40 mL), and then tetrabromomethane (1.20 g, 3.57 mmol) and triphenylphosphine (792 mg, 3.02 mmol) were 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 and the mixture was 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 give the title compound as a white solid. (552 mg, 85%) MS m / z: 236 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 7.29-7.25 (m, 1H), 6.97 (d, J = 8.7 Hz, 1H), 6.91 (d, J = 10.2 Hz, 1H), 4.50 (s, 2H), 2.48 (s, 3H).

[0262] [Preparation Example 13] Preparation of (4-(bromomethyl)-3-methoxyphenyl)(methyl)sulfane (Intermediate 13)

[0263] [ka] (Step 1) Preparation of 2-methoxy-4-(methylthio)benzaldehyde

[0264] [ka] 4-Fluoro-2-methoxy-benzaldehyde (500 mg, 3.24 mmol) was dissolved in anhydrous acetonitrile (7.00 mL), and then sodium thiomethoxide (239 mg, 3.41 mmol) was added to the mixture. The reaction mixture was stirred at room temperature under nitrogen for 16 hours. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a white solid. (427 mg, 72%) MS m / z: 183 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 10.35 (s, 1H), 7.74 (d, J = 8.3 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 6.79 (s, 1H), 3.93 (s, 3H), 2.54 (s, 3H). (Step 2) Preparation of (2-methoxy-4-(methylthio)phenyl)methanol

[0265] [ka] The compound prepared above (Step 1) (427 mg, 2.34 mmol) was dissolved in methanol (7.00 mL) and then cooled to 0°C. 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 the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the title compound as a colorless liquid. (429 mg, 99%) MS m / z: 185 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 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). (Step 3) Preparation of (4-(bromomethyl)-3-methoxyphenyl)(methyl)sulfane (Intermediate 13)

[0266] [ka] The compound prepared above (Step 2) (429 mg, 2.33 mmol) was dissolved in methylene chloride (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 under nitrogen for 16 hours. After the reaction was completed, distilled water was added and the mixture was 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 as a colorless liquid. (113 mg, 20%) MS m / z: 248 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 7.23 (d, J = 7.9 Hz, 1H), 6.80-6.77 (m, 2H), 4.54 (s, 2H), 3.89 (s, 3H), 2.49 (s, 3H).

[0267] [Preparation Example 14] Preparation of (4-(bromomethyl)-3-methylphenyl)(methyl)sulfane (Intermediate 14)

[0268] [ka] (Step 1) Preparation of 2-methyl-4-(methylthio)benzaldehyde

[0269] [ka] 4-Fluoro-2-methyl-benzaldehyde (1.00 g, 7.23 mmol) was dissolved in anhydrous acetonitrile (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 under nitrogen for 16 hours. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a colorless liquid. (1.03 g, 85%) MS m / z: 167 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 10.16 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H), 7.05 (s, 1H), 2.64 (s, 3H), 2.52 (s, 3H). (Step 2) Preparation of (2-methyl-4-(methylthio)phenyl)methanol

[0270] [ka] The compound prepared above (Step 1) (1.00 g, 6.18 mmol) was dissolved in methanol (10.0 mL) and then cooled to 0°C. 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 the mixture was 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 as a colorless liquid. (972 mg, 93%) MS m / z: 169 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 7.28 (s, 1H), 7.13-7.04 (m, 2H), 4.66 (s, 2H), 2.48 (s, 3H), 2.35 (s, 3H). (Step 3) Preparation of (4-(bromomethyl)-3-methylphenyl)(methyl)sulfane (Intermediate 14)

[0271] [ka] The compound prepared above (Step 2) (472 mg, 2.81 mmol) was dissolved in methylene chloride (10.0 mL), and then tetrabromomethane (1.20 g, 3.65 mmol) and triphenylphosphine (809 mg, 3.08 mmol) were 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 and the mixture was 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 as a colorless liquid. (573 mg, 88%) MS m / z: 232 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 7.21 (d, J = 7.9 Hz, 1H), 7.06-7.03 (m, 2H), 4.50 (s, 2H), 2.47 (s, 3H), 2.39 (s, 3H).

[0272] [Preparation Example 15] Preparation of (4-(bromomethyl)-2-fluorophenyl)(methyl)sulfane (Intermediate 15)

[0273] [ka] (Step 1) Preparation of 3-fluoro-4-(methylthio)benzaldehyde

[0274] [ka] 3,4-Difluorobenzaldehyde (800 mg, 5.63 mmol) was dissolved in anhydrous acetonitrile (11.0 mL), and then sodium thiomethoxide (434 mg, 6.19 mmol) was added to the mixture. The reaction mixture was stirred at room temperature under nitrogen for 16 hours. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a colorless liquid. (616 mg, 64%) MS m / z: 171 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 9.91 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 10.0 Hz 1H), 7.35-7.29 (m, 1H), 2.54 (s, 3H). (Step 2) Preparation of (3-fluoro-4-(methylthio)phenyl)methanol

[0275] [ka] The compound prepared above (Step 1) (616 mg, 3.62 mmol) was dissolved in methanol (7.00 mL) and then cooled to 0°C. 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 the mixture was 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 colorless liquid without further purification. (656 mg) MS m / z: 173 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 7.26 (s, 1H), 7.12-7.06 (m, 2H), 4.67 (s, 2H), 2.46 (s, 3H). (Step 3) Preparation of (4-(bromomethyl)-2-fluorophenyl)(methyl)sulfane (Intermediate 15)

[0276] [ka] The compound prepared above (Step 2) (656 mg, 3.62 mmol) was dissolved in methylene chloride (7.20 mL), and then tetrabromomethane (1.60 g, 4.71 mmol) and triphenylphosphine (1.00 g, 3.98 mmol) were 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 and the mixture was 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 as a colorless liquid. (825 mg, 97%) MS m / z: 236 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 7.21-7.07 (m, 3H), 4.44 (s, 2H), 2.47 (s, 3H).

[0277] [Preparation Example 16] Preparation of (4-(bromomethyl)phenyl)(cyclopropyl)sulfane (Intermediate 16)

[0278] [ka] (Step 1) Preparation of (4-bromophenyl)(cyclopropyl)sulfane

[0279] [ka] 4-Bromobenzenethiol (1.50 g, 7.93 mmol) was dissolved in dimethyl sulfoxide (10.0 mL), and then potassium tert-butoxide (979.3 mg, 8.73 mmol) and bromocyclopropane (1.58 mL, 19.83 mmol) were added to the mixture. The reaction mixture was stirred under reduced pressure at 80 °C for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature. Distilled water was slowly added, and the mixture was adjusted to pH 2-3 with 1 M aqueous HCl, followed by extraction 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:n-hexane = 0:10 to 1:9) to obtain the title compound as a pale yellow liquid. (1.66 g, 92%). 1H NMR (400 MHz, CDCl3) δ ppm: 7.39 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 2.16 (td, J = 8.3, 3.5 Hz, 1H), 1.16-1.01 (m, 2H), 0.72-0.66 (dd, J = 4.8, 2.0 Hz, 2H). (Step 2) Preparation of 4-(cyclopropylthio)benzoic acid

[0280] [ka] The compound prepared above (Step 1) (1.66 g, 7.24 mmol) was dissolved in anhydrous tetrahydrofuran (25.0 mL) and then cooled to -78 °C. n-Butyllithium (5.4 mL, 8.69 mmol, 1.6 M in hexane) was added to the mixture and stirred for 20 minutes. Carbon dioxide gas (CO2) was injected into the reaction mixture and stirred for 1 hour. After the reaction was completed, distilled water was slowly added, the pH was adjusted to 2-3 with 1 M aqueous HCl, and then the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the title compound as a pale yellow solid. (1.48 g). MS m / z: 195 [M+1]+ 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.74-7.63 (m, 2H), 7.27 (d, J = 8.5 Hz, 2H), 2.14 (td, J = 7.1, 4.4 Hz, 1H), 0.97 (dd, J = 7.3, 2.3 Hz, 2H), 0.48-0.38 (m, 2H). (Step 3) Preparation of (4-(cyclopropylthio)phenyl)methanol

[0281] [ka] The compound prepared above (Step 2) (700 mg, 3.60 mmol) was dissolved in anhydrous tetrahydrofuran (6.00 mL), and then lithium aluminum hydride (7.20 mL, 7.20 mmol, 1 M in THF) was added to the mixture at 0°C. The reaction mixture was stirred under nitrogen at 0°C for 2 hours. After the reaction was completed, distilled water was slowly added, and 1N aqueous sodium hydroxide solution (1.00 mL) was added thereto. The reaction mixture was filtered through Celite and then washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the mixture was purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:9 to 1:1) to obtain the title compound as a colorless liquid. (411 mg, 63%). MS m / z: 181 [M+1]+ 1H NMR (400 MHz, CDCl3,) δ ppm: 7.36 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 4.65 (s, 2H), 2.25-2.15 (m, 1H), 1.10-1.04 (m, J = 5.9 Hz, 2H), 0.72-0.66 (q, J = 4.6 Hz, 2H). (Step 4) Preparation of (4-(bromomethyl)phenyl)(cyclopropyl)sulfane

[0282] [ka] The compound prepared above (Step 3) (411 mg, 2.28 mmol) was dissolved in methylene chloride (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 at room temperature under nitrogen for 18 hours. After the reaction was completed, distilled water was added and the mixture was 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 as a colorless liquid. (460 mg, 83%). 1H NMR (400 MHz, CDCl3) δ ppm: 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).

[0283] [Preparation Example 17] Preparation of (4-(bromomethyl)-3-(trifluoromethyl)phenyl)(methyl)sulfane (Intermediate 17)

[0284] [ka] (Step 1) Preparation of (4-(methylthio)-2-(trifluoromethyl)phenyl)methanol

[0285] [ka] 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 under reduced pressure at 70 °C for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature. Distilled water was slowly added, and the mixture was 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 as a colorless liquid. (400 mg, 34%). 1H NMR (400 MHz, CDCl3) δ ppm: 7.61 (d, J=8.1 Hz, 1 H), 7.49 (s, 1 H), 7.42 (d, J=8.1 Hz, 1 H), 4.82 (s, 2 H), 2.52 (s, 3 H). (Step 2) Preparation of (4-(bromomethyl)-3-(trifluoromethyl)phenyl)(methyl)sulfane (Intermediate 17)

[0286] [ka] The compound prepared above (Step 1) (400 mg, 1.80 mmol) was dissolved in methylene chloride (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 the reaction was confirmed to be 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).

[0287] [Preparation Example 18] Preparation of diethyl ((4-(bromomethyl)phenyl)difluoromethyl)phosphonate (Intermediate 18)

[0288] [ka] TIFF2025525335000100.tif26146 (Step 1) Preparation of diethyl (difluoro(p-tolyl)methyl)phosphonate

[0289] [ka] Diethyl (bromodifluoromethyl)phosphonate (1.47 g, 5.5 mmol) was dissolved in N,N-dimethylamide (5.0 mL), and then zinc (359 mg, 5.5 mmol) was added to the mixture. The reaction mixture was stirred at 55 °C under nitrogen for 30 minutes. The mixture was sonicated for 3 hours, and copper(I) bromide (770 mg, 5.37 mmol) was added, followed by further stirring at room temperature for 30 minutes. 4-Iodotoluene (300 mg, 1.38 mmol) dissolved in N,N-dimethylformacetamide (5.0 mL) was slowly added to the mixture, which was then stirred at 25 °C under nitrogen for 18 hours. After the reaction was complete, distilled water was slowly added, and the mixture was 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 give the title compound as a colorless oil. (147.0 mg, 38%). MS m / z: 279 [M+1]+ 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.9 Hz, 2H), 7.24 (s, 2H), 4.23 - 4.11 (m, 4H), 2.40 (d, J = 5.0 Hz, 3H), 1.31 (t, J = 7.1 Hz, 6H). (Step 2) Preparation of diethyl ((4-(bromomethyl)phenyl)difluoromethyl)phosphonate (Intermediate 18)

[0290] [ka] The compound prepared above (Step 1) (70.0 mg, 0.25 mmol) was dissolved in carbon tetrachloride (1.00 mL), and then N-bromosuccinimide (53.4 mg, 0.30 mmol) and α,α'-azobis(isobutyronitrile) (1.00 mg) were added to the mixture. The mixture was stirred at 80°C under 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 as a white solid mixture (41.0 mg, 46%). MS m / z: 358 [M+1]+

[0291] [Example 2] Synthesis of Examples [Example 1] Preparation of (4-((9H-pyrido[3,4-b]indol-9-yl)methyl)phenyl)(imino)(methyl)-16-sulfanone (Compound 1)

[0292] [ka] (Step 1) Preparation of 9-(4-(methylthio)benzyl)-9H-pyrido[3,4-b]indole

[0293] [ka] 9H-Pyrido[3,4-b]indole (50.0 mg, 0.30 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0 °C. 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 (0.50 mL) was slowly added to the reaction mixture, which was then stirred at 0 °C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (32.0 mg, 35%) MS m / z: 305 [M+1] + (Step 2) Preparation of (4-((9H-pyrido[3,4-b]indol-9-yl)methyl)phenyl)(imino)(methyl)-16-sulfanone (Compound 1)

[0294] [ka] The compound prepared above (Step 1) (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 under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a yellow solid. (5.80 mg, 16%) MS m / z: 336 [M+1] + 1H NMR (400 MHz, CD3OD) δ 9.37 (s, 1H), 8.81 (d, J = 6.3 Hz, 1H), 8.58 (d, J = 6.3 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.04 - 7.99 (m, 2H), 7.86 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.57 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.49 (dd, J = 8.7, 2.1 Hz, 2H), 6.07 (s, 2H), 3.36 (s, 3H).

[0295] [Example 2] Preparation of 4-((6-methoxy-9H-pyrido[3,4-b]indol-9-yl)methyl)benzenesulfonamide (Compound 2)

[0296] [ka] (Step 1) Preparation of 6-methoxy-9H-pyrido[3,4-b]indole

[0297] [ka] 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 under nitrogen at 110° C. for 16 hours. The precipitate was removed by filtration using Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography (ethyl acetate:methanol=10:0 to 9:1) to give the title compound as a yellow solid. (1.0 g, 56%) MS m / z: 199 [M+1] + 1H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 0.8 Hz, 1H), 8.46 (d, J = 5.6 Hz, 1H), 7.93 (d, J = 5.2 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 6.4 Hz, 1H), 3.95 (s, 3H). (Step 2) Preparation of 4-((6-methoxy-9H-pyrido[3,4-b]indol-9-yl)methyl)benzenesulfonamide (Compound 2)

[0298] [ka] The compound prepared above (Step 1) (50.0 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (2.50 mL) and cooled to 0°C. 60% sodium hydride (20.2 mg, 0.50 mmol) was added to the mixture, which was then 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a yellow solid. (45.4 mg, 49.0%) MS m / z: 368 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.75 (d, J = 6.0 Hz, 1H), 8.60 (d, J = 6.0 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.75 - 7.71 (m, 3H), 7.44 (dd, J = 2.6, 9.0 Hz, 1H), 7.34-7.30 (m, 4H), 5.97 (s, 2H), 3.90 (s, 3H).

[0299] [Example 3] Preparation of imino(4-((6-methoxy-9H-pyrido[3,4-b]indol-9-yl)methyl)phenyl)(methyl)-16-sulfanone (compound 3)

[0300] [ka] (Step 1) Preparation of 6-methoxy-9-(4-(methylthio)benzyl)-9H-pyrido[3,4-b]indole

[0301] [ka] The compound prepared in Example 2 (Step 1) (50.0 mg, 0.252 mmol) was dissolved in N,N-dimethylformamide (2.50 mL) and cooled to 0°C. 60% sodium hydride (20.2 mg, 0.50 mmol) was added to the mixture, which was then 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, which was then stirred at 80°C under nitrogen for 15 hours. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a yellow solid. (64.4 mg, 76%) MS m / z: 335 [M+1] + (Step 2) Preparation of imino(4-((6-methoxy-9H-pyrido[3,4-b]indol-9-yl)methyl)phenyl)(methyl)-16-sulfanone (compound 3)

[0302] [ka] The compound prepared above (Step 1) (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 under nitrogen for 16 hours. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a yellow solid. (22.6 mg, 32%) MS m / z: 366 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.81 (d, J = 6.0 Hz, 1H), 8.64 (d, J = 5.6 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 9.2 Hz, 2H), 7.48 (dd, J = 2.0, 9.2 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 6.03 (s, 2H), 3.92 (s, 3H), 3.10 (s, 3H).

[0303] [Example 4] Preparation of 4-((8-methoxy-5H-pyrido[4,3-b]indol-5-yl)methyl)benzenesulfonamide (Compound 4)

[0304] [ka] TIFF2025525335000113.tif76159 (Step 1) Preparation of tert-butyl 8-methoxy-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0305] [ka] 1,3-Dimethylurea (5.30 g, 60.2 mmol) and L-(+)-tartaric acid (2.26 g, 15.0 mmol) were mixed, and the reaction mixture was stirred at 80 °C for 2 hours under nitrogen. 4-Methoxyphenylhydrazine hydrochloride (1.05 g, 6.02 mmol) and tert-butyl-4-oxopiperidine-1-carboxylate (1.00 g, 5.01 mmol) were added sequentially to the reaction mixture, which was then stirred at 80 °C for 2 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate were added, and the mixture was extracted twice with methylene chloride. 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 3:7) to give the title compound as a yellow solid. (391 mg, 26%) MS m / z: 303 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 7.26 - 7.14 (m, 1H), 6.91 (s, 1H), 6.68 (dd, J = 8.7, 2.5 Hz, 1H), 4.51 (s, 2H), 3.77 (d, J = 1.3 Hz, 3H), 3.71 (t, J = 5.8 Hz, 2H), 2.76 (s, 2H), 1.57 - 1.39 (m, 9H). (Step 2) Preparation of 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-trifluoroacetic acid

[0306] [ka] The compound prepared above (Step 1) (105 mg, 0.35 mmol) was dissolved in methylene chloride (3.00 mL), and then trifluoroacetic acid (1.00 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ethyl ether, and then n-hexane was added. The resulting solid was filtered, washed with a mixed solution of ethyl ether / n-hexane, and dried to give the title compound as a brown solid. (110 mg, 100%) MS m / z: 203 [M+1] + (Step 3) Preparation of 8-methoxy-5H-pyrido[4,3-b]indole

[0307] [ka] The compound prepared above (Step 2) (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 under nitrogen for 6 hours. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a yellow solid. (5.30 mg, 8%) MS m / z: 199 [M+1] + (Step 4) Preparation of 4-((8-methoxy-5H-pyrido[4,3-b]indol-5-yl)methyl)benzenesulfonamide (Compound 4)

[0308] [ka] The compound prepared above (Step 3) (5.30 mg, 0.03 mmol) was dissolved in N,N-dimethylformamide (0.30 mL) and cooled to 0 °C. 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, which was then stirred at 0 °C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (1.30 mg, 21%) MS m / z: 368 [M+1] + 1 H NMR (400 MHz, CD3OD) δ 9.60 (d, J = 2.9 Hz, 1H), 8.58 - 8.49 (m, 1H), 8.09 (s, 1H), 7.99 (s, 1H), 7.83 (d, J = 7.8 Hz, 2H), 7.71 - 7.56 (m, 2H), 7.40 - 7.28 (m, 2H), 5.93 (s, 2H), 3.96 (s, 3H).

[0309] [Example 5] Preparation of 4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 5)

[0310] [ka] TIFF2025525335000119.tif75162 (Step 1) Preparation of tert-butyl 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0311] [ka] 4-Methoxyphenylhydrazine hydrochloride (5.00 g, 28.6 mmol) was dissolved in toluene (95.4 mL), and then tert-butyl-3-oxopiperidine-1-carboxylate (6.85 g, 34.4 mmol) and propanephosphonic anhydride (2.90 mL, 5.73 mmol) were added sequentially to the mixture. The reaction mixture was stirred at 90 °C under nitrogen for 6 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate were added, and the mixture was 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 give the title compound as a yellow solid. (4.20 g, 48 %) MS m / z: 303 [M+1] + (Step 2) Preparation of 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0312] [ka] The compound prepared above (Step 1) (8.30 g, 27.5 mmol) was dissolved in methylene chloride (109 mL), and then trifluoroacetic acid (10.0 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ethyl ether, and then n-hexane was added. The resulting solid was filtered, washed with a mixed solution of ethyl ether / n-hexane, and dried to give the title compound as a brown solid. (8.70 g, 100%) MS m / z: 203 [M+1] + (Step 3) Preparation of 8-methoxy-5H-pyrido[3,2-b]indole

[0313] [ka] The compound prepared above (Step 2) (4.00 g, 12.6 mmol) was dissolved in toluene (126 mL), and then Pd / C (10% by weight, 2.00 g) was added to the mixture. The reaction mixture was stirred at 90° C. under nitrogen for 36 hours. The precipitate was removed by filtration using Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography (ethyl acetate:methanol=10:0 to 9:1) to give the title compound as a yellow solid. (1.23 g, 49%) MS m / z: 199 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ 11.2 (s, 1H), 8.41 (d, J = 4.4 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.35 (dd, J = 4.6, 8.2 Hz, 1H), 7.14 (dd, J = 2.4, 8.8 Hz, 1H), 3.86 (s, 3H). (Step 4) Preparation of ((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 5)

[0314] [ka] The compound prepared above (Step 3) (100 mg, 0.51 mmol) was dissolved in N,N-dimethylformamide (5.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was complete, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (23.2 mg, 13%) MS m / z: 368 [M+1] + 1 H NMR (400 MHz, CD3OD) δ 8.53 (d, J = 4.4 Hz, 1H), 8.44 (d, J = 8.4 Hz, 1H), 7.77 (s, 1H), 7.72-7.70 (m, 3H), 7.56 (d, J = 9.2 Hz, 1H), 7.31 (d, J = 9.2 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 5.77 (s, 2H), 3.85 (s, 3H).

[0315] [Example 6] Preparation of 4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)piperidine-1-sulfonamide (Compound 6)

[0316] [ka] (Step 1) Preparation of tert-butyl ((4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)piperidin-1-yl)sulfonyl)carbamate

[0317] [ka] The compound prepared in Example 5 (Step 3) (20.0 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 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, which was then stirred at 80°C under nitrogen for 15 hours. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a yellow solid. (17.0 mg, 35%)MS m / z: 475 [M+1] + (Step 2) Preparation of 4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)piperidine-1-sulfonamide (Compound 6)

[0318] [ka] The compound prepared above (Step 1) (17.0 mg, 0.04 mmol) was dissolved in methylene chloride (1.00 mL), and then trifluoroacetic acid (1.00 mL) was added to the mixture. The reaction mixture was stirred at room temperature under 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 as a yellow solid. (1.20 mg, 9%) MS m / z: 375 [M+1] +1H NMR (400 MHz, CD3OD) δ 8.04 (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).

[0319] [Example 7] Preparation of 4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)-N-methylbenzenesulfonamide (Compound 7)

[0320] [ka] TIFF2025525335000128.tif38162 (Step 1) Preparation of tert-butyl ((4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)sulfonyl)(methyl)carbamate

[0321] [ka] The compound prepared in Example 5 (Step 3) (30.0 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (46.0 mg, 63%) MS m / z: 482 [M+1]+ 1 H NMR (400 MHz, CDCl3) δ ppm: 8.56 (dd, J = 4.7, 1.3 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.55 (dd, J = 8.3, 1.4 Hz, 1H), 7.30 (dd, J = 8.3, 4.8 Hz, 1H), 7.24-7.19 (m, 3H), 7.15 (dd, J = 8.9, 2.5 Hz, 1H), 5.56 (s, 2H), 3.95 (s, 3H), 3.31 (s, 3H), 1.29 (s, 9H). (Step 2) Preparation of 4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)-N-methylbenzenesulfonamide (Compound 7)

[0322] [ka] The compound prepared above (Step 1) (46.0 mg, 0.10 mmol) was dissolved in methylene chloride (1.00 mL), and then trifluoroacetic acid (1.00 mL) was added to the mixture. The reaction mixture was stirred at room temperature under nitrogen for 2 hours. After the reaction was completed, distilled water and aqueous sodium bicarbonate solution were slowly added to neutralize the mixture, followed by extraction twice with methylene chloride. 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 as a yellow solid. (12.0 mg, 32%) MS m / z: 382 [M+1] + 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.47 (dd, J = 4.6, 1.4 Hz, 1H), 8.02 (dd, J = 8.4, 1.4 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 9.0 Hz, 1H), 7.41 (dd, J = 8.4, 4.6 Hz, 1H), 7.37 (d, J = 4.8 Hz, 1H), 7.30 (d, J = 8.5 Hz, 2H), 7.18 (dd, J = 9.0, 2.6 Hz, 1H), 5.78 (s, 2H), 3.88 (s, 3H), 2.35 (d, J = 4.4 Hz, 3H).

[0323] [Example 8] Preparation of N-(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)sulfamide (Compound 8)

[0324] [ka] (Step 1) Preparation of tert-butyl (4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)carbamate

[0325] [ka] The compound prepared in Example 5 (Step 3) (50.0 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 2 hours. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (36.0 mg, 51%) MS m / z: 404 [M+1] + (Step 2) Preparation of 4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)aniline

[0326] [ka] The compound prepared above (Step 1) (36.0 mg, 0.09 mmol) was dissolved in methylene chloride (0.50 mL), and then trifluoroacetic acid (0.50 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ethyl ether, and then n-hexane was added. The resulting solid was filtered, washed with a mixed solution of ethyl ether / n-hexane, and dried to give the title compound as a red solid. (27.0 mg, 99%) MS m / z: 304 [M+1] + (Step 3) Preparation of N-(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)sulfamide (Compound 8)

[0327] [ka] The compound prepared above (Step 2) (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 (4-nitrophenyl)sulfamate (223 mg, 1.01 mmol) were added sequentially to the mixture. The reaction mixture was stirred at room temperature under nitrogen for 3 hours. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a white solid. (2.30 mg, 6%) MS m / z: 383 [M+1] + 1 H NMR (400 MHz, CD3OD) δ 8.41 (dd, J = 4.8, 1.2 Hz, 1H), 7.95 (dd, J = 8.4, 1.2 Hz, 1H), 7.86 (d, J = 2.5 Hz, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.43 (dd, J = 8.4, 4.8 Hz, 1H), 7.20 (dd, J = 9.0, 2.5 Hz, 1H), 7.15 - 7.07 (m, 4H), 5.57 (s, 2H), 3.92 (s, 3H).

[0328] [Example 9] Preparation of 4-(2-(8-methoxy-5H-pyrido[3,2-b]indol-5-yl)ethyl)benzenesulfonamide (Compound 9)

[0329] [ka] The compound prepared in Example 5 (Step 3) (25.0 mg, 0.13 mmol) and Intermediate 5 (23.0 mg, 0.13 mmol) were dissolved in dimethyl sulfoxide (1.00 mL). Potassium hydroxide (14.0 mg, 0.25 mmol) was then added to the mixture, which was then stirred at 110°C for 48 hours. After cooling to room temperature, distilled water was slowly added, and the mixture was 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 as a white solid. (6.70 mg, 14%) MS m / z: 382 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.40 (dd, J = 4.6, 1.4 Hz, 1H), 7.91 (dd, J = 8.3, 1.4 Hz, 1H), 7.70-7.61 (m, 4H), 7.42 (d, J = 8.4 Hz, 2H), 7.34 (dd, J = 8.3, 4.6 Hz, 1H), 7.26 (s, 2H), 7.17 (dd, J = 8.9, 2.6 Hz, 1H), 4.64 (t, J = 7.4 Hz, 2H), 3.87 (s, 3H), 3.12 (t, J = 7.3 Hz, 2H).

[0330] [Example 10] Preparation of imino(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(methyl)-16-sulfanone (compound 10)

[0331] [ka] (Step 1) Preparation of 8-methoxy-5-(4-(methylthio)benzyl)-5H-pyrido[3,2-b]indole

[0332] [ka] The compound prepared in Example 5 (Step 3) (140 mg, 0.71 mmol) was dissolved in N,N-dimethylformamide (3.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (95.0 mg, 40%) MS m / z: 335 [M+1] + (Step 2) Preparation of imino(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(methyl)-16-sulfanone (compound 10)

[0333] [ka] The compound prepared above (Step 1) (95.0 mg, 0.28 mmol) 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 under nitrogen for 16 hours. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid (90.0 mg, 86%). Compound 10 was purified by preparative high-performance liquid chromatography (preparative HPLC, chiralpak (250 × 30 mm, 5 μm), hexane:methanol:ethanol=40:30:30) to give 10a and 10b, which are white enantiomers. 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 (400 MHz, CD3OD) δ 8.69 (d, J = 4.9 Hz, 1H), 8.47 (d, J = 8.3 Hz, 1H), 7.96 (d, J = 8.0 Hz, 2H), 7.89 (s, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 9.1 Hz, 1H), 5.97 (s, 2H), 3.89 (s, 3H), 3.53 (s, 3H).

[0334] [Example 11] Preparation of ethyl(imino)(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)-16-sulfanone (Compound 11)

[0335] [ka] TIFF2025525335000140.tif37163 (Step 1) Preparation of 5-(4-(ethylthio)benzyl)-8-methoxy-5H-pyrido[3,2-b]indole

[0336] [ka] The compound prepared in Example 5 (Step 3) (30.0 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (16.3 mg, 31%) MS m / z: 349 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 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 = 8.4 Hz, 2H), 7.16 (d, J = 8.9 Hz, 1H), 7.01 (d, J = 8.3 Hz, 2H), 5.45 (s, 2H), 3.95 (s, 3H), 2.88 (q, J = 7.4 Hz, 2H), 1.31-1.24 (m, 3H). (Step 2) Preparation of ethyl(imino)(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)-16-sulfanone (Compound 11)

[0337] [ka] The compound prepared above (Step 1) (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 under 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 as a yellow solid. (8.20 mg, 46%) MS m / z: 380 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.56 (d, J = 3.6 Hz, 1H), 8.22 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 2.5 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.54 (dd, J = 8.3, 4.8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.24 (dd, J = 8.9, 2.6 Hz, 1H), 5.87 (s, 2H), 3.88 (s, 3H), 3.29 (q, J = 7.2 Hz, 2H), 1.04 (t, J = 7.3 Hz, 3H).

[0338] [Example 12] Preparation of benzyl(imino)(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)-16-sulfanone (Compound 12)

[0339] [ka] (Step 1) Preparation of 5-(4-(benzylthio)benzyl)-8-methoxy-5H-pyrido[3,2-b]indole

[0340] [ka] The compound prepared in Example 5 (Step 3) (30.0 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (1.0 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (20.9 mg, 34%) MS m / z: 411 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 8.54 (dd, J = 4.7, 1.4 Hz, 1H), 7.90 (d, J = 2.6 Hz, 1H), 7.59 (dd, J = 8.4, 1.5 Hz, 1H), 7.33-7.25 (m, 5H), 7.23-7.14 (m, 5H), 6.98 (d, J = 8.4 Hz, 2H), 5.43 (s, 2H), 4.05 (s, 2H), 3.95 (s, 3H). (Step 2) Preparation of ethyl(imino)(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)-16-sulfanone (Compound 12)

[0341] [ka] The compound prepared above (Step 1) (20.9 mg, 0.05 mmol) 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 under 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 as a yellow solid. (8.10 mg, 36%) MS m / z: 442 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 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 = 7.5 Hz, 2H), 6.97 (d, J = 7.8 Hz, 2H), 5.83 (s, 2H), 4.52 (s, 2H), 3.89 (s, 3H).

[0342] [Example 13] Preparation of (4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)phosphonic acid (compound 13)

[0343] [ka] (Step 1) Preparation of 5-(4-bromobenzyl)-8-methoxy-5H-pyrido[3,2-b]indole

[0344] [ka] The compound prepared in Example 5 (Step 3) (40.0 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 60% sodium hydride (9.60 mg, 0.24 mmol) was added to the mixture, which was then 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (30.0 mg, 40%) MS m / z: 368 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 8.55 (dd, J = 4.8, 1.4 Hz, 1H), 7.89 (d, J = 2.5 Hz, 1H), 7.57 (dd, J = 8.4, 1.4 Hz, 1H), 7.43-7.36 (m, 2H), 7.33-7.26 (m, 2H), 7.17 (dd, J = 8.9, 2.5 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 5.44 (s, 2H), 3.95 (s, 3H). (Step 2) Preparation of diethyl (4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)phosphonate

[0345] [ka] The compound prepared above (Step 1) (36.0 mg, 0.10 mmol) and diethyl phosphite (14.0 μL, 0.11 mmol) were dissolved in toluene (2.00 mL). Triethylamine (15.0 μL, 0.11 mmol) and tetrakis(triphenylphosphine)palladium(0) (11.3 mg, 0.01 mmol) were then added to the mixture, which was then stirred at 90°C for 3 hours. After cooling to room temperature, the precipitate was removed by filtration with diethyl ether, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:1 to 10:0, methanol:methylene chloride = 1:19) to give the title compound as a yellow liquid. (32.0 mg, 77%) MS m / z: 425 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 8.56 (dd, J = 4.7, 1.3 Hz, 1H), 7.93 (d, J = 2.6 Hz, 1H), 7.69 (dd, J = 13.0, 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 1H), 7.31 (dd, J = 8.3, 4.7 Hz, 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 = 7.1 Hz, 6H). (Step 3) Preparation of (4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)phosphonic acid (compound 13)

[0346] [ka] The compound prepared above (Step 2) (32.0 mg, 0.08 mmol) was dissolved in methylene chloride (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 under 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 as a yellow solid. (18.3 mg, 65%) MS m / z: 369 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.63 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.75-7.63 (m, 2H), 7.55 (dd, J = 12.8, 8.1 Hz, 2H), 7.29 (d, J = 9.0 Hz, 1H), 7.20 (dd, J = 8.1, 3.4 Hz, 2H), 5.81 (s, 2H), 3.88 (s, 3H).

[0347] [Example 14] Preparation of (4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid (compound 14)

[0348] [ka] (Step 1) Preparation of diethyl (4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonate

[0349] [ka] The compound prepared in Example 5 (Step 3) (20.0 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 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, which was then stirred at 80°C under nitrogen for 3 hours. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (12.0 mg, 27%) MS m / z: 439 [M+1] + (Step 2) Preparation of (4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzyl)phosphonic acid (compound 14)

[0350] [ka] The compound prepared above (Step 1) (12.0 mg, 0.03 mmol) was dissolved in methylene chloride (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 under 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 as a yellow solid. (3.00 mg, 28%) MS m / z: 383 [M+1] + 1H NMR (400 MHz, CD3OD) δ 8.72 (d, J = 8.4 Hz, 1H), 8.66 (d, J = 5.6 Hz, 1H), 7.92 (dd, J = 8.5, 5.7 Hz, 1H), 7.87 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 9.2 Hz, 1H), 7.47 (dd, J = 9.2, 2.5 Hz, 1H), 7.25 (dd, J = 8.1, 2.3 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 5.79 (s, 2H), 3.97 (s, 3H), 3.08 (s, 1H), 3.03 (s, 1H).

[0351] [Example 15] Preparation of 3-fluoro-4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 15)

[0352] [ka] The compound prepared in Example 5 (Step 3) (30.0 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (1.50 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a yellow solid. (3.50 mg, 6%) MS m / z: 386 [M+1] + 1H NMR (400 MHz, DMSO-d6) δ ppm: 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).

[0353] [Example 16] Preparation of 3-chloro-4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 16)

[0354] [ka] The compound prepared in Example 5 (Step 3) (30.0 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (1.50 mL) and cooled to 0°C. 60% sodium hydride (12.1 mg, 0.30 mmol) was added to the mixture, which was then 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a yellow solid. (4.00 mg, 7%) MS m / z: 402 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 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).

[0355] [Example 17] Preparation of (3-fluoro-4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(imino)(methyl)-16-sulfanone (Compound 17)

[0356] [ka] TIFF2025525335000156.tif36163 (Step 1) Preparation of 5-(2-fluoro-4-(methylthio)benzyl)-8-methoxy-5H-pyrido[3,2-b]indole

[0357] [ka] The compound prepared in Example 5 (Step 3) (33.0 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow liquid. (24.0 mg, 41%) MS m / z: 353 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 8.55 (s, 1H), 7.89 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 8.3 Hz, 1H), 6.97 (d, J = 9.8 Hz, 1H), 6.78 (s, 1H), 6.69-6.68 (m, 1H), 5.48 (s, 2H), 3.95 (s, 3H), 2.42 (s, 3H). (Step 2) Preparation of (3-fluoro-4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(imino)(methyl)-16-sulfanone (Compound 17)

[0358] [ka] The compound prepared above (Step 1) (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 under 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 as a yellow solid. (18.0 mg, 68%) MS m / z: 384 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.61 (s, 1H), 8.30 (s, 1H), 7.86-7.74 (m, 2H), 7.67 (d, J = 10.4 Hz, 1H), 7.61 (s, 2H), 7.27 (d, J = 7.4 Hz, 1H), 7.08 (s, 1H), 5.90 (s, 2H), 3.88 (s, 3H), 3.14 (s, 3H).

[0359] [Example 18] Preparation of imino(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)-3-methylphenyl)(methyl)-16-sulfanone (compound 18)

[0360] [ka] (Step 1) Preparation of 8-methoxy-5-(2-methyl-4-(methylthio)benzyl)-5H-pyrido[3,2-b]indole

[0361] [ka] The compound prepared in Example 5 (Step 3) (40.0 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (33.5 mg, 48%) MS m / z: 349 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 8.54 (dd, J = 4.6, 1.4 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.51 (dd, J = 8.3, 1.4 Hz, 1H), 7.27 (dd, J = 8.3, 4.6 Hz, 1H), 7.21 (d, J = 8.9 Hz, 1H), 7.19-7.10 (m, 2H), 6.85 (dd, J = 8.2, 2.2 Hz, 1H), 6.44 (d, J = 8.0 Hz, 1H), 5.41 (s, 2H), 3.95 (s, 3H), 2.42 (s, 3H), 2.39 (s, 3H). (Step 2) Preparation of imino(4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)-3-methylphenyl)(methyl)-16-sulfanone (compound 18)

[0362] [ka] The compound prepared above (Step 1) (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 under 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 as a yellow solid. (36.1 mg, 98%) MS m / z: 380 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.61 (dd, J = 4.9, 1.3 Hz, 1H), 8.15 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 2.5 Hz, 1H), 7.62-7.53 (m, 3H), 7.26 (dd, J = 9.0, 2.6 Hz, 1H), 6.28 (d, J = 8.4 Hz, 1H), 5.87 (s, 2H), 3.90 (s, 3H), 3.42 (s, 3H), 2.60 (s, 3H).

[0363] [Example 19] Preparation of imino(3-methoxy-4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(methyl)-16-sulfanone (Compound 19)

[0364] [ka] TIFF2025525335000163.tif38162 (Step 1) Preparation of 8-methoxy-5-(2-methoxy-4-(methylthio)benzyl)-5H-pyrido[3,2-b]indole

[0365] [ka] The compound prepared in Example 5 (Step 3) (30.0 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (20.0 mg, 36%) MS m / z: 365 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 8.53 (dd, J = 4.6, 1.4 Hz, 1H), 7.89 (d, J = 2.6 Hz, 1H), 7.65 (dd, J = 8.4, 1.4 Hz, 1H), 7.36-7.28 (m, 2H), 7.16 (dd, J = 8.9, 2.5 Hz, 1H), 6.82 (d, J = 1.8 Hz, 1H), 6.60 (dd, J = 7.9, 1.8 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 5.43 (s, 2H), 3.95 (s, 3H), 3.89 (s, 3H), 2.42 (s, 3H). (Step 2) Preparation of imino(3-methoxy-4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(methyl)-16-sulfanone (Compound 19)

[0366] [ka] The compound prepared above (Step 1) (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 under 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 as a yellow solid. (20.9 mg, 95%) MS m / z: 396 [M+1] +1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.63 (d, J = 4.3 Hz, 1H), 8.31 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 2.5 Hz, 1H), 7.64 (dd, J = 8.7, 4.8 Hz, 2H), 7.57 (d, J = 1.9 Hz, 1H), 7.40 (dd, J = 8.0, 1.9 Hz, 1H), 7.28 (dd, J = 9.0, 2.6 Hz, 1H), 6.87 (d, J = 7.9 Hz, 1H), 5.77 (s, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 3.34 (s, 3H).

[0367] [Example 20] Preparation of (2-fluoro-4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(imino)(methyl)-16-sulfanone (Compound 20)

[0368] [ka] (Step 1) Preparation of 5-(3-fluoro-4-(methylthio)benzyl)-8-methoxy-5H-pyrido[3,2-b]indole

[0369] [ka] The compound prepared in Example 5 (Step 3) (40.0 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (30.0 mg, 42%) MS m / z: 353 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 8.56 (s, 1H), 7.90 (s, 1H), 7.65-7.54 (m, 1H), 7.35-7.27 (m, 2H), 7.19-7.13 (m, 2H), 6.81 (m, 2H), 5.44 (s, 2H), 3.95 (s, 3H), 2.41 (s, 3H). (Step 2) Preparation of (2-fluoro-4-((8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(imino)(methyl)-16-sulfanone (Compound 20)

[0370] [ka] The compound prepared above (Step 1) (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 under 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 as a yellow solid. (25.4 mg, 99%) MS m / z: 384 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.60 (s, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.61 (s, 1H), 7.30 (s, 1H), 7.21 (d, J = 10.1 Hz, 1H), 7.09 (s, 1H), 5.85 (s, 2H), 3.89 (s, 3H), 3.15 (s, 3H).

[0371] [Example 21] Preparation of 4-((8-chloro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 21)

[0372] [ka] TIFF2025525335000170.tif72164 (Step 1) Preparation of tert-butyl 8-chloro-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0373] [ka] 4-Chlorophenylhydrazine hydrochloride (500 mg, 2.79 mmol) was dissolved in toluene (22.0 mL), and then tert-butyl-3-oxopiperidine-1-carboxylate (668 mg, 3.35 mmol) and propanephosphonic anhydride (0.34 mL, 0.56 mmol) were added to the mixture, successively. The reaction mixture was stirred at 90 °C under nitrogen for 4 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate were added, and the mixture was 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 give the title compound as a yellow solid. (350 mg, 34%) MS m / z: 307 [M+1] + 1 H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.64 (s, 1H), 7.15 - 7.09 (m, 1H), 7.07 - 7.03 (m, 1H), 3.75 (dt, J = 7.8, 2.2 Hz, 2H), 2.85 - 2.77 (m, 2H), 2.11 - 2.00 (m, 2H), 1.54 (s, 9H). (Step 2) Preparation of 8-chloro-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0374] [ka] The compound prepared above (Step 1) (350 mg, 1.69 mmol) was dissolved in methylene chloride (4.00 mL), and then trifluoroacetic acid (8.00 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at room temperature for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ethyl ether, and then n-hexane was added. The resulting solid was filtered, washed with a mixed solution of ethyl ether / n-hexane, and dried to give the title compound as a red solid. (245 mg, 70%) MS m / z: 207 [M+1] + (Step 3) Preparation of 8-chloro-5H-pyrido[3,2-b]indole

[0375] [ka] The compound prepared above (Step 2) (245 mg, 1.18 mmol) was dissolved in dimethyl sulfoxide (5.00 mL) and then stirred at 90°C under nitrogen for 12 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate solution were added, and the mixture was 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 as a yellow solid. (51.0 mg, 22%) MS m / z: 203 [M+1] + (Step 4) Preparation of 4-((8-chloro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 21)

[0376] [ka] The compound prepared above (Step 3) (20.0 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 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 (0.50 mL) was slowly added to the reaction mixture, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (3.60 mg, 10%) MS m / z: 372 [M+1] + 1H NMR (400 MHz, CD3OD) δ 8.66 (dd, J = 5.3, 1.3 Hz, 1H), 8.43 (dd, J = 8.4, 1.2 Hz, 1H), 8.39 (dd, J = 1.9, 0.8 Hz, 1H), 7.85 - 7.80 (m, 2H), 7.78 (dd, J = 8.5, 5.3 Hz, 1H), 7.74 - 7.65 (m, 2H), 7.35 - 7.28 (m, 2H), 5.87 (s, 2H).

[0377] [Example 22] Preparation of 4-((8-(trifluoromethoxy)-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 22)

[0378] [ka] (Step 1) Preparation of (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride

[0379] [ka] 4-(Trifluoromethoxy)aniline (800 mg, 4.52 mmol) was dissolved in 6N HCl (9.00 mL), and then sodium nitrite (467 mg, 6.78 mmol) dissolved in saturated brine (3.00 mL) was slowly added to the mixture at -20 °C. The reaction mixture was stirred under nitrogen at -20 °C for 30 minutes, and then tin(II) chloride dihydrate (3.60 g, 15.8 mmol) dissolved in concentrated HCl (2.00 mL) was slowly added. After stirring at 0 °C for 2 hours, a mixture of ethanol and ethyl ether (3:7) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The resulting solid was filtered, washed with ethyl ether, and then dried to give the title compound (800 mg, 81%) as a white solid. MS m / z: 193 [M+1] + (Step 2) Preparation of tert-butyl 8-(trifluoromethoxy)-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0380] [ka] The compound prepared above (Step 1) (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 sequentially to the mixture. The reaction mixture was stirred at 90 °C under nitrogen for 4 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate were added, and the mixture was 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 give the title compound as a yellow solid. (137 mg, 18%) MS m / z: 357 [M+1] + (Step 3) Preparation of 8-(trifluoromethoxy)-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0381] [ka] The compound prepared above (Step 2) (137 mg, 0.38 mmol) was dissolved in methylene chloride (3.00 mL), and then trifluoroacetic acid (3.00 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ethyl ether, and then n-hexane was added. The resulting solid was filtered, washed with a mixed solution of ethyl ether / n-hexane, and dried to give the title compound as a brown solid. (98.0 mg, 99%) MS m / z: 257 [M+1] + (Step 4) Preparation of 8-(trifluoromethoxy)-5H-pyrido[3,2-b]indole

[0382] [ka] The compound prepared above (Step 3) (98.0 mg, 0.38 mmol) was dissolved in dimethyl sulfoxide (2.00 mL) and then stirred at 90°C under nitrogen for 12 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate solution were added, and the mixture was 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 as a yellow solid. (48.0 mg, 50%) MS m / z: 253 [M+1] + (Step 5) Preparation of 4-((8-(trifluoromethoxy)-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 22)

[0383] [ka] The compound prepared above (Step 4) (10.0 mg, 0.04 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 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 (0.50 mL) was slowly added to the reaction mixture, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (2.10 mg, 13%) MS m / z: 422 [M+1] + 1H NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 8.34 (d, J = 11.5 Hz, 2H), 7.86 - 7.70 (m, 4H), 7.60 (d, J = 9.2 Hz, 1H), 7.36 - 7.29 (m, 2H), 5.88 (d, J = 3.4 Hz, 2H).

[0384] [Example 23] Preparation of imino(methyl)(4-((6-methyl-9H-pyrido[3,4-b]indol-9-yl)methyl)phenyl)-16-sulfanone (Compound 23)

[0385] [ka] (Step 1) Preparation of tert-butyl 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0386] [ka] 4-Methylphenylhydrazine hydrochloride (1.00 g, 6.30 mmol) was dissolved in toluene (30.0 mL), and then tert-butyl-3-oxopiperidine-1-carboxylate (1.03 g, 6.30 mmol) and propanephosphonic anhydride (0.80 mL, 1.26 mmol) were added sequentially to the mixture. The reaction mixture was stirred at 90 °C under nitrogen for 4 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate were added, and the mixture was 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 give the title compound as a yellow solid. (630 mg, 35%) MS m / z: 287 [M+1] + 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.44 (s, 1H), 7.10 (t, J = 10.4 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 3.79 - 3.71 (m, 2H), 2.80 (t, J = 6.7 Hz, 2H), 2.43 (s, 3H), 2.11 - 2.00 (m, 2H), 1.54 (s, 9H). (Step 2) Preparation of 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0387] [ka] The compound prepared above (Step 1) (280 mg, 0.98 mmol) was dissolved in methylene chloride (4.00 mL), and then trifluoroacetic acid (3.00 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ethyl ether, and then n-hexane was added. The resulting solid was filtered, washed with a mixed solution of ethyl ether / n-hexane, and dried to give the title compound as a red solid. (130 mg, 71%) MS m / z: 187 [M+1] + (Step 3) Preparation of 8-methyl-5H-pyrido[3,2-b]indole

[0388] [ka] The compound prepared above (Step 2) (130 mg, 0.70 mmol) was dissolved in toluene (3.00 mL), and then Pd / C (50% by weight, 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 Celite. 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 as a green solid. (100 mg, 79%) MS m / z: 183 [M+1] + (Step 4) Preparation of 8-methyl-5-(4-(methylthio)benzyl)-5H-pyrido[3,2-b]indole

[0389] [ka] The compound prepared above (Step 3) (27.0 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 60% sodium hydride (17.8 mg, 0.45 mmol) was added to the mixture, which was then 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, which was then stirred at 0°C under nitrogen for 3 hours. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (30.0 mg, 64%) MS m / z: 319 [M+1] + (Step 5) Preparation of imino(methyl)(4-((8-methyl-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)-16-sulfanone (Compound 23)

[0390] [ka] The compound prepared above (Step 4) (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 under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a yellow solid. (15.0 mg, 46%) MS m / z: 350 [M+1] + 1 H NMR (400 MHz, CD3OD) δ 8.69 (d, J = 5.5 Hz, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.24 (s, 1H), 8.04 (d, J = 8.5 Hz, 2H), 7.91 (dd, J = 8.5, 5.6 Hz, 1H), 7.66 (s, 2H), 7.51 (d, J = 8.4 Hz, 2H), 6.00 (s, 2H), 3.54 (s, 3H), 2.59 (s, 3H).

[0391] [Example 24] Preparation of (4-((8-ethoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(imino)(methyl)-16-sulfanone (compound 24)

[0392] [ka] (Step 1) Preparation of (4-ethoxyphenyl)hydrazine hydrochloride

[0393] [ka] 4-Ethoxyaniline (840 mg, 6.12 mmol) was dissolved in 6N HCl (5.00 mL), and then sodium nitrite (592 mg, 8.57 mmol) dissolved in 2.00 mL of saturated brine solution was slowly added to the mixture at -20 °C. The reaction mixture was stirred under nitrogen at -20 °C for 30 minutes, and then tin(II) chloride dihydrate (2.30 g, 12.3 mmol) dissolved in concentrated HCl (2.00 mL) was slowly added. After stirring at 0 °C for 1 hour, a mixture of ethanol and ethyl ether (3:7) was added to the reaction mixture and stirred for an additional hour. The resulting solid was filtered, washed with ethyl ether, and then dried to give the title compound (530 mg, 57%) as a pale pink solid. MS m / z: 189 [M+1] + (Step 2) Preparation of tert-butyl 8-ethoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0394] [ka] The compound prepared above (Step 1) (500 mg, 2.65 mmol) was dissolved in toluene (10.0 mL), and then tert-butyl-3-oxopiperidine-1-carboxylate (528 mg, 2.65 mmol) and propanephosphonic anhydride (0.33 mL, 0.53 mmol) were added sequentially to the mixture. The reaction mixture was stirred at 90 °C under nitrogen for 4 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate were added, and the mixture was 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 as a yellow solid. (101 mg, 12%) MS m / z: 317 [M+1] + (Step 3) Preparation of 8-ethoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0395] [ka] The compound prepared above (Step 2) (100 mg, 0.32 mmol) was dissolved in methylene chloride (2.00 mL), and then trifluoroacetic acid (1.00 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ethyl ether, and then n-hexane was added. The resulting solid was filtered, washed with a mixed solution of ethyl ether / n-hexane, and dried to give the title compound as a red solid. (68.5 mg) MS m / z: 217 [M+1] + (Step 4) Preparation of 8-ethoxy-5H-pyrido[3,2-b]indole

[0396] [ka] The compound prepared above (Step 3) (68.5 mg, 0.32 mmol) was dissolved in toluene (2.00 mL), and then Pd / C (50% by weight, 34.0 mg) was added to the mixture. The mixture was stirred at 100° C. under nitrogen for 15 hours. It was cooled to room temperature, and the precipitate was removed by filtration using Celite. 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 as a green solid. (65.0 mg, 97%) MS m / z: 213 [M+1] + (Step 5) Preparation of 8-ethoxy-5-(4-(methylthio)benzyl)-5H-pyrido[3,2-b]indole

[0397] [ka] The compound prepared above (Step 4) (31.0 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (13.0 mg, 26%) MS m / z: 349 [M+1] + (Step 6) Preparation of (4-((8-ethoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(imino)(methyl)-16-sulfanone (compound 24)

[0398] [ka] The compound prepared above (Step 5) (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 under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a yellow solid. (8.20 mg, 55%) MS m / z: 380 [M+1] + 1H NMR (400 MHz, CD3OD) δ 8.66 (d, J = 5.4 Hz, 1H), 8.57 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 2.3 Hz, 1H), 7.84 (dd, J = 8.6, 5.4 Hz, 1H), 7.66 (d, J = 9.1 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.41 (dd, J = 9.1, 2.5 Hz, 1H), 5.97 (s, 2H), 4.20 (q, J = 7.0 Hz, 2H), 3.45 (s, 3H), 1.51 - 1.43 (m, 3H).

[0399] [Example 25] Preparation of 4-((6-fluoro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 25)

[0400] [ka] TIFF2025525335000195.tif71163 (Step 1) Preparation of (2-fluoro-4-methoxyphenyl)hydrazine hydrochloride

[0401] [ka] 2-Fluoro-4-methoxyaniline (1.00 g, 7.09 mmol) was dissolved in a 1:1 mixture of concentrated HCl and distilled water (12.0 mL). Sodium nitrite (538 mg, 7.79 mmol) dissolved in 5.00 mL of saturated brine was then slowly added to the mixture at -20 °C. The reaction mixture was stirred under nitrogen at -20 °C for 30 minutes, and then tin(II) chloride dihydrate (3.18 g, 14.2 mmol) dissolved in concentrated HCl (4.00 mL) was slowly added. After stirring at 0 °C for 1 hour, a 3:7 mixture of ethanol and ethyl ether was added to the reaction mixture, which was then further stirred for 2 hours. The resulting solid was filtered, washed with ethyl ether, and dried to give the title compound (582 mg, 53%) as a gray solid. MS m / z: 157 [M+1] + (Step 2) Preparation of tert-butyl 6-fluoro-8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0402] [ka] The compound prepared above (Step 1) (100 mg, 0.52 mmol) was dissolved in toluene (63.0 mL), and then tert-butyl-3-oxopiperidine-1-carboxylate (124 mg, 0.62 mmol) and propanephosphonic anhydride (53.0 μL, 0.10 mmol) were added sequentially to the mixture. The reaction mixture was stirred at 90°C under nitrogen for 6 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate were added, and the mixture was 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 give the title compound as a yellow solid. (34.9 mg, 21%) MS m / z: 321 [M+1] + (Step 3) Preparation of 6-fluoro-8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0403] [ka] The compound prepared above (Step 2) (34.9 mg, 0.11 mmol) was dissolved in methylene chloride (1.10 mL), and then trifluoroacetic acid (0.50 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ethyl ether, and then n-hexane was added. The resulting solid was filtered, washed with a mixed solution of ethyl ether / n-hexane, and dried to give the title compound as a brown solid. (34.0 mg, 100%) MS m / z: 221 [M+1] + (Step 4) Preparation of 6-fluoro-8-methoxy-5H-pyrido[3,2-b]indole

[0404] [ka] The compound prepared above (Step 3) (34.0 mg, 0.11 mmol) was dissolved in dimethyl sulfoxide (1.00 mL) and then stirred at 90°C under nitrogen for 12 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate solution were added, and the mixture was 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 as a yellow solid. (10.6 mg, 45%) MS m / z: 217 [M+1] + (Step 5) Preparation of 4-((6-fluoro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 25)

[0405] [ka] The compound prepared above (Step 4) (10.6 mg, 0.05 mmol) was dissolved in N,N-dimethylformamide (0.50 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (7.00 mg, 37%) MS m / z: 386 [M+1] + 1 H NMR (400 MHz, CD3OD) δ 8.61 (s, 1H), 8.38 (d, J = 8.3 Hz, 1H), 7.80 (d, J = 7.6 Hz, 2H), 7.72 (d, J = 9.5 Hz, 2H), 7.31 - 7.23 (m, 2H), 7.13 (d, J = 14.8 Hz, 1H), 5.90 (s, 2H), 3.94 (s, 3H).

[0406] [Example 26] Preparation of 4-((6-methoxy-8-methyl-9H-pyrido[3,4-b]indol-9-yl)methyl)benzenesulfonamide (Compound 26)

[0407] [ka] TIFF2025525335000202.tif72162 (Step 1) Preparation of (4-methoxy-2-methylphenyl)hydrazine hydrochloride

[0408] [ka] 4-Methoxy-2-methylaniline (2.00 g, 14.6 mmol) was dissolved in a 1:1 mixture of concentrated HCl and distilled water (20.0 mL). Sodium nitrite (1.11 g, 16.0 mmol) dissolved in 5.00 mL of saturated brine was then slowly added to the mixture at -20 °C. The reaction mixture was stirred under nitrogen at -20 °C for 30 minutes, and then tin(II) chloride dihydrate (6.58 g, 29.2 mmol) dissolved in concentrated HCl (5.00 mL) was slowly added. After stirring at 0 °C for 1 hour, a 3:7 mixture of ethanol and ethyl ether was added to the reaction mixture, which was further stirred for 2 hours. The resulting solid was filtered, washed with ethyl ether, and then dried to give the title compound (1.85 g, 83%) as a gray solid. MS m / z: 151 [M+1] + (Step 2) Preparation of tert-butyl 8-methoxy-6-methyl-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0409] [ka] The compound prepared above (Step 1) (300 mg, 1.59 mmol) was dissolved in toluene (15.9 mL), and then tert-butyl-3-oxopiperidine-1-carboxylate (380 mg, 1.91 mmol) and propanephosphonic anhydride (202 mL, 0.32 mmol) were added sequentially to the mixture. The reaction mixture was stirred at 90°C under nitrogen for 6 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate were added, and the mixture was 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 give the title compound as a yellow solid. (38.9 mg, 7%) MS m / z: 317 [M+1] + (Step 3) Preparation of 8-methoxy-6-methyl-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0410] [ka] The compound prepared above (Step 2) (38.9 mg, 0.123 mmol) was dissolved in methylene chloride (1.00 mL), and then trifluoroacetic acid (0.50 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ethyl ether, and then n-hexane was added. The resulting solid was filtered, washed with a mixed solution of ethyl ether / n-hexane, and dried to give the title compound as a brown solid. (38.7 mg, 100%) MS m / z: 217 [M+1] + (Step 4) Preparation of 8-methoxy-6-methyl-5H-pyrido[3,2-b]indole

[0411] [ka] The compound prepared above (Step 3) (38.7 mg, 0.12 mmol) was dissolved in dimethyl sulfoxide (0.20 mL) and then stirred at 90°C under nitrogen for 12 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate solution were added, and the mixture was 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 as a yellow solid. (13.5 mg, 52%) MS m / z: 213 [M+1] + (Step 5) Preparation of 4-((8-methoxy-6-methyl-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 26)

[0412] [ka] The compound prepared above (Step 4) (13.5 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (0.60 mL) and cooled to 0 °C. 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, which was then stirred at 0 °C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (3.9 mg, 16%) MS m / z: 382 [M+1] + 1 H NMR (400 MHz, CD3OD) δ 8.53 (s, 1H), 8.20 (s, 1H), 7.80 (d, J = 7.6 Hz, 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).

[0413] [Example 27] Preparation of 4-((6-chloro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 27)

[0414] [ka] TIFF2025525335000209.tif71162 (Step 1) Preparation of (2-chloro-4-methoxyphenyl)hydrazine hydrochloride

[0415] [ka] (2-Chloro-4-methoxyphenyl)hydrazine (800 mg, 5.08 mmol) was dissolved in 6N HCl (9.00 mL), and then sodium nitrite (525 mg, 7.61 mmol) dissolved in saturated brine solution (3.00 mL) was slowly added to the mixture at -20 °C. The reaction mixture was stirred under nitrogen at -20 °C for 30 minutes, and then tin(II) chloride dihydrate (4.00 g, 17.8 mmol) dissolved in concentrated HCl (2.00 mL) was slowly added. After stirring at 0 °C for 1 hour, a mixture of ethanol and ethyl ether (3:7) was added to the reaction mixture and stirred for an additional hour. The resulting solid was filtered, washed with ethyl ether, and then dried to give the title compound (303 mg, 35%) as a white solid. MS m / z: 173 [M+1] + (Step 2) Preparation of tert-butyl 6-chloro-8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0416] [ka] The compound prepared above (Step 1) (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 sequentially to the mixture. The reaction mixture was stirred at 90 °C under nitrogen for 6 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate were added, and the mixture was 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 as a yellow solid. (90.0 mg, 15%) MS m / z: 337 [M+1] + (Step 3) Preparation of 6-chloro-8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0417] [ka] The compound prepared above (Step 2) (90.0 mg, 0.27 mmol) was dissolved in methylene chloride (2.00 mL), and then trifluoroacetic acid (2.00 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ethyl ether, and then n-hexane was added. The resulting solid was filtered, washed with a mixed solution of ethyl ether / n-hexane, and dried to give the title compound as a brown solid. (51.0 mg, 80%) MS m / z: 237 [M+1] + (Step 4) Preparation of 6-chloro-8-methoxy-5H-pyrido[3,2-b]indole

[0418] [ka] The compound prepared above (Step 3) (51.0 mg, 0.22 mmol) was dissolved in dimethyl sulfoxide (2.00 mL) and then stirred at 90°C under nitrogen for 12 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate were added, and the mixture was 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 as a yellow solid. (21.0 mg, 41%) MS m / z: 233 [M+1] + (Step 5) Preparation of 4-((6-chloro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 27)

[0419] [ka] The compound prepared above (Step 4) (11.0 mg, 0.05 mmol) was dissolved in N,N-dimethylformamide (0.50 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 2 hours. After the reaction was completed, distilled water was slowly added to the mixture, and the mixture was 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 as a yellow solid. (1.60 mg, 8%) MS m / z: 402 [M+1] + 1 H NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 8.34 (d, J = 8.5 Hz, 1H), 7.91 (s, 1H), 7.85 - 7.69 (m, 3H), 7.35 (s, 1H), 7.19 (q, J = 2.8 Hz, 2H), 6.20 (s, 2H), 3.96 (t, J = 2.4 Hz, 3H).

[0420] [Example 28] Preparation of 4-((7,8-dimethoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 28)

[0421] [ka] TIFF2025525335000216.tif78163 (Step 1) Preparation of (3,4-dimethoxyphenyl)hydrazine hydrochloride

[0422] [ka] 3,4-Dimethoxyaniline (1.00 g, 6.52 mmol) was dissolved in 6 N HCl (9.00 mL), and then sodium nitrite (675 mg, 6.79 mmol) dissolved in 2.00 mL of saturated brine solution was slowly added to the mixture at -20 °C. The reaction mixture was stirred under nitrogen at -20 °C for 30 minutes, and then tin(II) chloride dihydrate (4.42 g, 19.6 mmol) dissolved in concentrated HCl (2.00 mL) was slowly added. After stirring at 0 °C for 1 hour, a mixture of ethanol and ethyl ether (3:7) was added to the reaction mixture and stirred for an additional hour. The resulting solid was filtered, washed with ethyl ether, and then dried to give the title compound (713 mg, 53%) as a white solid. MS m / z: 205 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 3H), 7.02 (d, J = 8.6 Hz, 1H), 6.98 (s, 1H), 6.70 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H) (Step 2) Preparation of tert-butyl 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0423] [ka] The compound prepared above (Step 1) (713 mg, 3.48 mmol) was dissolved in toluene (10.0 mL), and then tert-butyl-3-oxopiperidine-1-carboxylate (833 mg, 4.18 mmol) and propanephosphonic anhydride (0.35 mL, 0.69 mmol) were added sequentially to the mixture. The reaction mixture was stirred at 90 °C under nitrogen for 3 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate were added, and the mixture was 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 give the title compound as a yellow solid. (492 mg, 42 %) MS m / z: 333 [M+1] + 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.14 (s, 1H), 6.77 (s, 1H), 3.91 (dd, J = 14.2, 2.4 Hz, 6H), 3.75 (d, J = 5.3 Hz, 2H), 2.80 (s, 2H), 2.04 (d, J = 2.6 Hz, 2H), 1.53 (d, J = 2.1 Hz, 9H). (Step 3) Preparation of 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0424] [ka] The compound prepared above (Step 2) (492 mg, 1.48 mmol) was dissolved in methylene chloride (5.00 mL), and then trifluoroacetic acid (2.00 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ethyl ether, and then n-hexane was added. The resulting solid was filtered, washed with a mixed solution of ethyl ether / n-hexane, and dried to give the title compound as a brown solid. (512 mg, 100%) MS m / z: 233 [M+1] + (Step 4) Preparation of 7,8-dimethoxy-5H-pyrido[3,2-b]indole

[0425] [ka] The compound prepared above (Step 3) (512 mg, 1.48 mmol) was dissolved in dimethyl sulfoxide (1.00 mL), and the reaction mixture was 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 give the title compound as a yellow solid (40.0 mg, 12%). MS m / z: 0.229 [M+1] + (Step 5) Preparation of 4-((7,8-dimethoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 28)

[0426] [ka] The compound prepared above (Step 4) (40.0 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (1.00 mg, 1%) MS m / z: 398 [M+1] + 1 H NMR (400 MHz, CD3OD) δ 8.56 (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)

[0427] [Example 29] Preparation of 4-((7-fluoro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 29)

[0428] [ka] TIFF2025525335000223.tif73164 (Step 1) Preparation of (3-fluoro-4-methoxyphenyl)hydrazine hydrochloride

[0429] [ka] 3-Fluoro-4-methoxyaniline (1.00 g, 7.08 mmol) was dissolved in 6N HCl (9.00 mL), and then sodium nitrite (733 mg, 10.6 mmol) dissolved in 2.00 mL of saturated brine solution was slowly added to the mixture at -20 °C. The reaction mixture was stirred under nitrogen at -20 °C for 30 minutes, and then tin(II) chloride dihydrate (4.80 g, 21.3 mmol) dissolved in concentrated HCl (2.00 mL) was slowly added. After stirring at 0 °C for 1 hour, a mixture of ethanol and ethyl ether (3:7) was added to the reaction mixture and stirred for an additional hour. The resulting solid was filtered, washed with ethyl ether, and then dried to give the title compound (1.20 g, 88%) as a white solid. MS m / z: 193 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 3H), 8.08 (s, 1H), 7.12 (td, J = 9.0, 5.3 Hz, 1H), 6.95 (dd, J = 13.1, 2.7 Hz, 1H), 6.79 (d, J = 9.4 Hz, 1H), 3.78 (s, 3H). (Step 2) Preparation of tert-butyl 7-fluoro-8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0430] [ka] The compound prepared above (Step 1) (1.20 g, 6.22 mmol) was dissolved in toluene (10.0 mL), and then tert-butyl-3-oxopiperidine-1-carboxylate (1.49 mg, 7.47 mmol) and propanephosphonic anhydride (0.64 mL, 1.24 mmol) were added sequentially to the mixture. The reaction mixture was stirred at 90 °C under nitrogen for 3 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate were added, and the mixture was 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 as a yellow solid. (760 mg, 38%) MS m / z: 321 [M+1] + 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 5.5 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 6.98 (d, J = 11.3 Hz, 1H), 3.93 (s, 3H), 3.80 - 3.71 (m, 2H), 2.81 (t, J = 6.7 Hz, 2H), 2.11 - 1.99 (m, 2H), 1.56 (s, 9H) (Step 3) Preparation of 7-fluoro-8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0431] [ka] The compound prepared above (Step 2) (760 mg, 2.37 mmol) was dissolved in methylene chloride (5.00 mL), and then trifluoroacetic acid (2.00 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ethyl ether, and then n-hexane was added. The resulting solid was filtered, washed with a mixed solution of ethyl ether / n-hexane, and dried to give the title compound as a brown solid. (792 mg, 99%) MS m / z: 221 [M+1] + (Step 4) Preparation of 7-fluoro-8-methoxy-5H-pyrido[3,2-b]indole

[0432] [ka] The compound prepared above (Step 3) (392 mg, 2.37 mmol) was dissolved in toluene (15.0 mL), and then Pd / C (10 wt%, 370 mg) was added to the mixture. The reaction mixture was stirred under nitrogen at 120° C. for 25 hours. The precipitate was removed by filtration using Celite, and the filtrate was 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 as a yellow solid. (370 mg, 72%) MS m / z: 217 [M+1] + 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 4.4 Hz, 1H), 8.34, (bs, 1H), 7.89 (d, J = 8.4 Hz, 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). (Step 5) Preparation of 4-((7-fluoro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 29)

[0433] [ka] The compound prepared above (Step 4) (80.0 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 60% sodium hydride (29.0 mg, 0.74 mmol) was added to the mixture, which was then 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was complete, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (36.0 mg, 25%) MS m / z: 386 [M+1] + 1 H NMR (400 MHz, CD3OD) δ 8.65 (dd, J = 5.5, 1.1 Hz, 1H), 8.55 (dd, J = 8.4, 1.1 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.85 - 7.79 (m, 3H), 7.63 (d, J = 11.3 Hz, 1H), 7.38 - 7.28 (m, 2H), 5.86 (s, 2H), 4.04 (s, 3H).

[0434] [Example 30] Preparation of (4-((7-fluoro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(imino)(methyl)-16-sulfanone (Compound 30)

[0435] [ka] (Step 1) Preparation of 7-fluoro-8-methoxy-5-(4-(methylthio)benzyl)-5H-pyrido[3,2-b]indole

[0436] [ka] The compound prepared in Example 29 (Step 4) (50.0 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (50.0 mg, 60%) MS m / z: 353 [M+1] + 1 H NMR (400 MHz, CDCl3) δ 8.54 (dd, J = 4.7, 1.3 Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.62 (dd, J = 8.3, 1.4 Hz, 1H), 7.30 (dd, J = 8.3, 4.6 Hz, 1H), 7.19 - 7.09 (m, 3H), 7.01 (d, J = 8.6 Hz, 2H), 5.40 (s, 2H), 4.02 (s, 3H), 2.43 (s, 3H). (Step 2) Preparation of (4-((7-fluoro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(imino)(methyl)-16-sulfanone (Compound 30)

[0437] [ka] The compound prepared above (Step 1) (50.0 mg, 0.14 mmol) 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 under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid (53.0 mg, 96%). Compound 30 was purified by preparative high performance liquid chromatography (preparative HPLC, chiralpak IC (5 × 100 mm, 5 μm), hexane:methanol:ethanol=40:30:30) to give 30a and 30b, which were white optical isomers, respectively. 30a: [α]D23 + 3 ° (c 0.1, CHCl3), 30b: [α]D23 - 3 ° (c 0.1, CHCl3).MS m / z: 384 [M+1] +1 H NMR (400 MHz, CD3OD) δ 8.72 (dd, J = 5.6, 1.1 Hz, 1H), 8.66 (dd, J = 8.4, 1.1 Hz, 1H), 8.09 (dt, J = 8.4, 2.0 Hz, 3H), 7.89 (dd, J = 8.5, 5.6 Hz, 1H), 7.62 (d, J = 11.1 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 6.01 (s, 2H), 4.05 (s, 3H), 3.70 (s, 3H).

[0438] [Example 31] Preparation of (3-fluoro-4-((7-fluoro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(imino)(methyl)-16-sulfanone (Compound 31)

[0439] [ka] TIFF2025525335000233.tif42162 (Step 1) Preparation of 7-fluoro-5-(2-fluoro-4-(methylthio)benzyl)-8-methoxy-5H-pyrido[3,2-b]indole

[0440] [ka] The compound prepared in Example 29 (Step 4) (50.0 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (50.0 mg, 58%) MS m / z: 371 [M+1] + (Step 2) Preparation of (3-fluoro-4-((7-fluoro-8-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(imino)(methyl)-16-sulfanone (Compound 31)

[0441] [ka] The compound prepared above (Step 1) (42.0 mg, 0.11 mmol) 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 under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid (45.0 mg, 99%). Compound 31 was purified by preparative high performance liquid chromatography (preparative HPLC, chiralpak IC (5 × 100 mm, 5 μm), hexane:methanol:ethanol=40:30:30) to give 31a and 31b, which were white optical isomers. 31a: [α]D23 + 9 ° (c 0.12, CHCl3), 3b: [α]D23 - 7 ° (c 0.12, CHCl3). MS m / z: 402 [M+1] + 1 H NMR (400 MHz, CD3OD) δ 8.75 - 8.67 (m, 2H), 8.07 (d, J = 8.1 Hz, 1H), 7.98 - 7.88 (m, 2H), 7.85 - 7.77 (m, 1H), 7.68 (d, J = 11.1 Hz, 1H), 7.37 - 7.28 (m, 1H), 6.01 (s, 2H), 4.04 (s, 3H), 3.50 (s, 3H).

[0442] [Example 32] Preparation of (4-((8-fluoro-7-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(imino)(methyl)-16-sulfanone (Compound 32)

[0443] [ka] (Step 1) Preparation of (4-fluoro-3-methoxyphenyl)hydrazine hydrochloride

[0444] [ka] 4-Fluoro-3-methoxyaniline (1.00 g, 7.08 mmol) was dissolved in 6N HCl (4.00 mL), and then sodium nitrite (733 mg, 10.6 mmol) dissolved in 2.00 mL of saturated brine solution was slowly added to the mixture at −20° C. The reaction mixture was stirred under nitrogen at −20° C. for 30 minutes, and then tin(II) chloride dihydrate (4.80 g, 21.3 mmol) dissolved in concentrated HCl (2.00 mL) was slowly added. After stirring at 0° C. for 1 hour, the solid formed in the reaction mixture was filtered, washed with concentrated hydrochloric acid, and then dried to give the title compound (1.10 g, 80%) as a white solid. MS m / z: 193 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 2H), 8.08 (s, 1H), 7.15 (dd, J = 11.4, 8.8 Hz, 1H), 6.85 (dd, J = 7.4, 2.7 Hz, 1H), 6.49 (dt, J = 8.6, 3.1 Hz, 1H), 3.81 (s, 3H). (Step 2) Preparation of tert-butyl 8-fluoro-7-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0445] [ka] The compound prepared above (Step 1) (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 sequentially to the mixture. The reaction mixture was stirred at 90 °C under nitrogen for 3 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate were added, and the mixture was 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 as a pale yellow solid. (95.0 mg, 28%) MS m / z: 321 [M+1] + 1 H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.46 - 7.29 (m, 1H), 6.76 (d, J = 7.1 Hz, 1H), 3.88 (s, 3H), 3.79 - 3.70 (m, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.04 (q, J = 3.3 Hz, 2H), 1.53 (s, 9H). (Step 3) Preparation of 8-fluoro-7-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-trifluoroacetic acid

[0446] [ka] The compound prepared above (Step 2) (95.0 mg, 0.29 mmol) was dissolved in methylene chloride (1.00 mL), and then trifluoroacetic acid (1.00 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was dissolved in ethyl ether, and then n-hexane was added. The resulting solid was filtered, washed with a mixed solution of ethyl ether / n-hexane, and dried to give the title compound as a brown solid. (95.0 mg, 99%) MS m / z: 221 [M+1] + (Step 4) Preparation of 8-fluoro-7-methoxy-5H-pyrido[3,2-b]indole

[0447] [ka] The compound prepared above (Step 3) (95.0 mg, 0.29 mmol) was dissolved in toluene (5.00 mL), and then Pd / C (10% by weight, 50.0 mg) was added to the mixture. The reaction mixture was stirred under nitrogen at 120° C. for 18 hours. The precipitate was removed by filtration using Celite, and the filtrate was 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 as a yellow solid. (40.0 mg, 65%) MS m / z: 217 [M+1] + (Step 5) Preparation of 8-fluoro-7-methoxy-5-(4-(methylthio)benzyl)-5H-pyrido[3,2-b]indole

[0448] [ka] The compound prepared above (Step 4) (40.0 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 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 stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a pale yellow solid. (25.0 mg, 39%) MS m / z: 353 [M+1] + 1H NMR (400 MHz, CD3OD) δ 8.39 (dd, J = 4.8, 1.4 Hz, 1H), 7.97 (d, J = 10.9 Hz, 1H), 7.88 (dd, J = 8.3, 1.4 Hz, 1H), 7.37 (dd, J = 8.3, 4.8 Hz, 1H), 7.23 (d, J = 6.9 Hz, 1H), 7.21 - 7.14 (m, 2H), 7.07 (d, J = 8.4 Hz, 2H), 5.60 (s, 2H), 3.95 (s, 3H), 2.40 (s, 3H). (Step 6) Preparation of (4-((8-fluoro-7-methoxy-5H-pyrido[3,2-b]indol-5-yl)methyl)phenyl)(imino)(methyl)-16-sulfanone (Compound 32)

[0449] [ka] The compound prepared above (Step 5) (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 under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a yellow solid. (19.5 mg, 71%) MS m / z: 384 [M+1] + 1H NMR (400 MHz, CD3OD) δ 8.66 (d, J = 5.8 Hz, 1H), 8.58 (d, J = 8.5 Hz, 1H), 8.15 - 8.04 (m, 3H), 7.83 (dd, J = 8.4, 5.7 Hz, 1H), 7.57 - 7.51 (m, 2H), 7.46 (d, J = 6.8 Hz, 1H), 6.06 (s, 2H), 4.02 (s, 3H), 3.60 (s, 3H).

[0450] [Example 33] Preparation of 4-((6-methoxy-3-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-9-yl)methyl)benzenesulfonamide (Compound 33)

[0451] [ka] (Step 1) Preparation of (E)-5-methoxy-3-(2-nitroprop-1-en-1-yl)-1H-indole

[0452] [ka] Nitroethane (257 mg, 3.42 mmol) and ammonium acetate (329 mg, 4.27 mmol) were added sequentially to 5-methoxy-1H-indole-3-carbaldehyde (500 mg, 2.85 mmol). The reaction mixture was stirred at 90°C under nitrogen for 6 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate solution were added, and the mixture was 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 as a white solid. (410 mg, 75%) MS m / z: 233 [M+1] + 1H NMR (400 MHz, DMSO-d6) δ 12.11 (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). (Step 2) Preparation of 1-(5-methoxy-1H-indol-3-yl)propan-2-amine

[0453] [ka] The compound prepared above (Step 1) (410 mg, 1.75 mmol) was dissolved in tetrahydrofuran (3.00 mL), and then lithium aluminum hydride (133 mg, 3.52 mmol) was added to the mixture. The reaction mixture was stirred at 80°C under nitrogen for 10 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate solution were added, and the mixture was 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 as a white solid. (280 mg, 55%) MS m / z: 205 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ 8.51(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). (Step 3) Preparation of 6-methoxy-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

[0454] [ka] Formaldehyde (5.0 mL) was added to the compound (100 mg, 0.49 mmol) prepared above (Step 2). The reaction mixture was stirred at 80°C for 5 hours under nitrogen. After cooling to room temperature, distilled water and aqueous sodium bicarbonate solution were added, and the mixture was 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 as a white solid. (33.0 mg) MS m / z: 217 [M+1] + (Step 4) Preparation of tert-butyl 6-methoxy-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate

[0455] [ka] The compound prepared above (Step 3) (33.0 mg, 0.15 mmol) was dissolved in methylene chloride (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, successively. The reaction mixture was stirred at room temperature under nitrogen for 8 hours. After the reaction was completed, distilled water and aqueous sodium bicarbonate were added, and the mixture was 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 as a white solid. (13.0 mg, 48%) MS m / z: 317 [M+1] + (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

[0456] [ka] The compound prepared above (Step 4) (13.0 mg, 0.04 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 (methylene chloride:methanol = 20:1 → 9:1) to give the title compound as a yellow solid. (8.50 mg, 43%) MS m / z: 486 [M+1] + (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)

[0457] [ka] The compound prepared above (Step 5) (8.00 mg, 0.02 mmol) was dissolved in methylene chloride (1.50 mL), and then trifluoroacetic acid (1.50 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at room temperature 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 as a yellow solid. (4.10 mg, 5%) MS m / z: 386 [M+1] + 1H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J=8.4 Hz, 2H), 7.32 (s, 3H), 7.17 (d, J=8.4 Hz, 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=6.4 Hz, 3H).

[0458] [Example 34] Preparation of 4-((3-methoxy-5,6,7,8-tetrahydro-9H-pyrrolo[2,3-b:5,4-c']dipyridin-9-yl)methyl)benzenesulfonamide (compound 34)

[0459] [ka] (Step 1) Preparation of 5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde

[0460] [ka] Phosphoryl chloride (51.7 g, 337 mmol) and N,N-dimethylformamide (30.0 mL) were added sequentially to the mixture at 0° C., followed by stirring 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, followed by stirring at 80° C. for 3 hours. After the reaction was completed, it was cooled to room temperature, and 2 M aqueous sodium hydroxide solution (pH=9) was added. The reaction mixture was extracted three times with ethyl acetate. Ethyl acetate was added to the mixture, and the resulting solid was filtered and dried to give the title compound as a yellow solid. (2.68 g, 45%) MS m / z: 304 [M+1] + 1H NMR (400 MHz, DMSO-d6) δ 12.60 (br s, 1H), 9.89 (s, 1H), 8.40 (s, 1H), 8.11 (d, J=2.9 Hz, 1H), 7.91 (d, J=2.9 Hz, 1H), 3.86 (s, 3H). (Step 2) Preparation of (E)-5-methoxy-3-(2-nitrovinyl)-1H-pyrrolo[2,3-b]pyridine

[0461] [ka] The compound prepared above (Step 1) (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 under nitrogen at 85°C for 1 hour. After the reaction was completed, distilled water was added and extracted with methylene chloride. 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 (400 MHz, 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). (Step 3) Preparation of 2-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-amine

[0462] [ka] The compound prepared above (Step 2) (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 under nitrogen for 5 hours. After the reaction was completed, distilled water and 15% aqueous sodium hydroxide solution (2.6 mL) were added, followed by extraction twice with a mixed solution of methylene chloride:methanol = 5:1. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The title compound was obtained as a brown oil without further purification. (2.00 g) MS m / z: 192 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ 11.66 (br s, 1H), 8.04 (br d, J=2.5 Hz, 3H), 7.86 (d, J=2.4 Hz, 1H), 7.41 (d, J=2.3 Hz, 1H), 3.87 (s, 3H), 3.12 - 2.97 (m, 4H). (Step 4) Preparation of 3-methoxy-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:5,4-c']dipyridine

[0463] [ka] The compound prepared above (Step 3) (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. under nitrogen for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give the title compound as a yellow solid without further purification. (75.0 mg, 53%) MS m / z: 204 [M+1] + (Step 5) Preparation of tert-butyl 3-methoxy-5,6,8,9-tetrahydro-7H-pyrrolo[2,3-b:5,4-c']dipyridine-7-carboxylate

[0464] [ka] The compound prepared above (Step 4) (75.0 mg, 0.37 mmol) was dissolved in methylene chloride (2.00 mL) and then cooled to 0°C. Triethylamine (80.0 μL, 0.55 mmol) and di-tert-butyl dicarbonate (93.0 μL, 0.41 mmol) were added to the mixture, which was then stirred at room temperature under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was extracted twice with methylene chloride. 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 give the title compound as a yellow solid. (30.0 mg, 26%) MS m / z: 304 [M+1] + (Step 6) Preparation of tert-butyl 3-methoxy-9-(4-sulfamoylbenzyl)-5,6,8,9-tetrahydro-7H-pyrrolo[2,3-b:5,4-c']dipyridine-7-carboxylate

[0465] [ka] The compound prepared above (Step 5) (30.0 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (25.0 mg, 53%) MS m / z: 473 [M+1] + (Step 7) Preparation of 4-((3-methoxy-5,6,7,8-tetrahydro-9H-pyrrolo[2,3-b:5,4-c']dipyridin-9-yl)methyl)benzenesulfonamide (compound 34)

[0466] [ka] The compound prepared above (Step 6) (25.0 mg, 0.05 mmol) was dissolved in methylene chloride (0.50 mL), and then trifluoroacetic acid (0.50 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at room temperature 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 as a yellow solid. (2.30 mg, 12%) MS m / z: 373 [M+1] + 1 H NMR (400 MHz, CD3OD) δ 8.04 (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).

[0467] [Example 35] Preparation of 4-((7-methoxy-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)methyl)benzenesulfonamide (Compound 35)

[0468] [ka] (Step 1) Preparation of tert-butyl 7-methoxy-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0469] [ka] (3-Methoxyphenyl)hydrazine hydrochloride (2.00 g, 11.5 mmol) was dissolved in toluene (5.00 mL), and then tert-butyl-4-oxopiperidine-1-carboxylate (2.70 g, 13.8 mmol) and propanephosphonic anhydride (2.50 g, 17.2 mmol) were added to the mixture in sequence. The reaction mixture was stirred at 90 °C under nitrogen for 6 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate were added, and the mixture was 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 1:2) to obtain the title compound as a yellow solid. (180 mg) MS m / z: 303 [M+1] + (Step 2) Preparation of tert-butyl 7-methoxy-5-(4-sulfamoylbenzyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0470] [ka] The compound prepared above (Step 1) (20.0 mg, 0.07 mmol) was dissolved in N,N-dimethylformamide (1.50 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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:methylene chloride = 5:95 → 10:90) to give the title compound as a yellow solid. (5.10 mg, 16%) MS m / z: 472 [M+1] + (Step 3) Preparation of 4-((7-methoxy-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)methyl)benzenesulfonamide (Compound 35)

[0471] [ka] The compound prepared above (Step 2) (5.00 mg, 0.01 mmol) was dissolved in methylene chloride (2.00 mL), and then trifluoroacetic acid (2.00 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at room temperature 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 as a yellow solid. (1.50 mg, 40%) MS m / z: 372 [M+1] +

[0472] [Example 36] Preparation of 4-((8-methoxy-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)methyl)benzenesulfonamide (Compound 36)

[0473] [ka] (Step 1) Preparation of tert-butyl 8-methoxy-5-(4-sulfamoylbenzyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0474] [ka] The compound prepared in Example 4 (Step 1) (180 mg, 0.60 mmol) was dissolved in N,N-dimethylformamide (3.00 mL) and cooled to 0°C. 60% sodium hydride (90.0 mg, 2.25 mmol) was added to the mixture, which was then stirred for 30 minutes. Intermediate 1 (178 mg, 0.71 mmol) was slowly added to the reaction mixture, which was then stirred for 2 hours at 0°C under nitrogen. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a yellow solid. (128 mg, 46%) MS m / z: 472 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 7.81 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.9 Hz, 1H), 6.95 (s, 1H), 6.79 (d, J = 8.6 Hz, 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). (Step 2) Preparation of 4-((8-methoxy-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)methyl)benzenesulfonamide (Compound 36)

[0475] [ka] The compound prepared above (Step 1) (128 mg, 0.27 mmol) was dissolved in methylene chloride (1.00 mL), and then trifluoroacetic acid (1.00 mL) was added to the mixture. The reaction mixture was stirred at room temperature under 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 as a yellow solid. (48.0 mg, 47%) MS m / z: 372 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.03 (s, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.45-7.30 (m, 3H), 7.20 (d, J = 8.1 Hz, 2H), 7.09 (s, 1H), 6.79 (d, J = 8.9 Hz, 1H), 5.48 (s, 2H), 4.35 (s, 2H), 3.78 (s, 3H), 2.99 (s, 2H).

[0476] [Example 37] Preparation of 4-((7-methoxy-1,2,3,4-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 37)

[0477] [ka] (Step 1) Preparation of tert-butyl 7-methoxy-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0478] [ka] 1,3-Dimethylurea (8.81 g, 100 mmol) and L-(+)-tartaric acid (4.50 g, 30.0 mmol) were mixed, and the reaction mixture was stirred at 80 °C for 2 hours under nitrogen. (3-Methoxyphenyl)hydrazine hydrochloride (1.87 g, 11.0 mmol) and tert-butyl-3-oxopiperidine-1-carboxylate (2.00 mg, 10.0 mmol) were added sequentially to the reaction mixture, which was then stirred at 80 °C for 2 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate were added, and the mixture was extracted twice with methylene chloride. 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 2:8) to give the title compound as a yellow solid. (471 mg, 15%) MS m / z: 303 [M+1] + 1 H NMR (400 MHz, CDCl3) δ 7.56-7.48 (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) (Step 2) Preparation of tert-butyl 7-methoxy-5-(4-sulfamoylbenzyl)-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0479] [ka] The compound prepared above (Step 1) (100 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (64.0 mg, 41%) MS m / z: 472 [M+1] + (Step 3) Preparation of 4-((7-methoxy-1,2,3,4-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 37)

[0480] [ka] The compound prepared above (Step 2) (64.0 mg, 0.13 mmol) was dissolved in methylene chloride (2.00 mL), and then hydrogen chloride (4 M in 1,4-dioxane, 1.00 mL) was added to the mixture. The reaction mixture was stirred at room temperature under 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 as a yellow solid. (33.0 mg, 52%) MS m / z: 372 [M+1] + 1H NMR (400 MHz, CD3OD) δ 7.83 (d, J=7.6 Hz, 2H), 7.50-7.41 (m, 1H), 7.19 (d, J=8.4 Hz, 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)

[0481] [Example 38] Preparation of 4-((8-methoxy-1,2,3,4-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (compound 38)

[0482] [ka] (Step 1) Preparation of tert-butyl 8-methoxy-5-(4-sulfamoylbenzyl)-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0483] [ka] The compound prepared in Example 5 (Step 1) (200 mg, 0.66 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a yellow solid. (22.0 mg, 7%) MS m / z: 472 [M+1] + (Step 2) Preparation of 4-((8-methoxy-1,2,3,4-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (compound 38)

[0484] [ka] The compound prepared above (Step 1) (11.0 mg, 0.02 mmol) was dissolved in methylene chloride (1.00 mL), and then 4N hydrogen chloride in dioxane (1.00 mL) was added to the mixture. The reaction mixture was stirred at room temperature under 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 as a yellow solid. (6.00 mg, 68%) MS m / z: 372 [M+1] +1 H NMR (400 MHz, CD3OD) δ 7.78(d, J=7.4 Hz, 2H), 7.10 (d, J= 7.7Hz, 3H), 7.00(s, 1H), 6.72 (s, 1H), 5.33 (s, 2H), 3.82 (d= J=1.62 Hz, 3H), 3.23 (s, 2H), 2.69(s, 2H), 2.02 (s, 2H).

[0485] [Example 39] Preparation of 3-((8-methoxy-1,2,3,4-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 39)

[0486] [ka] (Step 1) Preparation of tert-butyl 8-methoxy-5-(3-sulfamoylbenzyl)-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0487] [ka] The compound prepared in Example 5 (Step 1) (50.0 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 60% sodium hydride (19.8 mg, 0.50 mmol) was added 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (22.0 mg, 28%) MS m / z: 472 [M+1] + (Step 2) Preparation of 3-((8-methoxy-1,2,3,4-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 39)

[0488] [ka] The compound prepared above (Step 1) (22.0 mg, 0.05 mmol) was dissolved in methylene chloride (0.50 mL), and then trifluoroacetic acid (0.50 mL) was added to the mixture. The reaction mixture was stirred at room temperature under 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 as a yellow solid. (5.00 mg, 29%) MS m / z: 372 [M+1] + 1H NMR (400 MHz, CD3OD) δ 7.64 (d, J = 8.8 Hz, 2H), 7.40 - 7.34 (m, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.13 (dd, J = 9.2, 2.6 Hz, 1H), 6.84 (d, J = 2.6 Hz, 1H), 6.74 (d, J = 9.2 Hz, 1H), 4.14 - 3.95 (m, 2H), 3.69 (s, 3H), 3.58 (d, J = 13.6 Hz, 1H), 3.26 (d, J = 13.7 Hz, 1H), 2.59 (ddd, J = 12.7, 8.2, 3.8 Hz, 1H), 2.28 (tdd, J = 16.9, 10.6, 6.3 Hz, 1H), 2.06 - 1.92 (m, 1H), 1.83 (dt, J = 13.2, 9.1 Hz, 1H).

[0489] [Example 40] Preparation of 4-((8-methyl-1,2,3,4-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 40)

[0490] [ka] (Step 1) Preparation of tert-butyl 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0491] [ka] p-Tolylhydrazine hydrochloride (400 mg, 2.52 mmol) was dissolved in toluene (25.0 mL), and then tert-butyl-3-oxopiperidine-1-carboxylate (603 mg, 3.03 mmol) and propanephosphonic anhydride (0.30 mL, 0.50 mmol) were added to the mixture, successively. The reaction mixture was stirred at 90°C under nitrogen for 6 hours. After cooling to room temperature, distilled water and aqueous sodium bicarbonate were added, and the mixture was 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 give the title compound as a yellow solid. (320 mg, 44%) MS m / z: 287 [M+1] + (Step 2) Preparation of tert-butyl 8-methyl-5-(4-sulfamoylbenzyl)-2,3,4,5-tetrahydro-1H-pyrido[3,2-b]indole-1-carboxylate

[0492] [ka] The compound prepared above (Step 1) (50.0 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (2.40 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a white solid. (17.1 mg, 21%) MS m / z: 456 [M+1] + (Step 3) Preparation of 4-((8-methyl-1,2,3,4-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)methyl)benzenesulfonamide (Compound 40)

[0493] [ka] The compound prepared above (Step 2) (17.1 mg, 0.04 mmol) was dissolved in methylene chloride (0.80 mL), and then trifluoroacetic acid (0.40 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at room temperature 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 as a pink solid. (10.6 mg, 79%) MS m / z: 356 [M+1] + 1 H NMR (400 MHz, CD3OD) δ 7.86 - 7.74 (m, 2H), 7.35 (s, 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.23 - 7.12 (m, 2H), 7.08 (d, J = 9.1 Hz, 1H), 5.48 (s, 2H), 3.60 (d, J = 5.9 Hz, 2H), 2.85 (t, J = 5.9 Hz, 2H), 2.45 (s, 3H), 2.36 - 2.16 (m, 2H).

[0494] [Example 41] Preparation of 4-((8-methoxy-1-oxo-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)methyl)benzenesulfonamide (Compound 41)

[0495] [ka] (Step 1) Preparation of 4-(2-(4-methoxyphenyl)hydrazineyl)-5,6-dihydropyridin-2(1H)-one

[0496] [ka] 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 completed, the mixture was concentrated under reduced pressure. The title compound was obtained as a brown solid without further purification. (9.80 g) MS 1m / z: 234 [M+1] + (Step 2) Preparation of 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one

[0497] [ka] The compound (8.80 g, 37.7 mmol) prepared in Step 1 above was slowly dissolved in a 3:1 sulfuric acid:distilled water mixture (44.0 mL) at 0°C and then stirred at room temperature for 3 hours. After the reaction was completed, distilled water and 2 M aqueous sodium hydroxide solution (200 mL) were slowly added, and the mixture was extracted twice with a 10:1 methylene chloride:methanol mixture. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol = 100:1 to 10:1) to obtain the title compound as a yellow solid. (1.06 g, 13%) MS m / z: 217 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 7.35 (d, J=2.5 Hz, 1H), 7.25 (d, J=8.7 Hz, 1H), 6.96 (br s, 1H), 6.72 (dd, J=2.6, 8.8 Hz, 1H), 3.74 (s, 3H), 3.43 (dt, J=2.3, 6.9 Hz, 2H), 2.92 (t, J=6.9 Hz, 2H). (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)

[0498] [ka] The compound prepared above (Step 2) (50.0 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a yellow solid. (2.80 mg, 3%) MS m / z: 386 [M+1] + 1 H NMR (400 MHz, CD3OD) δ 7.92 (d, J=8.0 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.62 (d, J=9.2 Hz, 2H), 7.26 (t, J=9.7 Hz, 2H), 6.83 (d, J=9.5 Hz, 1H), 5.54 (s, 2H), 3.87 (s, 3H), 3.65 (s, 2H), 3.03 (s, 2H)

[0499] [Example 42] Preparation of 4-((7-methoxy-1-oxo-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)methyl)benzenesulfonamide (Compound 42)

[0500] [ka] (Step 1) Preparation of 4-(2-(3-methoxyphenyl)hydrazineyl)-5,6-dihydropyridin-2(1H)-one

[0501] [ka] Piperidine-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 completed, 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] + (Step 2) Preparation of 7-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one

[0502] [ka] The compound prepared in Step 1 (10.0 g, 42.9 mmol) was slowly dissolved in a 3:1 sulfuric acid:distilled water mixture (45.0 mL) at 0°C and then stirred at room temperature for 3 hours. After the reaction was completed, distilled water and 2 M aqueous sodium hydroxide solution (200 mL) were slowly added to the mixture, and the mixture was extracted twice with a 10:1 methylene chloride:methanol mixture. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol = 100:1 to 10:1) to obtain the title compound as a yellow solid. (354 mg, 4%) MS m / z: 217 [M+1] + 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 7.70 (d, J=8.6 Hz, 1H), 6.93 (br s, 1H), 6.88 (d, J=2.1 Hz, 1H), 6.73 (dd, J=2.3, 8.6 Hz, 1H), 3.76 (s, 3H), 3.44 (dt, J=2.4, 6.9 Hz, 2H), 2.91 (t, J=6.9 Hz, 2H). (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)

[0503] [ka] The compound prepared above (Step 2) (50.0 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (2.40 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a white solid. (16.2 mg, 18%) MS m / z: 386 [M+1] + 1 H NMR (400 MHz, CD3OD) δ 7.96 - 7.73 (m, 3H), 7.30 - 7.10 (m, 2H), 6.92 - 6.75 (m, 2H), 5.50 (s, 2H), 3.75 (s, 3H), 3.59 (t, J = 7.2 Hz, 2H), 2.96 (t, J = 7.1 Hz, 2H).

[0504] [Example 43] Preparation of 4-((7-methoxy-1-oxo-1,2-dihydro-5H-pyrido[4,3-b]indol-5-yl)methyl)benzenesulfonamide (Compound 43)

[0505] [ka] (Step 1) Preparation of 7-methoxy-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one

[0506] [ka] (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. The reaction mixture was stirred under nitrogen 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 purified by silica gel column chromatography (ethyl acetate:n-hexane=0:10 to methanol:methylene chloride=1:9) to obtain the title compound as a yellow solid. (196 mg, 34%) MS m / z: 0.215 [M+1] + 1 H NMR (400 MHz, 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). (Step 2) Preparation of 4-((7-methoxy-1-oxo-1,2-dihydro-5H-pyrido[4,3-b]indol-5-yl)methyl)benzenesulfonamide (Compound 43)

[0507] [ka] The compound prepared above (Step 1) (52.0 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 60% sodium hydride (19.0 mg, 0.48 mmol) was added to the mixture, which was then 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a yellow solid. (3.70 mg, 3%) MS m / z: 384 [M+1] + 1 H NMR (400 MHz, CD3OD) δ 8.06 (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)

[0508] [Example 44] Preparation of 4-((8-methoxy-1-oxo-1,2-dihydro-5H-pyridazino[4,5-b]indol-5-yl)methyl)benzenesulfonamide (compound 44)

[0509] [ka] TIFF2025525335000291.tif72162 (Step 1) Preparation of 2,2,2-trifluoro-1-(5-methoxy-1H-indol-3-yl)ethan-1-one

[0510] [ka] 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 as a white solid. (6.40 g, 129%) MS m / z: 244 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.60 (s, 1H), 8.40 (s, 1H), 7.68 (s, 1H), 7.49 (d, J = 8.9 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 3.81 (s, 3H). (Step 2) Preparation of 5-methoxy-1H-indole-3-carboxylic acid

[0511] [ka] The compound prepared above (Step 1) (6.40 g) was dissolved in 5N aqueous sodium hydroxide (20.0 mL), and then tetrahydrofuran (5.00 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure. After cooling to room temperature, distilled water was slowly added, and the mixture was extracted twice with ethyl acetate. The pH of the aqueous layer was adjusted to 2 or less by adding 1N aqueous hydrogen chloride solution to it, and the resulting solid was filtered and dried to obtain the title compound as a white solid. (2.90 g, 76%) MS m / z: 192 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 11.66 (s, 1H), 7.92 (d, J = 2.5 Hz, 1H), 7.49 (d, J = 2.6 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.82 (dd, J = 8.8, 2.5 Hz, 1H), 3.78 (s, 3H). (Step 3) Preparation of ethyl 5-methoxy-1H-indole-3-carboxylate

[0512] [ka] The compound prepared above (Step 2) (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 an additional 16 hours. Distilled water was slowly added to the reaction mixture, and it was 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 as a white solid. (1.10 g, 74%) MS m / z: 220 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 11.78 (s, 1H), 7.98 (d, J = 2.9 Hz, 1H), 7.48 (d, J = 2.6 Hz, 1H), 7.35 (d, J = 8.9 Hz, 1H), 6.82 (dd, J = 8.8, 2.6 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). (Step 4) Preparation of ethyl 2-formyl-5-methoxy-1H-indole-3-carboxylate

[0513] [ka] Phosphoryl chloride (0.39 mL, 4.20 mmol) and N,N-dimethylformamide (0.28 mL, 3.65 mmol) were added thereto sequentially under nitrogen at 0°C, followed by stirring for 1 minute. The reaction mixture was dissolved in methylene chloride (5.00 mL), and the compound prepared above (Step 3) (400 mg, 1.82 mmol) was slowly added to the mixture, followed by stirring at room temperature for 16 hours. After the reaction was completed, it was concentrated under reduced pressure, and 10 mL of saturated aqueous sodium acetate solution was added, followed by stirring for an additional 12 hours. The reaction mixture was extracted twice with methylene chloride. 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 give the title compound as a white solid. (80.0 mg, 18%) MS m / z: 248 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.07 (s, 1H), 10.66 (s, 1H), 8.09 (d, J = 3.4 Hz, 1H), 7.66 (dd, J = 8.9, 3.4 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 4.05-4.00 (m, 2H), 3.85 (s, 3H), 1.16 (t, J = 4.8 Hz, 3H). (Step 5) Preparation of ethyl 2-formyl-5-methoxy-1-(4-sulfamoylbenzyl)-1H-indole-3-carboxylate

[0514] [ka] The compound prepared above (Step 4) (25.0 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 60% sodium hydride (4.90 mg, 0.12 mmol) was added to the mixture, which was then stirred for 30 minutes. Intermediate 1 (30.3 mg, 0.12 mmol) was slowly added to the reaction mixture, which was then stirred for 2 hours at 0°C under nitrogen. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (23.0 mg, 55%) MS m / z: 417 [M+1] + 1 H NMR (400 MHz, CD3OD) δ ppm: 10.77 (s, 1H), 8.19 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 9.2 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 9.1 Hz, 1H), 5.60 (s, 2H), 4.32 (q, J = 6.7 Hz, 2H), 3.92 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). (Step 6) Preparation of 4-((8-methoxy-1-oxo-1,2-dihydro-5H-pyridazino[4,5-b]indol-5-yl)methyl)benzenesulfonamide (compound 44)

[0515] [ka] The compound prepared above (Step 5) (23.0 mg, 0.055 mmol) 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 under nitrogen at 90° C. 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 as a yellow solid. (4.70 mg, 17%) MS m / z: 499 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 10.18 (s, 1H), 8.07 (s, 1H), 7.77 (d, J = 7.6 Hz, 2H), 7.63 (s, 1H), 7.47-7.27 (m, 5H), 6.93 (d, J = 8.7 Hz, 1H), 5.50 (s, 2H), 3.81 (s, 3H).

[0516] [Example 45] Preparation of 4-((7-methoxy-1-oxo-1,2-dihydro-5H-pyridazino[4,5-b]indol-5-yl)methyl)benzenesulfonamide (Compound 45)

[0517] [ka] TIFF2025525335000299.tif79162 (Step 1) Preparation of 2,2,2-trifluoro-1-(6-methoxy-1H-indol-3-yl)ethan-1-one

[0518] [ka] 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 as a white solid. (7.00 g, 141%) MS m / z: 244 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.50 (s, 1H), 8.36 (s, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.06 (s, 1H), 6.95 (d, J = 8.6 Hz, 1H), 3.81 (s, 3H). (Step 2) Preparation of 6-methoxy-1H-indole-3-carboxylic acid

[0519] [ka] The compound prepared above (Step 1) (7.00 g) was dissolved in 5N aqueous sodium hydroxide (20.0 mL), and then tetrahydrofuran (5.00 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure. After cooling to room temperature, distilled water was slowly added, and the mixture was extracted twice with ethyl acetate. The aqueous layer was adjusted to pH 2 or less by adding 1N aqueous hydrogen chloride solution, and the resulting solid was filtered and dried to give the title compound as a white solid. (3.50 g, 90%) MS m / z: 192 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ ppm: 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). (Step 3) Preparation of ethyl 6-methoxy-1H-indole-3-carboxylate

[0520] [ka] The compound prepared above (Step 2) (500 mg, 2.61 mmol) was dissolved in methanol:distilled water (10.0 mL, 9:1), and then cesium carbonate (810 mg, 2.48 mmol) was added to the mixture, followed by stirring at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure, and iodoethane (0.19 mL, 2.35 mmol) was added, followed by stirring for an additional 16 hours. Distilled water was slowly added to the reaction mixture, which was 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 = 0:10 to 2:3) to give the title compound as a white solid. (372 mg, 64%) MS m / z: 220 [M+1] + 1 H NMR (400 MHz, CDCl3) δ ppm: 8.37 (br, 1H), 8.06 (d, J = 8.8 Hz, 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 = 7.2 Hz, 3H). (Step 4) Preparation of ethyl 2-formyl-6-methoxy-1H-indole-3-carboxylate

[0521] [ka] Phosphoryl chloride (0.39 mL, 4.20 mmol) and N,N-dimethylformamide (0.28 mL, 3.65 mmol) were added sequentially to the mixture under nitrogen at 0°C, followed by stirring for 1 minute. The compound prepared above (Step 3) (400 mg, 1.82 mmol) dissolved in methylene chloride (5.20 mL) was slowly added to the reaction mixture, which was then stirred at room temperature for 16 hours. After the reaction was completed, it was concentrated under reduced pressure, and 10.0 mL of saturated aqueous sodium acetate solution was added, followed by stirring for an additional 12 hours. The reaction mixture was extracted twice with methylene chloride. 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 give the title compound as a white solid. (330 mg, 37%) MS m / z: 248 [M+1] + (Step 5) Preparation of ethyl 2-formyl-6-methoxy-1-(4-sulfamoylbenzyl)-1H-indole-3-carboxylate

[0522] [ka] The compound prepared above (Step 4) (50.0 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (35.0 mg, 42%) MS m / z: 417 [M+1] + (Step 6) Preparation of 4-((7-methoxy-1-oxo-1,2-dihydro-5H-pyridazino[4,5-b]indol-5-yl)methyl)benzenesulfonamide (Compound 45)

[0523] [ka] The compound prepared above (Step 5) (35.0 mg, 0.08 mmol) 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 under nitrogen at 80° C. 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 as a yellow solid. (4.60 mg, 14%) MS m / z: 385 [M+1] + 1 H NMR (400 MHz, CD3OD) δ 8.53 (s, 1H), 8.22 (d, J = 9.3 Hz, 1H), 7.94 - 7.73 (m, 2H), 7.33 (d, J = 5.4 Hz, 2H), 7.17 (s, 1H), 7.07 (d, J = 8.6 Hz, 1H), 5.86 (s, 2H), 3.88 (s, 3H).

[0524] [Example 46] Preparation of 7-methoxy-5-(4-(S-methylsulfonimidoyl)benzyl)-2,5-dihydro-1H-pyridazino[4,5-b]indol-1-one (compound 46)

[0525] [ka] TIFF2025525335000307.tif87139 (Step 1) Preparation of ethyl 2-formyl-6-methoxy-1-(4-(methylthio)benzyl)-1H-indole-3-carboxylate

[0526] [ka] The compound prepared in Example 45 (Step 4) (50.0 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and cooled to 0°C. 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added to the mixture, and the mixture was 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 give the title compound as a yellow solid. (75.0 mg, 97%) MS m / z: 384 [M+1] + (Step 2) Preparation of 7-methoxy-5-(4-(methylthio)benzyl)-2,5-dihydro-1H-pyridazino[4,5-b]indol-1-one

[0527] [ka] The compound prepared above (Step 1) (75.0 mg, 0.20 mmol) 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 under nitrogen at 80°C 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 as a yellow solid. (38.0 mg, 55%) MS m / z: 352 [M+1] + (Step 3) Preparation of 7-methoxy-5-(4-(S-methylsulfonimidoyl)benzyl)-2,5-dihydro-1H-pyridazino[4,5-b]indol-1-one (compound 46)

[0528] [ka] The compound prepared above (Step 2) (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 under nitrogen for 16 hours. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a white solid. (4.60 mg, 21%) MS m / z: 383 [M+1] + 1 H NMR (400 MHz, CD3OD) δ 8.49 (s, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.10 (d, J = 5.6 Hz, 2H), 7.52 (d, J = 3.6 Hz, 2H), 7.12 (s, 1H), 7.07 (d, J = 7.2 Hz, 1H), 5.95 (s, 2H), 3.86 (s, 3H), 2.03 (s, 3H).

[0529] [Example 47] Preparation of 4-((7-methoxy-5H-pyridazino[4,5-b]indol-5-yl)methyl)benzenesulfonamide (Compound 47)

[0530] [ka] (Step 1) Preparation of 7-methoxy-2,5-dihydro-1H-pyridazino[4,5-b]indol-1-one

[0531] [ka] The compound prepared in Example 45 (Step 4) (75.0 mg, 0.30 mmol) was dissolved in acetic anhydride (3.00 mL), and then hydrazine monohydrate (44.0 μL, 0.91 mmol) was added to the mixture. The reaction mixture was stirred under nitrogen at 80° C. 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 as a yellow solid. (12.1 mg, 19%) MS m / z: 216 [M+1] + (Step 2) Preparation of 1-chloro-7-methoxy-2,5-dihydro-1H-pyridazino[4,5-b]indole

[0532] [ka] The compound prepared above (Step 1) (12.1 mg, 0.06 mmol) was dissolved in trichlorophosphate (1.00 mL) and then stirred under nitrogen at 60°C for 3 hours. After the reaction was completed, it was cooled to room temperature, and then distilled water was slowly added to the mixture, followed by extraction 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] + (Step 3) Preparation of 7-methoxy-5H-pyridazino[4,5-b]indole

[0533] [ka] The compound prepared above (Step 2) (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 under nitrogen for 12 hours. The precipitate was removed by filtration using Celite, 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] + (Step 4) Preparation of 4-((7-methoxy-5H-pyridazino[4,5-b]indol-5-yl)methyl)benzenesulfonamide (Compound 47)

[0534] [ka] The compound prepared above (Step 3) (11.2 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (0.60 mL) and cooled to 0 °C. 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, which was then stirred at 0 °C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (1.70 mg, 8%) MS m / z: 369 [M+1] + 1 H NMR (400 MHz, CD3OD) δ 9.99 (s, 1H), 9.64 (s, 1H), 8.34 (d, J = 5.2 Hz, 1H), 7.86 (d, J = 4.4 Hz, 2H), 7.38 (s, 2H), 7.30 (s, 1H), 7.21 (d, J = 6.4 Hz, 1H), 6.06 (s, 2H), 3.99 (s, 3H).

[0535] [Example 48] Preparation of 4-((7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)methyl)benzenesulfonamide (Compound 48)

[0536] [ka] TIFF2025525335000317.tif44143 (Step 1) Preparation of 7-methoxy-9H-pyrimido[4,5-b]indole

[0537] [ka] 4-Amino-5-bromopyrimidine (500 mg, 2.87 mmol) was dissolved in 1,4-dioxane (6.00 mL). Then, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (165 mg, 0.29 mmol), Xantphos (166 mg, 0.29 mmol), and sodium tert-butoxide (828 mg, 8.62 mmol) were added sequentially to the mixture, which was then stirred at 110 °C for 24 hours. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a pale yellow solid. (220 mg, 38%) MS m / z: 0.200 [M+1] + 1 H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 9.21 (d, J = 5.3 Hz, 1H), 8.99 (d, J = 5.6 Hz, 1H), 7.99 (s, 1H), 7.11 - 6.84 (m, 2H), 3.93 (d, J = 1.3Hz, 3H). (Step 2) Preparation of 4-((7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)methyl)benzenesulfonamide (Compound 48)

[0538] [ka] The compound prepared above (Step 1) (50.0 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0°C. 60% sodium hydride (20.0 mg, 0.50 mmol) was added to the mixture, which was then 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, which was then stirred at 0°C under nitrogen for 1 hour. After the reaction was completed, distilled water was slowly added, and the mixture was 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 as a yellow solid. (49.0 mg, 51%) MS m / z: 369 [M+1] + 1 H NMR (400 MHz, CD3OD) δ 9.58 - 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 = 3.2 Hz, 3H).

[0539] [Example 49] Preparation of 4-((6-methoxy-9H-pyrido[2,3-b]indol-9-yl)methyl)benzenesulfonamide (Compound 49)

[0540] [ka] (Step 1) Preparation of 3-chloro-N-(4-methoxyphenyl)pyridin-2-amine

[0541] [ka] The compounds 4-methoxyaniline (500 mg, 4.05 mmol) and 2,3-dichloropyridine (500 mg, 3.34 mmol) were dissolved in toluene (10.0 mL). Palladium acetate (75.8 mg, 0.34 mmol), BINAP (421 mg, 0.68 mmol), and potassium carbonate (1.60 g, 11.8 mol) were then added to the mixture, which was then stirred at 100 °C under nitrogen for 18 hours. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (540 mg, 68%).MS m / z: 235 [M+1]+ 1H NMR (400 MHz, CDCl3) δ 8.07 (dd, J = 4.9, 1.4 Hz, 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 = 0.8 Hz, 3H). (Step 2) Preparation of 6-methoxy-9H-pyrido[2,3-b]indole

[0542] [ka] The compound prepared above (Step 1) (35.0 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (1.0 mL). Palladium acetate (3.30 mg, 0.01 mmol) and potassium carbonate (31.0 mg, 0.22 mmol) were then added to the mixture, which was then stirred at 135 °C under nitrogen for 18 hours. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (5.0 mg, 17%). MS m / z: 199 [M+1]+ 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.45 (dd, J = 5.0, 1.6 Hz, 1H), 8.30 (dd, J = 7.8, 1.6 Hz, 1H), 7.54 (d, J = 2.6 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.15 (ddd, J = 13.9, 8.3, 3.8 Hz, 2H), 3.93 (s, 3H). (Step 3) Preparation of 4-((6-methoxy-9H-pyrido[2,3-b]indol-9-yl)methyl)benzenesulfonamide (Compound 49)

[0543] [ka] The compound prepared above (Step 2) (19.0 mg, 0.096 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and cooled to 0 °C. 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, which was then stirred at 0 °C under nitrogen for 2 hours. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (2.9 mg, 8%). MS m / z: 368 [M+1]+ 1H NMR (400 MHz, CD3OD) δ 8.62 (dd, J = 7.8, 1.5 Hz, 1H), 8.45 (d, J = 5.3 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 2.9 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.34 (dd, J = 7.8, 5.1 Hz, 3H), 7.15 (dd, J = 8.9, 2.6 Hz, 1H), 5.81 (s, 2H), 3.93 (d, J = 1.0 Hz, 3H).

[0544] [Example 50] Preparation of 4-((8-methoxy-5H-pyridazino[4,5-b]indol-5-yl)methyl)benzenesulfonamide (Compound 50)

[0545] [ka] (Step 1) Preparation of dimethyl 5-methoxy-1H-indole-2,3-dicarboxylate

[0546] [ka] 2-Iodo-4-methoxyaniline (5.0 g, 20.1 mmol) and dimethylacetylenedicarboxylate (3.14 g, 22.1 mmol) were dissolved in dimethyl sulfoxide (50.0 mL). Tris(dibenzylideneacetone)dipalladium(0) (919 mg, 1.00 mmol) and triethylamine (8.38 mL, 60.2 mmol) were then added to the mixture, which was stirred at 90 °C under nitrogen for 16 hours. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (960 mg, 18%). MS m / z: 264 [M+1]+ 1H NMR (400 MHz, CDCl3) δ 9.19 (br s, 1 H), 7.49 (d, J = 2.4 Hz, 1 H), 7.33 (d, J = 9.2 Hz, 1 H), 7.05 (dd, J = 9.2, 2.4 Hz, 1 H), 3.99 (s, 3 H), 3.99 (s, 3 H), 3.89 (s, 3 H). (Step 2) Preparation of 8-methoxy-2,3-dihydro-1H-pyridazino[4,5-b]indole-1,4(5H)-dione

[0547] [ka] 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% purity) was slowly added to the mixture. The mixture was stirred under nitrogen at 80 °C 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, 1 H), 7.49 (d, J = 8.8 Hz, 1 H), 7.04 (dd, J = 8.8, 2.4 Hz, 1 H), 3.82 (s, 3 H). (Step 3) Preparation of 1,4-dichloro-8-methoxy-5H-pyridazino[4,5-b]indole

[0548] [ka] The compound prepared above (Step 2) (970 mg, 4.20 mmol) was cooled to 0 °C, and then phosphoryl chloride (5.00 mL) was slowly added to the mixture. The mixture was stirred under nitrogen at 110 °C for 16 hours. The reaction was completed by slowly adding aqueous sodium carbonate, and the resulting solid was filtered to give the title compound as 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, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.42 (dd, J = 8.8, 2.4 Hz, 1 H), 3.91 (s, 3 H). (Step 4) Preparation of 8-methoxy-5H-pyridazino[4,5-b]indole

[0549] [ka] The compound prepared above (Step 3) (870 mg, 3.25 mmol) was dissolved in methanol (30.0 mL), and then Pd / C (300 mg, 10% purity, 50% water content) was added to the mixture. The mixture was stirred under hydrogen at room temperature for 2 hours. After the reaction was completed, it was filtered through a Celite pad to remove impurities, and the solvent was then removed from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (methanol:methylene chloride = 1:10) to give the title compound as a brown solid. (403 mg, 62%). MS m / z: 200 [M+1]+ 1H NMR (400 MHz, DMSO-d6) δ 12.44 - 13.76 (m, 1 H), 10.21 (s, 1 H), 9.64 (s, 1 H), 8.05 (d, J = 2.4 Hz, 1 H), 7.79 (d, J = 8.8 Hz, 1 H), 7.40 (dd, J = 8.8, 2.4 Hz, 1 H), 3.90 (s, 3 H) (Step 5) Preparation of 4-((6-methoxy-9H-pyrido[2,3-b]indol-9-yl)methyl)benzenesulfonamide (Compound 49)

[0550] [ka] The compound prepared above (Step 4) (50.0 mg, 0.251 mmol) was dissolved in N,N-dimethylformamide (2.50 mL) and cooled to 0 °C. 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, which was then stirred at 0 °C under nitrogen for 2 hours. After the reaction was completed, distilled water was slowly added, and the mixture was 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 give the title compound as a yellow solid. (5.6 mg, 6%). MS m / z: 369 [M+1]+ 1H NMR (400 MHz, CD3OD) δ 10.21 (s, 1H), 10.01 (s, 1H), 8.00-7.95 (m, 3H), 7.84 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.57 (dd, J = 2.2, 9.0 Hz, 1H), 6.14 (s, 2H), 3.98 (s, 3H)

[0551] [Example 51] Preparation of 4-((8-methoxy-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzenesulfonamide (Compound 51)

[0552] [ka] (Step 1) Preparation of 5-methoxy-1H-indole-3-carbonyl azide

[0553] [ka] 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, which was then stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 2:3) to give the title compound as a white solid. (870 mg, 77%). MS m / z: 217 [M+1]+ 1H NMR (400 MHz, CDCl3) δ ppm: 12.11 (s, 1H), 8.12 (s, 1H), 7.53 (d, J = 2.6 Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H), 6.89 (dd, J = 8.9, 2.6 Hz, 1H), 3.80 (s, 3H) (Step 2) Preparation of tert-butyl (5-methoxy-1H-indol-3-yl)carbamate

[0554] [ka] The compound prepared above (Step 1) (870 mg, 4.02 mmol) was dissolved in tert-butanol (30.0 mL), and the reaction mixture was stirred at 80 °C under 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 give the title compound as 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). (Step 3) Preparation of 5-methoxy-1H-indol-3-amine

[0555] [ka] The compound prepared above (Step 2) (100 mg, 0.38 mmol) was dissolved in methylene chloride (1.50 mL), and then trifluoroacetic acid (0.14 mL, 1.91 mmol) was added to the mixture, which was stirred at room temperature under nitrogen for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the solvent, affording a brown mixture (140 mg) without further purification. MS m / z: 163 [M+1]+ (Step 4) Preparation of N'-(2-formyl-5-methoxy-1H-indol-3-yl)-N,N-dimethylformimidamide

[0556] [ka] Phosphoryl chloride (0.18 mL, 1.96 mmol) was dissolved in methylene chloride (1.00 mL) under nitrogen at 0°C, and then N,N-dimethylformamide (0.15 mL, 1.96 mmol) was added to the mixture and stirred for 30 minutes. The compound prepared above (Step 3) (140 mg) dissolved in methylene chloride (3.00 mL) was slowly added, followed by stirring at room temperature for 24 hours. After the reaction was completed, the reaction mixture was placed in an ice-filled Erlenmeyer flask, aqueous sodium bicarbonate solution was added, and the mixture was 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 as a yellow solid (7.5 mg). MS m / z: 246 [M+1]+ (Step 5) Preparation of 8-methoxy-5H-pyrimido[5,4-b]indole

[0557] [ka] The compound prepared above (Step 4) (7.50 mg, 0.03 mmol) was dissolved in ethanol (0.50 mL), and then aqueous ammonia (0.30 mL) was added to the mixture. The reaction mixture was stirred under nitrogen at 80°C for 2 hours. After the reaction was completed, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:methylene chloride = 1:19) to give the title compound as 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). (Step 6) Preparation of 4-((8-methoxy-5H-pyrimido[5,4-b]indol-5-yl)methyl)benzenesulfonamide (Compound 51)

[0558] [ka] The compound prepared above (Step 5) (4.80 mg, 0.024 mmol) was dissolved in N,N-dimethylformamide (0.40 mL) and cooled to 0 °C. 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 ...

Claims

1. A compound having the structure represented by formula I, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In the formula, Each R 1 These are independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azide, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, or sulfonamide. A is an aryl, heteroaryl, or heterocyclyl. Y is CH, CR 1 , or N, R 2 These are aralkyl, heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. n is 0, 1, 2, 3, or 4.

2. The compound according to claim 1, wherein A is a heteroaryl (e.g., pyridinyl, pyrimidinyl, or pyridadinyl, preferably pyridinyl) or a heterocyclyl (e.g., piperidinyl, piperidonyl, or tetrahydropyridazinonyl).

3. The compound according to claim 1, having a structure represented by formula Ia or a pharmaceutically acceptable salt thereof. 【Chemistry 2】 (In the formula, X 1 CR 3 or N, X 2 CR 4 or N, X 3 is CR 5 or N, and X 4 CR 6 or N, R 3 , R 4 , R 5 , and R 6 Each of these is independently selected from H, alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azide, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, and sulfonamide.

4. X 1 The compound according to claim 3, wherein is N.

5. X 1 CR 3 The compound according to claim 3, wherein R3 is H.

6. X 2 The compound according to claim 3, wherein is N.

7. X 2 CR 4 The compound according to claim 3, wherein R4 is H.

8. X 3 The compound according to claim 3, wherein is N.

9. X 3 The compound according to claim 3, wherein R is CR5 and R 5 is H.

10. X 4 The compound according to claim 3, wherein is N.

11. X 4 CR 6 The compound according to claim 3, wherein R 6 is H.

12. The compound according to claim 1, wherein n is 1.

13. The compound according to claim 1, wherein n is 2.

14. The compound according to claim 1, wherein Y is CH.

15. The compound according to claim 1, wherein Y is N.

16. The compound according to claim 1, having a structure represented by formula Ib or formula Ic, or a pharmaceutically acceptable salt thereof. 【Transformation 3】 【Chemistry 4】

17. The compound according to claim 1, having a structure represented by formula Id, formula Ie, or formula If, or a pharmaceutically acceptable salt thereof. 【Transformation 5】 【Transformation 6】 【Transformation 7】 (In the formula, R 7 These are alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azide, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, or sulfonamide.

18. R 2 The compound according to claim 1, wherein R2 is an aralkyl (e.g., phenylalkyl, e.g., phenylmethyleneyl or phenylethyleneyl, preferably phenylmethyleneyl) or R2 is a heterocyclylalkyl (e.g., piperidinylmethyleneyl).

19. The compound according to claim 1, having a structure represented by formula IIa, formula IIb, formula IIc, formula IId, or formula IIe, or a pharmaceutically acceptable salt thereof. 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 (In the formula, R7 is alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azide, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, or sulfonamide. Each R 8 These are independently alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, amino, amide, cyano, nitro, azide, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, or sulfonamide. R 9 These are alkyl, alkoxy, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyl, carboxyl, acyl, ester, thioester, phosphoryl, phosphoramidityl, phosphoramidatyl, amino, amide, cyano, nitro, azide, cycloalkyl, heterocyclyl, alkylsulfoxidyl, alkylsulfonyl, sulfonamide, iminosulfanonyl, or sulfamidyl. y is 1, 2, 3, or 4.

20. R 1 The compound according to claim 1, wherein is alkyl (e.g., methyl), alkoxy (e.g., methoxy, trifluoromethoxy, or ethoxy, preferably methoxy), or halo (e.g., fluoro or chloro).

21. R 7 The compound according to claim 17, wherein is alkyl (e.g., methyl), alkoxy (e.g., methoxy), or halo (e.g., fluoro or chloro).

22. The compound according to claim 19, wherein y is 0 or 1.

23. R 8 The compound according to claim 19, wherein is a halo (e.g., fluoro or chloro) or an alkyl (e.g., methyl or trifluoromethyl).

24. The compound according to claim 19, wherein R8 is an alkoxy (e.g., methoxy).

25. R 9 The compound according to claim 19, wherein is a sulfonamide (e.g., methylsulfonamide), iminosulfanol (e.g., (imino)(methyl)iminosulfanol, (imino)(ethyl)iminosulfanol, (imino)(benzyl)iminosulfanol, (imino)(cyclopropyl)iminosulfanol), sulfamidyl (e.g., (imino)(methyl)iminosulfamidyl), phosphoryl, alkyl (e.g., phosphorylmethyl or phosphoryldifluoromethyl), phosphoramidityl, or phosphoramidatyl. 【Request Item 26】 【Chemistry 13】 【change】 【change】 【change】 【change】 The compound according to claim 1, or selected from pharmaceutically acceptable salts thereof.

27. ​​A pharmaceutical composition for use in the treatment of cancer, comprising a compound or pharmaceutically acceptable salt according to any one of claims 1 to 26.

28. The pharmaceutical composition according to claim 27, 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 lymphoma or non-Hodgkin lymphoma), or fibroadenoma.

29. A pharmaceutical composition for use in the treatment of a disease or disorder characterized by ENPP-1, comprising a compound or pharmaceutically acceptable salt according to any one of claims 1 to 26.

30. Use of a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmacopoeia for treating or preventing cancer in a subject requiring treatment or prevention of cancer.

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