RNA methyltransferase inhibitors, screening method thereof, marker for determining efficacy of anticancer drugs, and kit for predicting efficacy of FTSJ1 inhibitors

Abstract

An RNA methyltransferase inhibitor containing at least one type of compound selected from the group consisting of sulfonamide-based compounds represented by general formula (1) and pyrazoline-based compounds represented by general formula (2). Formula (1) [In formula (1), R1 represents any of groups (1-1) to (1-5) below. (1-1) a nitrogen-containing heterocyclic group having a substituent, (1-2) a cycloalkyl group having a substituent, (1-3) an alkyl group having a substituent, (1-4) a pyrazolyl amino group, (1-5) a phenyl group; R2 represents (2-1) a hydrogen atom or (2-2) an alkyl group. R3 represents any of groups (3-1) to (3-9) below. (3-1) a phenyl group, (3-2) a naphthalene group, (3-3) a nitrogen- or sulfur-containing heterocyclic group, (3-4) a dihydrocarbostyril group, (3-5) a tetrahydronaphthalene group, (3-6) an indanyl group, (3-7) a benzodioxolyl group, (3-8) a benzodiazepinezole group, (3-9) a dihydrobenzodioxepinyl group; wherein each group represented by (3-1) to (3-9) may further have a substituent. Alternatively, R1 and R2 may bond to each via a nitrogen atom bonded thereto to form a ring.] Formula (2) [In formula (2), n represents an integer of 2 to 4. R4 is the same or different and represents any of groups (4-1) to (4-34). (4-1) a phenyl group, (4-2) a phenylsulfonyl group, (4-3) an alkylcarbonyl group, (4-4) an aminothiocarbonyl group, (4-5) a benzodioxolyl group, (4-6) an alkylsulfonyl group, (4-7) an adamantanecarbonyl group, (4-8) a benzopyrazil group, (4-9) a phenylcarbonyl group, (4-10) a naphthalene group, (4-11) a furylcarbonyl group, (4-12) a thienylcarbonyl group, (4-13) a kinazolyl group, (4-14) a kinoxalyl group, (4-15) a hydroxy group, (4-16) an alkenyl group, (4-17) a thiazolyl group, (4-18) a cycloalkylcarbonyl group, (4-19) an aminocarbonyl group, (4-20) a furyl group, (4-21) a thienyl group, (4-22) a pyridyl group, (4-23) a cycloalkenyl group (4-24) an alkyl group, (4-25) a pyrazolyl group (4-26) a quinolyl group, (4-27) an alkenylcarbonyl group, (4-28) a benzopyranyl group, (4-29) a benzopyrimidyl group, (4-30) a pyrrolidino alkylcarbonyl group, (4-31) a quinolylcarbonyl group, (4-32) an alkoxycarbonyl group, (4-33) a morpholino group, (4-34) a pyrrolidino carbonylalkoxy group, (4- 35) a benzodioxy-6-yl group; wherein each group represented by (4-1) to (4-35) may further have a substituent group. The bond between the 4-position carbon atom and the 5-position carbon atom of the pyrazole skeleton represents a single bond or a double bond. Alternatively, the two adjacent carbon atoms constituting the pyrazoline ring may bond to each other to form a ring. Alternatively, the nitrogen atom and the carbon atom adjacent thereto, which constitute the pyrazoline ring, may bond to each other to form a ring.]

Description

[Technical field]

[0001] The present invention relates to an RNA methyltransferase inhibitor, a screening method therefor, a marker for determining the effectiveness of an anticancer drug, and a kit for predicting the effectiveness of an FTSJ1 inhibitor. [Background technology]

[0002] For example, in the field of anticancer drugs, from the viewpoint of suppressing the proliferation of cancer cells and thereby suppressing the hypertrophy of tumor tissues, anticancer drugs having an action mechanism related to the activity of the cell cycle have been proposed.

[0003] However, many cancer cells have extremely long cell cycles or are in the resting phase of the cell cycle, and conventional anticancer drugs that have a mechanism of action related to cell cycle activity cannot effectively exert their anticancer effects on these cancer cells. Summary of the Invention [Problem to be solved by the invention]

[0004] With the recent development of nucleic acid analysis techniques, it is becoming clear that translational forms based on specific nucleic acid modifications play important roles in maintaining the functions of cells and viruses.

[0005] For example, in cancer cells, translation formats specific to cancer cells are being elucidated, and it is becoming clear that such translation formats play an important role in various phenomena such as cancer cell survival, proliferation, metastasis, and maintenance of stemness. Enzymes involved in the cellular translation function, such as RNA methyltransferase, are attracting attention.

[0006] In view of the above circumstances, an object of the present invention is to provide an RNA methyltransferase inhibitor and a screening method for the same. [Means for solving the problem]

[0007] As a result of intensive research aimed at solving the above problems, the present inventors have found that at least one compound selected from the group consisting of sulfonamide compounds represented by the following general formula (1) and pyrazoline compounds represented by the following general formula (2) has a desired RNA methyltransferase inhibitory effect. The present invention has been completed based on this finding.

[0008] That is, the present invention provides the following RNA methyltransferase inhibitors, novel sulfonamide compounds, screening methods, markers for determining the effectiveness of anticancer agents, and kits for predicting the effectiveness of FTSJ1 inhibitors.

[0009] Section 1. An RNA methyltransferase inhibitor comprising at least one compound selected from the group consisting of sulfonamide compounds represented by the following general formula (1) and pyrazoline compounds represented by the following general formula (2).

[0010] [ka]

[0011] [In formula (1), R 1 represents any one of the following groups (1-1) to (1-5). (1-1) a nitrogen-containing heterocyclic group which may have a substituent, (1-2) a cycloalkyl group which may have a substituent, (1-3) an alkyl group which may have a substituent; (1-4) a pyrazolylamino group, (1-5) Phenyl group; R 2 represents (2-1) a hydrogen atom or (2-2) an alkyl group. R 3 represents any one of the following groups (3-1) to (3-9). (3-1) a phenyl group, (3-2) naphthyl group, (3-3) nitrogen- or sulfur-containing heterocyclic groups, (3-4) dihydrocarbostyril group, (3-5) tetrahydronaphthyl group, (3-6) indanyl group, (3-7) benzoxolyl group, (3-8) benzothiadiazolyl group, (3-9) Dihydrobenzodioxepinyl group; Each of the groups represented by (3-1) to (3-9) may further have a substituent. 1 and R 2 may be bonded to the nitrogen atom to which they are bonded to form a ring.

[0012] [ka]

[0013] [In formula (2), n represents an integer of 2 to 4. 4 are the same or different and represent any one of the following groups (4-1) to (4-34). (4-1) phenyl group, (4-2) a phenylsulfonyl group, (4-3) alkylcarbonyl group, (4-4) aminothiocarbonyl group, (4-5) benzodioxolyl group, (4-6) an alkylsulfonyl group, (4-7) adamantylcarbonyl group, (4-8) benzopyrazyl group, (4-9) phenylcarbonyl group, (4-10) naphthyl group, (4-11) Furylcarbonyl group, (4-12) thienylcarbonyl group, (4-13) quinazolyl group, (4-14) quinoxalyl group, (4-15) Hydroxyl group, (4-16) an alkenyl group, (4-17) thiazolyl group, (4-18) cycloalkylcarbonyl group, (4-19) aminocarbonyl group, (4-20) furyl group, (4-21) thienyl group, (4-22) pyridyl group, (4-23) a cycloalkenyl group, (4-24) alkyl group, (4-25) a pyrazolyl group, (4-26) quinolyl group, (4-27) alkenylcarbonyl group, (4-28) benzopyranyl group, (4-29) a benzopyrimidyl group, (4-30) pyrrolidinoalkylcarbonyl group, (4-31) quinolylcarbonyl group, (4-32) an alkoxycarbonyl group, (4-33) morpholino group, (4-34) a pyrrolidinocarbonylalkoxy group, (4-35) Benzodioxy-6-yl group; Each of the groups represented by (4-1) to (4-35) may further have a substituent. The bond between the 4-position carbon atom and the 5-position carbon atom of the pyrazole skeleton represents a single bond or a double bond. Alternatively, two adjacent carbon atoms constituting a pyrazoline ring may be bonded to each other to form a ring. Alternatively, the nitrogen atom constituting the pyrazoline ring and the carbon atom adjacent thereto may be bonded to each other to form a ring.

[0014] Section 2. The RNA methyltransferase inhibitor according to claim 1, wherein the substituent on the nitrogen-containing heterocyclic group represented by (1-1) is at least one selected from the group consisting of an alkyl group, a hydroxyl group, a cyclopropyl group, a phenylthiopropylcarbonyl group, a phenylsulfonyl group, an alkylsulfonyl group, a thienylsulfonyl group, an alkylcarbonyl group, an alkoxycarbonyl group, a phenylsulfonylamino group, an aminocarbonylalkyl group, a pyrazolylcarbonyl group, a cyclopropylcarbonyl group, a piperidylsulfonyl group, and a morpholinosulfonyl group.

[0015] Section 3. Item 2. The RNA methyltransferase inhibitor according to Item 1, wherein the nitrogen-containing heterocyclic group represented by (1-1) has 1 to 5 substituents.

[0016] Section 4. Item 4. The RNA methyltransferase inhibitor according to Item 2 or 3, wherein the alkyl group and the alkoxy group constituting the alkyl group, the alkylsulfonyl group, the alkylcarbonyl group, the alkoxycarbonyl group and the aminocarbonylalkyl group on the nitrogen-containing heterocyclic group represented by (1-1) each have 1 to 4 carbon atoms.

[0017] Section 5. Item 5. The RNA methyltransferase inhibitor according to any one of Items 2 to 4, wherein the phenylsulfonyl group on the nitrogen-containing heterocyclic group represented by (1-1) further has at least one substituent selected from the group consisting of a halogen atom, an alkyl group, a fluoroalkyl group, an alkoxy group, and a nitro group.

[0018] Section 6. Item 2. The RNA methyltransferase inhibitor according to item 1, wherein the cycloalkyl group represented by (1-2) has 3 to 6 carbon atoms.

[0019] Section 7. Item 2. The RNA methyltransferase inhibitor according to Item 1, wherein the cycloalkyl group represented by (1-2) has 5 or 6 carbon atoms.

[0020] Section 8. Item 2. The RNA methyltransferase inhibitor according to Item 1, wherein the alkyl group represented by (1-3) is a linear alkyl group having 1 to 6 carbon atoms which may have a substituent.

[0021] Section 9. The RNA methyltransferase inhibitor according to any one of items 1 to 8, wherein the substituent on the cycloalkyl group represented by (1-2) and the substituent on the alkyl group represented by (1-3) are at least one selected from the group consisting of a phenyl group, a biphenyl group, a cycloalkyl group, a cycloalkenyl group, a nitrogen-containing heterocyclic group, and a hydroxyl group.

[0022] Section 10. Item 10. The RNA methyltransferase inhibitor according to any one of items 1 to 9, wherein the phenyl group, biphenyl group, cycloalkyl group, cycloalkenyl group, nitrogen-containing heterocyclic group, or hydroxyl group present on the alkyl group represented by (1-3) further has an alkyl group having 1 to 5 carbon atoms as a substituent.

[0023] Section 11. The RNA methyltransferase inhibitor according to claim 1, wherein the substituent on each of the groups (3-1) to (3-9) is at least one selected from the group consisting of an alkyl group, an alkoxy group, a halogen atom, a carboxyl group, an amino group, a nitro group, a phenyl group, and a cycloalkyl group.

[0024] Section 12. Item 2. The RNA methyltransferase inhibitor according to item 1, wherein each of the groups (3-1) to (3-9) has 1 to 5 substituents.

[0025] Section 13. Item 2. The RNA methyltransferase inhibitor according to item 1, wherein the alkyl group and alkoxy group on the phenyl group represented by (3-1) have 1 to 5 carbon atoms, and the cycloalkyl group has 3 to 7 carbon atoms.

[0026] Section 14. Item 2. The RNA methyltransferase inhibitor according to item 1, wherein each of the groups (4-1) to (4-35) has 1 to 6 substituents.

[0027] Section 15. The RNA methyltransferase inhibitor according to Item 1, wherein the substituent on each of the groups (4-1) to (4-35) is at least one selected from the group consisting of a linear or branched alkyl group, a cycloalkyl group, an alkoxy group, an alkylamino group, a phenyl group, a phenylalkyl group, a phenylalkenyl group, a halogen atom, a nitro group, a carboxy group, a furyl group, a dihydroxyphenyl group, a biphenylyl group, an alkylcarbonyl group, an oxo-substituted quinolyl group, a benzofuranyl group, a thienyl group, a trialkylamino group, an oxo group, and a pyridyl group.

[0028] Section 16. Item 2. The RNA transferase inhibitor according to Item 1, wherein the substituent on the phenyl group represented by (4-1) is at least one selected from the group consisting of halogen, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyl group, an alkylsulfonylamino group, a nitro group, an amino group, a carboxyl group, and a phenyl group.

[0029] Section 17. The substituent on the alkylcarbonyl group represented by (4-3) is preferably a phenylalkylamino group, a triazolylthio group, a phenoxy group, an oxadiazolylthio group, an ester group, a piperazinyl group, a carboxyl group, a pyrimidinylthio group, a quinazolyloxy group, a morpholinocarbonyl group, a morpholino group, a benzotriazolyl group, a pyrazolylcarbonyl group, a pyrimidyl group, a pyrrolidino group, a piperidino group, a tetrahydroimidazolyl group, a halogen atom, a naphthyloxy group, an alkoxy group, an imidazolyl group, a tetrazolylthio group, an alkylamino group, a pyridyl group, a tetrazolyl group, a benzodioxonyloxy group, an aminocarbonyl group, a piperazinyloxy group, ... phenylalkylamino group, a phenylalkylamino group, a phenylalkylamino group, a phenylalkylamino group, a phenylalkylamino group, a phenylalkylamino group, a phenylalkylamino group, a phenylalkylamino group, a phenylalkylamino group, Item 2. The RNA methyltransferase inhibitor according to Item 1, wherein the RNA methyltransferase inhibitor is at least one selected from the group consisting of an alkyl group, a phenylalkylthio group, an alkylcarbonyloxy group, a benzotriazolylthio group, a pyridazinyl group, a pyrrolylcarbonyloxy group, a piperidino group, a dihydrothiazolylthio group, a benzopyrazyl group, a thienopyridinoxy group, a thienopyrimidinylthio group, a cyclopentathienopyrimidinyl group, a thiadiazolylthio group, an azepinylthio group, a dioxoloquinolinyl group, a diazaspirononanyl group, an imidazolidinyl group, a triazolylthio group, a dihydropyridazinyl group, and a 1,3-diazaspirondecanyl group.

[0030] Section 18. Item 2. The RNA methyltransferase inhibitor according to item 1, wherein each group on the alkylcarbonyl group represented by (4-3) may further have 1 to 6 substituents.

[0031] Section 19. Item 2. The RNA methyltransferase inhibitor according to Item 1, wherein each group on the alkylcarbonyl group represented by (4-3) further has at least one substituent selected from the group consisting of a linear, branched or cyclic alkyl group, an alkoxy group, an alkoxyphenyl group, an amino group, a carbamoyl group, a carbamoylalkyl group, a thienyl group, a furyl group, a tetrazolyl group, an alkylcarbonyl group, a halogen atom, a phenyl group, a furanyl group, an alkylpyrrolidinyl group, a thiophenyl group, a furylcarbonyl group, an oxo group, a trifluoroalkyl group, a hydroxyl group, a thienylalkyl group, an alkylaminosulfonyl group, a hydroxyalkyl group, a furanylcarbonyl group, a benzylthio group, a nonanyl group, a bicyclononanyl group, an alkylthiadiazolyl group and an alkylisoxazolyl group.

[0032] Section 20. Item 2. The RNA methyltransferase inhibitor according to item 1, wherein in the general formula (2), a ring formed by bonding two adjacent carbon atoms constituting the pyrazoline ring to each other is a cyclohexane ring.

[0033] Section 21. Item 21. The RNA methyltransferase inhibitor according to item 20, wherein the cyclohexane ring has a vinyl group which may have a substituent.

[0034] Section 22. Item 22. The RNA methyltransferase inhibitor according to Item 21, wherein the substituent on the vinyl group is at least one selected from the group consisting of a phenyl group, a benzoxonyl group, a furyl group, a thienyl group, and a cyclopentane ring.

[0035] Section 23. Item 2. The RNA methyltransferase inhibitor according to item 1, wherein in the general formula (2), the nitrogen atom constituting the pyrazoline ring and the carbon atom adjacent thereto are bonded to each other to form a cyclohexane ring which may have a substituent.

[0036] Section 24. Item 2. The RNA methyltransferase inhibitor according to Item 1, wherein in the general formula (2), a nitrogen atom constituting the pyrazoline ring and a carbon atom adjacent thereto are bonded to each other to form a cyclohexane ring which may have a substituent, and the substituent on the cyclohexane ring is at least one selected from the group consisting of a halogen atom, an alkyl group, an alkoxy group, a (bi)phenyl group which may have a substituent, an alkylphenyl group, an alkoxyphenyl group, a pyridyl group, an alkoxyphenyl group, a nitrophenyl group, a (di)fluorophenyl group, a (di)chlorophenyl group, and a spiro ring.

[0037] Section 25. In the general formula (2), a nitrogen-containing heterocyclic group on a nitrogen atom constituting the pyrazoline ring; Item 2. The RNA methyltransferase inhibitor according to Item 1, wherein, on the pyrazoline ring, a hydroxyphenyl group on a carbon atom adjacent to a nitrogen atom constituting the pyrazoline ring is bonded to each other to form a ring.

[0038] Section 26. Item 26. The RNA transferase inhibitor according to any one of Items 1 to 25, which is used for treating cancer.

[0039] Section 27. A sulfonamide compound represented by the following general formula (1a):

[0040] [ka]

[0041] [In formula (1a), R 1a represents a piperidyl group which may have a substituent, a pyridyl group which may have a substituent, a pyrazolyl group which may have a substituent, a cyclohexyl group, a linear alkyl group having 1 to 5 carbon atoms which may have a substituent, a pyrazolylamino group which may have a substituent, or a phenylamino group which may have a substituent. R 2a R represents a hydrogen atom or a methyl group. 3arepresents a phenyl group which may have a substituent.

[0042] Section 28. R 1a Item 28. The sulfonamide compound according to Item 27, wherein the number of substituents on the piperidyl group which may have a substituent, the pyridyl group which may have a substituent, the pyrazolyl group which may have a substituent, the cyclohexyl group, the linear alkyl group having 1 to 5 carbon atoms which may have a substituent, the pyrazolylamino group which may have a substituent, or the phenylamino group which may have a substituent is 1 to 5.

[0043] Section 29. R 1a Item 28. The sulfonamide compound according to item 27, wherein the substituent on the piperidyl group represented by the formula: is at least one selected from the group consisting of a methyl group and a hydroxyl group.

[0044] Section 30. R 1a Item 28. The sulfonamide compound according to item 27, wherein the substituent on the linear alkyl group having 1 to 5 carbon atoms, represented by the formula:

[0045] Section 31. R 1a Item 28. The sulfonamide compound according to item 27, wherein the substituent on the linear alkyl group having 1 to 5 carbon atoms, represented by the formula:

[0046] Section 32. R 3a Item 28. The sulfonamide compound according to item 27, wherein the number of substituents on the phenyl group is 1 to 3 and the number is 1 to 3.

[0047] Section 33. R 3aItem 28. The sulfonamide compound according to item 27, wherein the substituent on the phenyl group represented by the formula: is at least one selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a phenyl group, a halogen atom, and a carboxyl group.

[0048] Section 34. R 3a Item 28. The sulfonamide compound according to item 27, wherein the substituent on the phenyl group represented by the formula: is at least one selected from a methyl group, an isopropyl group, a tert-butyl group, a tert-pentyl group, a methoxy group, a phenyl group, a cyclopropyl group, a chlorine atom, and a carboxyl group.

[0049] Section 35. A method for screening an RNA transferase inhibitor, comprising a step of measuring the RNA methylation inhibitory effect of a test substance on a cell or a virus.

[0050] Section 36. Item 36. The method according to Item 35, wherein the RNA methylation inhibitory effect is based on FTSJ inhibition.

[0051] Section 37. 36. The method of claim 35, wherein the FTSJ is FTSJ1.

[0052] Section 38. 38. The method according to any one of items 35 to 37, wherein the RNA methylation inhibitory effect is measured by a reporter assay using a sequence in which a translation regulatory region is added to a reporter region, The method of claim 1, wherein the translation regulatory region comprises a sequence formed by binding at least one selected from the group consisting of glutamine, phenylalanine, tryptophan, methionine and leucine.

[0053] Section 39. Item 39. The method according to Item 38, wherein the translation regulatory region comprises a sequence in which 5 to 50 of at least one kind selected from the group consisting of glutamine, phenylalanine, tryptophan, methionine, and leucine are consecutively linked.

[0054] Section 40. Item 39. The method according to Item 38, wherein the translation regulatory region is composed of polyglutamine, polyphenylalanine, polytryptophan, polymethionine, or polyleucine, each of which is composed of 5 to 50 consecutive glutamines, phenylalanines, tryptophans, methionines, or leucines.

[0055] Section 41. Item 39. The method according to Item 38, wherein the translation regulatory region is any one of SEQ ID NOs: 1 to 12.

[0056] Section 42. 42. The method according to any one of items 35 to 41, further comprising carrying out a reporter assay using a sequence comprising the transcription factor binding region shown in SEQ ID NO:13 and a reporter region.

[0057] Section 43. Adding a methyl group donor to the test substance to obtain a reaction product; and a step of measuring the FTSJ1 activity of the test substance using the reaction product, in this order;

[0058] Section 44. Item 44. The method of item 43, wherein the methyl group donor is S-adenosylmethionine (SAM).

[0059] Section 45. 45. The method according to claim 44, wherein the FTSJ1 activity measurement is carried out by luciferase assay.

[0060] Section 46. A method for predicting the effectiveness of an FTSJ1 inhibitor against cancer, or a method for predicting the prognosis of cancer by use of an FTSJ1 inhibitor, comprising step A of measuring the expression level of FTSJ1 in a sample.

[0061] Section 47. Item 47. The method according to Item 46, wherein step A is carried out by an immunological technique or a genetic technique.

[0062] Section 48. 48. The method of claim 46 or 47, wherein the sample is taken from a patient.

[0063] Section 49. Item 49. The method according to any one of items 46 to 48, further comprising step B of determining the efficacy of an FTSJ1 inhibitor against cancer or determining the prognosis of the patient's cancer pathology based on the FTSJ1 expression level obtained in step A.

[0064] Section 50. 50. The method according to any one of items 46 to 49, wherein the cancer is at least one selected from the group consisting of glioblastoma (malignant brain tumor), pancreatic cancer, acute myeloid leukemia, lung cancer, liver cancer, kidney cancer, gastric cancer, and breast cancer.

[0065] Section 51. A marker for determining the effectiveness of anticancer drugs, consisting of a genetic marker associated with sensitivity to FTSJ1 inhibitors or a genetic marker associated with resistance to FTSJ1 inhibitors.

[0066] Section 52. Item 52. The marker according to Item 51, wherein the FTSJ1 inhibitor sensitivity-associated gene marker or the FTSJ1 inhibitor resistance-associated gene marker is an FTSJ1 modified nucleic acid RNA.

[0067] Section 53. The FTSJ1 inhibitor resistance-associated gene markers include AHNAK nucleoprotein 2 (AHNAK2, SEQ ID NO: 14), extended synaptotagmin 1 (ESYT1, SEQ ID NO: 15), SLIT-ROBO Rho GTPase activating protein 1 (SRGAP1, SEQ ID NO: 16), ras homolog family member F, filopodia associated (RHOF, SEQ ID NO: 17), microRNA 4746 (MIR4746, SEQ ID NO: 18), UBX domain protein 6 (UBXN6, SEQ ID NO: 19), cytochrome c oxidase assembly factor COX16 (COX16, SEQ ID NO: 20), ferritin heavy chain 1 (FTH1, SEQ ID NO: 21), lysophosphatidic acid receptor 1 (LPAR1, SEQ ID NO: 22), ankyrin repeat domain 29 (ANKRD29, SEQ ID NO: 23), and twist family bHLH transcription factor 2 (TWIST2, SEQ ID NO: 24), JNK1 / MAPK8 associated membrane protein (JKAMP, SEQ ID NO: 25), protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2, SEQ ID NO: 26), cleavage stimulation factor subunit 2 tau variant (CSTF2T, SEQ ID NO: 27), thrombospondin type 1 domain containing 4 (THSD4, SEQ ID NO: 28), membrane associated guanylate kinase,Item 50. The marker according to Item 50, which is at least one selected from the group consisting of WW and PDZ domain containing 1 (MAGI1, SEQ ID NO: 29), ubiquitin conjugating enzyme E2 L3 (UBE2L3, SEQ ID NO: 30), glycosylphosphatidylinositol specific phospholipase D1 (GPLD1, SEQ ID NO: 31), FRY like transcription coactivator (FRYL, SEQ ID NO: 32), and myosin IXA (MYO9A, SEQ ID NO: 33).

[0068] Section 54. The FTSJ1 inhibitor sensitivity-related gene markers include RNA binding motif protein 15 (RBM15, SEQ ID NO: 34), nuclear autoantigenic sperm protein (NASP, SEQ ID NO: 35), pre-mRNA processing factor 38A (PRPF38A, SEQ ID NO: 36), chromosome 1 open reading frame 50 (C1orf50, SEQ ID NO: 37), peroxisomal biogenesis factor 16 (PEX16, SEQ ID NO: 38), zinc finger protein 213 (ZNF213, SEQ ID NO: 39), fem-1 homolog B (FEM1B, SEQ ID NO: 40), regulatory factor X associated protein (RFXAP, SEQ ID NO: 41), Sin3A associated protein 18 (SAP18, SEQ ID NO: 42), alanyl-tRNA synthetase 2, mitochondrial (AARS2, SEQ ID NO: 43), regulator of chromosome condensation 2 (RCC2, SEQ ID NO: 44), tyrosyl-tRNA synthetase 1 (YARS1, SEQ ID NO: 45), RNA binding motif protein 10 (RBM10, SEQ ID NO: 46), ribosomal protein L5 (RPL5, SEQ ID NO: 47), zinc finger HIT-type containing 2 (ZNHIT2, SEQ ID NO: 48), oxidative stress induced growth inhibitor family member 2 (OSGIN2, SEQ ID NO: 49), egl-9 family hypoxia inducible factor 3 (EGLN3, SEQ ID NO: 50), tRNA phosphotransferase 1 (TRPTI, SEQ ID NO: 51), CRACD like (CRACDL, SEQ ID NO: 52), capping actin protein,Item 50. The marker according to Item 50, which is at least one selected from the group consisting of gelsolin-like (CAPG, SEQ ID NO: 53), RAB11 family interacting protein 3 (RAB11FIP3, SEQ ID NO: 54), calcium homeostasis modulator family member 5 (CALHM5, SEQ ID NO: 55), BICD cargo adaptor 1 (BICD1, SEQ ID NO: 56) and FtsJ RNA 2'-O-Methyltransferase 1 (FTSJ1, SEQ ID NO: 57).

[0069] Section 55. Item 55. A kit for predicting the efficacy of an FTSJ1 inhibitor, comprising the marker according to any one of Items 51 to 54. Effect of the Invention

[0070] The present invention provides an RNA methyltransferase inhibitor, a screening method therefor, a marker for determining the effectiveness of an anticancer drug, and a kit for predicting the effectiveness of an FTSJ1 inhibitor. [Brief description of the drawings]

[0071] [Figure 1] 1 shows the results of animal experiments on the RNA methyltransferase inhibitor of the present invention. [Diagram 2] 1 shows the results of animal experiments on the RNA methyltransferase inhibitor of the present invention. [Diagram 3] 4 shows the results of detection of FTSJ1 inhibitory activity by the screening method of the present invention. [Figure 4] Evaluation results of genetic markers related to sensitivity to FTSJ1 inhibitors. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0072] 1. RNA methyltransferase inhibitors The RNA methyltransferase inhibitor of the present invention includes a compound represented by the following general formula (1) and / or a pyrazoline compound represented by the following general formula (2).

[0073] [ka]

[0074] [In formula (1), R 1 represents any one of the following groups (1-1) to (1-5). (1-1) a nitrogen-containing heterocyclic group which may have a substituent, (1-2) a cycloalkyl group which may have a substituent, (1-3) an alkyl group which may have a substituent; (1-4) a pyrazolylamino group, (1-5) Phenyl group; R 2 represents (2-1) a hydrogen atom or (2-2) an alkyl group. R 3 represents any one of the following groups (3-1) to (3-9). (3-1) a phenyl group, (3-2) naphthyl group, (3-3) nitrogen- or sulfur-containing heterocyclic groups, (3-4) dihydrocarbostyril group, (3-5) tetrahydronaphthyl group, (3-6) indanyl group, (3-7) benzoxolyl group, (3-8) benzothiadiazolyl group, (3-9) Dihydrobenzodioxepinyl group; Each of the groups represented by (3-1) to (3-9) may further have a substituent. Or, R 1 and R 2 may be bonded to the nitrogen atom to which they are bonded to form a ring.

[0075] [ka]

[0076] [In formula (2), n represents an integer of 2 to 4.4 are the same or different and represent any one of the following groups (4-1) to (4-35). (4-1) phenyl group, (4-2) a phenylsulfonyl group, (4-3) alkylcarbonyl group, (4-4) aminothiocarbonyl group, (4-5) benzodioxolyl group, (4-6) an alkylsulfonyl group, (4-7) adamantylcarbonyl group, (4-8) benzopyrazyl group, (4-9) phenylcarbonyl group, (4-10) naphthyl group, (4-11) Furylcarbonyl group, (4-12) thienylcarbonyl group, (4-13) quinazolyl group, (4-14) quinoxalyl group, (4-15) Hydroxyl group, (4-16) an alkenyl group, (4-17) thiazolyl group, (4-18) cycloalkylcarbonyl group, (4-19) aminocarbonyl group, (4-20) furyl group, (4-21) thienyl group, (4-22) pyridyl group, (4-23) a cycloalkenyl group, (4-24) alkyl group, (4-25) a pyrazolyl group, (4-26) quinolyl group, (4-27) an alkenylcarbonyl group, (4-28) Benzopyranyl group, (4-29) a benzopyrimidyl group, (4-30) pyrrolidinoalkylcarbonyl group, (4-31) quinolylcarbonyl group, (4-32) an alkoxycarbonyl group, (4-33) morpholino group, (4-34) a pyrrolidinocarbonylalkoxy group, (4-35) Benzodioxy-6-yl group; Each of the groups represented by (4-1) to (4-35) may further have a substituent. The bond between the nitrogen atom at the 2nd position and the carbon atom at the 3rd position of the pyrazole skeleton represents a single bond or a double bond. Alternatively, two adjacent carbon atoms constituting a pyrazoline ring may be bonded to each other to form a ring. Alternatively, the nitrogen atom constituting the pyrazoline ring and the carbon atom adjacent thereto may be bonded to each other to form a ring.

[0077] The present inventors have found that the compounds represented by the above general formulas (1) and (2) inhibit the methylation modification reaction of RNA by competitively binding to S-adenosylmethionine (hereinafter, also referred to simply as SAM) in the region (hereinafter, also referred to simply as SAM binding region) to which SAM binds in FTSJ, a tRNA methylation modification enzyme.

[0078] The present inventors have also found that the compounds represented by the general formulae (1) and (2) have an antitumor effect based on the above-mentioned RNA methylation modification inhibitory effect, and are useful as cancer therapeutic agents. In this specification, the cancer therapeutic agent is defined to include not only those generally called anticancer agents, but also cancer metastasis inhibitors.

[0079] The compounds represented by general formulas (1) and (2) are described in detail below.

[0080] In this specification, the alkyl group includes an alkyl group having 1 to 6 carbon atoms, specifically, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group, and the like.

[0081] In this specification, the alkoxy group refers to an alkoxy group having 1 to 6 carbon atoms, specifically, a methoxy group, an ethoxy group, an n-propyloxy group, an isopropyloxy group, an n-butyloxy group, an isobutyloxy group, a sec-butyloxy group, a tert-butyloxy group, an n-pentyloxy group, an n-hexyloxy group, etc.

[0082] In this specification, the cycloalkyl group includes a cycloalkyl group having 3 to 8 carbon atoms, specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, etc.

[0083] In this specification, the cycloalkenyl group refers to a cycloalkenyl group having 3 to 8 carbon atoms, specifically, a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, etc.

[0084] In the general formula (1), R 1 Examples of the nitrogen-containing heterocyclic group represented by the formula (I) include a piperidyl group, a pyridyl group, a pyrazolyl group, etc. A preferred nitrogen-containing heterocyclic group is a piperidyl group.

[0085] The substituent on the nitrogen-containing heterocyclic group is an alkyl group, a hydroxyl group, a cyclopropyl group, a phenylthiopropylcarbonyl group, a phenylsulfonyl group, an alkylsulfonyl group, a thienylsulfonyl group, an alkylcarbonyl group, an alkoxycarbonyl group, a phenylsulfonylamino group, an aminocarbonylalkyl group, a pyrazolylcarbonyl group, a cyclopropylcarbonyl group, a piperidylsulfonyl group, a morpholinosulfonyl group, etc. The preferred substituent on the nitrogen-containing heterocyclic group is an alkyl group, more preferably an isopropyl group. The number of the substituent is 1 to 5, preferably 1 to 4.

[0086] The alkyl group and alkoxy group constituting the alkyl group, alkylsulfonyl group, alkylcarbonyl group, alkoxycarbonyl group and aminocarbonylalkyl group on the nitrogen-containing heterocyclic group represented by (1-1) have 1 to 4 carbon atoms.

[0087] The phenylsulfonyl group on the nitrogen-containing heterocyclic group represented by (1-1) further has at least one substituent selected from the group consisting of a halogen atom, an alkyl group, a fluoroalkyl group, an alkoxy group and a nitro group.

[0088] In the general formula (1), R 1 The cycloalkyl group represented by the formula (I) includes a cycloalkyl group having 3 to 8 carbon atoms, specifically a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, etc. The cycloalkyl group preferably has 3 to 6 carbon atoms. More preferred cycloalkyl groups are a cyclopentyl group and a cyclohexyl group.

[0089] In the general formula (1), R 1 Examples of the alkyl group represented by the formula (I) include alkyl groups having 1 to 6 carbon atoms, specifically, methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, sec-butyl groups, tert-butyl groups, n-pentyl groups, n-hexyl groups, etc. Preferred alkyl groups are methyl groups, ethyl groups, isopropyl groups, etc.

[0090] The substituent on the cycloalkyl group represented by (1-2) and the substituent on the alkyl group represented by (1-3) are at least one selected from the group consisting of a phenyl group, a biphenyl group, a cycloalkyl group, a cycloalkenyl group, a nitrogen-containing heterocyclic group (e.g., a piperidyl group, a pyridyl group, a pyrazolyl group, etc.) and a hydroxyl group.

[0091] The phenyl group, biphenyl group, cycloalkyl group, cycloalkenyl group, nitrogen-containing heterocyclic group or hydroxyl group present on the alkyl group represented by (1-3) may further have an alkyl group having 1 to 5 carbon atoms as a substituent.

[0092] The substituent on each of the groups shown in (3-1) to (3-9) is at least one selected from the group consisting of an alkyl group, an alkoxy group, a halogen atom, a carboxyl group, an amino group, a nitro group, a phenyl group, and a cycloalkyl group. The number of substituents on each of the groups shown in (3-1) to (3-9) is 1 to 5, preferably 1 to 3.

[0093] The alkyl and alkoxy groups on the phenyl group represented by the above formula (3-1) each have 1 to 5 carbon atoms, and the cycloalkyl group has 3 to 7 carbon atoms. The preferred alkyl and alkoxy groups have 1 to 3 carbon atoms.

[0094] Examples of the nitrogen- or sulfur-containing heterocyclic group represented by (3-3) include a pyrrolyl group, a piperidyl group, a quinolyl group, and a thienyl group.

[0095] R 3 is preferably (3-1) a phenyl group or (3-2) a naphthyl group. The phenyl group is more preferably substituted with 1 to 3 alkyl groups having 1 to 5 carbon atoms, and particularly preferably substituted with 3 isopropyl groups.

[0096] In the general formula (2), R 4 The number of substituents on each of the groups represented by (4-1) to (4-35) is 1 to 6, and preferably 1 to 3.

[0097] The substituent on each of the groups (4-1) to (4-35) is at least one selected from the group consisting of a linear or branched alkyl group, a cycloalkyl group, an alkoxy group, an alkylamino group, a phenyl group, a phenylalkyl group, a phenylalkenyl group, a halogen atom, a nitro group, a carboxy group, a furyl group, a dihydroxyphenyl group, a biphenylyl group, an alkylcarbonyl group, an oxo-substituted quinolyl group, a benzofuranyl group, a thienyl group, a trialkylamino group, an oxo group, and a pyridyl group.

[0098] The substituent on the phenyl group represented by (4-1) is preferably at least one selected from the group consisting of halogen, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyl group, an alkylsulfonylamino group, a nitro group, an amino group, a carboxyl group, and a phenyl group.

[0099] The substituent on the alkylcarbonyl group represented by (4-3) above is preferably a phenylalkylamino group, a triazolylthio group, a phenoxy group, an oxadiazolylthio group, an ester group, a piperazinyl group, a carboxyl group, a pyrimidinylthio group, a quinazolyloxy group, a morpholinocarbonyl group, a morpholino group, a benzotriazolyl group, a pyrazolylcarbonyl group, a pyrimidyl group, a pyrrolidino group, a piperidino group, a tetrahydroimidazolyl group, a halogen atom, a naphthyloxy group, an alkoxy group, an imidazolyl group, a tetrazolylthio group, an alkylamino group, a pyridyl group, a tetrazolyl group, a benzodioxonyloxy group, an amino group, a phenylalkylamino group, a triazolylthio group, a phenoxy group, an oxadiazolylthio group, an ester group, a piperazinyl group, a carboxyl group, a pyrimidinylthio group, a quinazolyloxy group, a morpholinocarbonyl group, a morpholino group, a benzotriazolyl group, a pyrazolylcarbonyl group, a pyrimidyl group, a pyrrolidino group, a piperidino group, a tetrahydroimidazolyl group, a halogen atom, a naphthyloxy group, an alkoxy group, an imidazolyl group, a tetrazolylthio group, an alkylamino group, a pyridyl group, a tetrazolyl group, a benzodioxonyloxy group, an amine group, a phenylalkylamino ... and at least one selected from the group consisting of a phenylcarbonyl group, a piperazinyl group, a phenylalkylthio group, an alkylcarbonyloxy group, a benzotriazolylthio group, a pyridazinyl group, a pyrrolylcarbonyloxy group, a piperidino group, a dihydrothiazolylthio group, a benzopyrazyl group, a thienopyridinoxy group, a thienopyrimidinylthio group, a cyclopentathienopyrimidinyl group, a thiadiazolylthio group, an azepinylthio group, a dioxoloquinolinyl group, a diazaspirononanyl group, an imidazolidinyl group, a triazolylthio group, a dihydropyridazinyl group, and a 1,3-diazaspirondecanyl group.

[0100] Each group on the alkylcarbonyl group represented by (4-3) may further have 1 to 6, preferably 1 to 3, substituents.

[0101] Each group on the alkylcarbonyl group represented by (4-3) further has at least one substituent selected from the group consisting of a linear, branched or cyclic alkyl group, an alkoxy group, an alkoxyphenyl group, an amino group, a carbamoyl group, a carbamoylalkyl group, a thienyl group, a furyl group, a tetrazolyl group, an alkylcarbonyl group, a halogen atom, a phenyl group, a furanyl group, an alkylpyrrolidinyl group, a thiophenyl group, a furylcarbonyl group, an oxo group, a trifluoroalkyl group, a hydroxyl group, a thienylalkyl group, an alkylaminosulfonyl group, a hydroxyalkyl group, a furanylcarbonyl group, a benzylthio group, a nonanyl group, a bicyclononanyl group, an alkylthiadiazolyl group and an alkylisoxazolyl group.

[0102] In the general formula (2), the ring formed by bonding two adjacent carbon atoms constituting the pyrazoline ring is, for example, a cyclohexane ring. The cyclohexane ring preferably has a vinyl group which may have a substituent.

[0103] The substituent on the vinyl group is at least one selected from the group consisting of a phenyl group, a benzoxonyl group, a furyl group, a thienyl group, and a cyclopentane ring.

[0104] In the general formula (2), the nitrogen atom constituting the pyrazoline ring and the carbon atom adjacent thereto are preferably bonded to each other to form a cyclohexane ring which may have a substituent. The substituent on the cyclohexane ring is preferably at least one selected from the group consisting of a halogen atom, an alkyl group, an alkoxy group, a (bi)phenyl group which may have a substituent, an alkylphenyl group, an alkoxyphenyl group, a pyridyl group, an alkoxyphenyl group, a nitrophenyl group, a (di)fluorophenyl group, a (di)chlorophenyl group, and a spiro ring.

[0105] In addition, in the general formula (2), a nitrogen-containing heterocyclic group on a nitrogen atom constituting the pyrazoline ring; On the pyrazoline ring, the hydroxyphenyl group on the carbon atom adjacent to the nitrogen atom constituting the pyrazoline ring may be bonded to each other to form a ring.

[0106] Among the groups represented by (4-1) to (4-35), (4-1) a phenyl group, (4-2) a phenylsulfonyl group, (4-3) an alkylcarbonyl group, (4-4) an aminothiocarbonyl group, (4-6) an alkylsulfonyl group, (4-11) a furylcarbonyl group, (4-12) a thienylcarbonyl group, (4-20) a furyl group, (4-21) a thienyl group, (4-22) a pyridyl group, (4-25) a pyrazolyl group, or (4-35) a benzodioxy-6-yl group is preferred.

[0107] Among the groups represented by (4-1) to (4-35), (4-1) a phenyl group, (4-2) a phenylsulfonyl group, (4-3) an alkylcarbonyl group, (4-4) an aminothiocarbonyl group, (4-6) an alkylsulfonyl group, (4-11) a furylcarbonyl group, (4-12) a thienylcarbonyl group, (4-20) a furyl group, (4-21) a thienyl group, (4-22) a pyridyl group, (4-25) a pyrazolyl group, or (4-35) a benzodioxy-6-yl group is preferred.

[0108] Among the groups represented by (4-1) to (4-35), (4-1) a phenyl group, (4-3) an alkylcarbonyl group, (4-6) an alkylsulfonyl group, or (4-35) a benzodioxy-6-yl group are more preferred.

[0109] Among the groups represented by (4-1) to (4-35) above, (4-1) a phenyl group and (4-35) a benzodioxy-6-yl group are particularly preferred.

[0110] In the general formula (2), the substituent of the phenyl group represented by (4-1) may be a halogen atom such as a bromine atom, an alkoxy group such as a methoxy group, a hydroxyl group, etc., and is preferably a hydroxyl group. The number of the substituents on the phenyl group is 1 to 5, preferably 1 to 3, and more preferably 1.

[0111] When the RNA methyltransferase inhibitor of the present invention is used as a cancer treatment drug, it may further contain a pharma- ceutically acceptable carrier in addition to the above-mentioned compound. Examples of the pharma-ceutically acceptable carrier include fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, and other diluents and excipients that are commonly used in pharmaceutical preparations. The formulation of the RNA methyltransferase inhibitor of the present invention may be in the form of a general pharmaceutical preparation, such as tablets, flash-melt tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (liquids, suspensions, etc.), troches, intranasal sprays, transdermal patches, and the like. There is no particular limit to the types of cancer that can be applied, and the present invention can be applied to various cancers.

[0112] The method of administration of the RNA methyltransferase inhibitor of the present invention is not particularly limited, and is administered according to various formulations, the age, sex, and other conditions (such as the severity of the disease) of the patient. For example, tablets, pills, liquids, suspensions, emulsions, granules, and capsules are administered orally. Injections are administered intravenously alone or in combination with a common replacement fluid such as glucose or amino acids, or administered intramuscularly, intradermally, subcutaneously, or intraperitoneally. Suppositories are administered rectally.

[0113] 2. Sulfonamide compounds The present invention also includes an invention relating to a novel sulfonamide compound represented by the following general formula (1a):

[0114] [ka]

[0115] [In formula (1a), R1a represents a piperidyl group which may have a substituent, a pyridyl group which may have a substituent, a pyrazolyl group which may have a substituent, a cyclohexyl group, a linear alkyl group having 1 to 5 carbon atoms which may have a substituent, a pyrazolylamino group which may have a substituent, or a phenylamino group which may have a substituent. R 2a R represents a hydrogen atom or a methyl group. 3a represents a phenyl group which may have a substituent.

[0116] R 1a R represents a piperidyl group, a cyclohexyl group, or a linear alkyl group having 1 to 5 carbon atoms, which may have a substituent. 2a represents a hydrogen atom or a methyl group.

[0117] In general formula (1a), R 1a The substituent of the piperidyl group represented by the following formula: is preferably a trifluoromethyl-substituted pyridyl group.

[0118] In general formula (1a), R 1a The substituent of the pyridyl group represented by the following formula: is preferably a difluorophenyloxy group.

[0119] In general formula (1a), R 1a The substituent of the pyrazolyl group represented by the following formula: is preferably a trifluoromethyl-substituted phenyl group.

[0120] In general formula (1a), R 1a The substituent of the linear alkyl group having 1 to 5 carbon atoms represented by the following formula (I) is preferably a carbonylamino or piperidyl group.

[0121] In general formula (1a), R 3a The phenyl group represented by the following formula is preferably substituted with three alkyl groups having 1 to 5 carbon atoms (preferably isopropyl groups).

[0122] The compound represented by the above formula (1a) can be obtained based on the method described in the production examples described below or a method equivalent thereto.

[0123] 3. Screening Method Furthermore, the present invention includes an invention relating to a method for screening an anticancer agent. The screening method of the present invention uses cells or viruses and measures the RNA methylation inhibitory effect of a test substance.

[0124] The cells used are preferably cancer cells, and the type of cancer is not particularly limited.Specific examples include pharyngeal cancer (lip cancer, gingival cancer, tongue cancer, oral cancer, oral floor cancer, salivary gland cancer, etc.), digestive cancer (esophageal cancer, stomach cancer, appendix cancer, colon cancer, rectal cancer, etc.), lung cancer, liver cancer, hepatocellular carcinoma, bile duct cancer, bone cancer, articular cartilage cancer, malignant melanoma of the skin, squamous cell carcinoma, other skin cancers, mesothelioma, breast cancer, uterine cancer (cervical cancer, uterine body cancer, etc.), ovarian cancer, prostate cancer, bladder cancer, brain tumor, thyroid cancer, non-Hodgkin's lymphoma, lymphocytic leukemia, sarcoma, and cancer of metastatic tissues with these as primary foci.

[0125] Specific cancer cells are not particularly limited and may be any known cancer cells of the above-mentioned cancer types. Among them, it is preferable to use cancer stem cells.

[0126] As the test substance, preferably a low molecular weight compound is used, and the methylation inhibitory effect on the above-mentioned cells or viruses is measured, and test substances having a predetermined or higher inhibitory effect are selected.

[0127] As a preferred embodiment of the screening method of the present invention, the method for measuring the inhibitory effect of RNA methylation can be exemplified by a method for measuring the activity of an enzyme that modifies RNA methylation, i.e., RNA methyltransferase. As such RNA methyltransferase, widely known ones can be applied. Specifically, enzymes belonging to the ALKBH family and Mettle family can be mentioned.

[0128] Among FTSJs, FTSJ1 in particular is considered to be a poor prognostic factor for cancer. Therefore, in screening for anticancer agents, it is preferable to measure the FTSJ1 inhibitory activity of a test substance.

[0129] A more specific method for measuring the activity of RNA methyltransferase is not particularly limited, and a wide variety of known methods can be used. For example, ELISA, RIA, immunoprecipitation, bisulfite, quantitative PCR, and reporter assay can be used. Among them, it is preferable to use the reporter assay because it is easy and accurate to measure.

[0130] Here, in mammalian cells, FTSJ1 is predicted to 2´-O-methylate the 32nd and 34th nucleotides of tRNAs corresponding to the codons polyglutamine (Q), phenylalanine (F), methionine (M), and asparagine (N).

[0131] In a reporter assay, the sequence of the translation regulatory region to which the reporter region is bound preferably contains a sequence formed by binding at least one selected from the group consisting of glutamine, phenylalanine, tryptophan, methionine and leucine.

[0132] The translation regulatory region is preferably a repeat sequence of the above-mentioned five types of amino acids, i.e., polyglutamine, polyphenylalanine, polytryptophan, polymethionine, or polyleucine, but may also be a sequence containing a mixture of the five types. In addition, other amino acids may be included to the extent that they do not inhibit the function.

[0133] The number of amino acid repeats is preferably 3 or more, more preferably 5 or more, and even more preferably 8 or more. The upper limit of the number of repeats is not particularly limited, and can be set to 50, for example.

[0134] More specifically, examples of such translation regulatory regions include sequences represented by any of SEQ ID NOs: 1 to 12. Examples of polyglutamine include SEQ ID NO: 1 or 2, polyphenylalanine include SEQ ID NO: 3 or 4, polytryptophan include SEQ ID NO: 5, polymethionine include SEQ ID NO: 6, and polyleucine include SEQ ID NOs: 7 to 12.

[0135] Furthermore, as a result of the research of the present inventors, it is predicted that YAP / TAZ is a protein that controls cancer stemness and whose protein synthesis is promoted by FTSJ1, so in addition to the reporter assay in which the above-mentioned translation regulatory region is added to the reporter, it is also preferable to carry out a reporter assay in which the expression is regulated by a transcription factor binding region (GTIIC) that contains 3 to 15 repeats of the sequence shown in SEQ ID NO: 13 (however, other sequences may be included between each repeat unit). In addition, it is also preferable to carry out a sphere formation assay and / or mass spectrometry.

[0136] The reporter gene used in the reporter assay can be a wide variety of known reporter genes, and is not particularly limited. Specific examples include β-galactosidase gene, chloramphenicol acetyltransferase gene derived from bacterial transposon, and firefly luciferase gene. Among these, it is preferable to use the firefly luciferase gene because it provides excellent detection sensitivity.

[0137] The method for linking the transcriptional regulatory region and the reporter gene can be widely adopted from known methods and is not particularly limited. Specifically, a method can be mentioned in which the purified transcriptional sequence region is cleaved with an appropriate restriction enzyme and linked to the reporter gene.

[0138] As the vector into which the linked sequence is inserted, a wide variety of known vectors for reporter assays, such as plasmids, shuttle vectors, and helper plasmids, can be used.

[0139] The method for introducing a vector into a cell is not particularly limited, and any known method can be widely adopted, and is not particularly limited. Examples of the method include electroporation, the spheroplast method, and the lithium acetate method.

[0140] The luminescence intensity of the cells into which the vector has been introduced is measured using a luminometer or the like in a standard manner. In the screening method of the present invention, it is preferable to also measure the luminescence of a solvent such as DMSO as a control group (blank) and calculate the assay value of the test substance as a percentage (%) of this.

[0141] In a reporter assay in which a translational regulatory region containing a sequence formed by the binding of at least one selected from the group consisting of glutamine, phenylalanine, tryptophan, methionine, and leucine is added to a reporter, the reporter is screened to select those having an assay value of preferably 100 or less, more preferably 80 or less, and even more preferably 40 or less.

[0142] In addition, in a reporter assay in which the transcriptional regulatory region (GTIIC) represented by sequence number 13 is added to a reporter, the assay value obtained is preferably selected by screening to be 100 or less, more preferably 80 or less, and even more preferably 40 or less.

[0143] Another embodiment is a screening method comprising the steps of adding a methyl group donor to the above-mentioned test substance to obtain a reaction product, and measuring the test substance using the reaction product.

[0144] As the methyl group donor, for example, one that can become a precursor of ATP, described below, by elimination of a methyl group from the methyl group donor is preferable, and a specific example thereof is S-adenosylmethionine (hereinafter, also referred to simply as "SAM").

[0145] In the step of measuring the RNA methylation inhibitory effect on cells or viruses, for example, ELISA, RIA, immunoprecipitation, bisulfite, quantitative PCR, reporter assay, and luciferase assay can be used.

[0146] In particular, when SAM is used as a methyl group donor in the step of adding a methyl group donor to a test substance, SAM is converted to S-adenosylhomocysteine ​​(hereinafter, also simply referred to as "SAH") by FTSJ1 contained in the test substance. The obtained SAH is then reacted with a reagent that converts it to adenosine diphosphate (hereinafter, also simply referred to as "ADP"), and a specific reagent is further added to the ADP to obtain adenosine triphosphate (hereinafter, also simply referred to as "ATP"). By combining this with an assay system such as a luciferase assay, the activity value of FTSJ1 in the test substance can be evaluated more directly, and highly accurate evaluation results can be obtained.

[0147] 4. Method for predicting efficacy or prognosis of FTSJ1 inhibitor against cancer The present invention also includes an invention relating to a method for predicting the efficacy of an FTSJ1 inhibitor against cancer, and a method for predicting the prognosis of cancer by using an FTSJ1 inhibitor. In this specification, "prognosis" is defined as the medical outlook of a patient after chemotherapy.

[0148] The above-mentioned efficacy of the FTSJ1 inhibitor means the effect of the FTSJ1 inhibitor on the pathology of cancer. In other words, the method of predicting the efficacy of the FTSJ1 inhibitor of the present invention encompasses the concept of a method of predicting the sensitivity of a cancer patient, or of cancer tissues or cancer cells collected from a cancer patient, to an FTSJ1 inhibitor. The method of predicting the efficacy of the FTSJ1 inhibitor of the present invention also encompasses the concept of a method of predicting the resistance of a cancer patient, or of cancer tissues or cancer cells collected from a cancer patient, to an FTSJ1 inhibitor.

[0149] The method of predicting the efficacy of an FTSJ1 inhibitor against cancer and the method of predicting the prognosis of cancer using an FTSJ1 inhibitor according to the present invention include a step A of measuring the expression level of FTSJ1 in a sample.

[0150] Here, the specimen may preferably be a cancer tissue or cancer cells derived from a living body (including humans and animals). Specifically, the specimen may be a cancer tissue or cancer cells collected from a patient (cancer patient).

[0151] The expression level of FTSJ1 can be measured by a wide variety of known methods without any particular limitations. Either an immunological method or a genetic method can be suitably used.

[0152] The immunological technique is not particularly limited, and examples thereof include ELISA, immunostaining, flow cytometry, and immunoblot.

[0153] The genetic techniques are not particularly limited, and examples thereof include Western blotting and RT-PCR.

[0154] The method of predicting the effectiveness of an FTSJ1 inhibitor against cancer and the method of predicting the prognosis of cancer using an FTSJ1 inhibitor of the present invention may further include, after the above-mentioned step A, a step B for determining the effectiveness of the FTSJ1 inhibitor against cancer or for determining the prognosis of the patient's cancer pathology based on the FTSJ1 expression level obtained in step A.

[0155] Particularly in step B, it is preferable to set a predetermined cutoff value for the expression level of FTSJ1 in the sample obtained in step A. Then, for example, when predicting the effectiveness of an FTSJ1 inhibitor, it is predicted that the effectiveness of FTSJ1 is high for a sample obtained in step A with an expression level equal to or higher than the cutoff value, and conversely, it is predicted that the effectiveness of FTSJ1 is low for a sample with an expression level lower than the cutoff value.

[0156] Similarly, in a method for predicting the pathology of a patient's cancer after use of an FTSJ1 inhibitor, for example, for a sample in which an expression level equal to or above a predetermined cutoff value is obtained in step A, it is predicted that the patient's prognosis will be good after use of an FTSJ1 inhibitor, and conversely, for a sample in which an expression level equal to or below the cutoff value is obtained, it is predicted that the patient's prognosis will be poor after use of an FTSJ1 inhibitor.

[0157] In addition, the method for predicting the effectiveness of an FTSJ1 inhibitor against cancer and the method for predicting the prognosis of cancer by using an FTSJ1 inhibitor of the present invention can be widely applied to known cancer types without any particular limitation.Specific examples include glioblastoma (malignant brain tumor), pancreatic cancer, acute myeloid leukemia, lung cancer, liver cancer, kidney cancer, stomach cancer, and breast cancer.

[0158] 5. Anticancer drug efficacy assessment marker The present invention also includes an invention relating to a marker for determining the effectiveness of an anticancer drug. The marker is a genetic marker, which is a genetic marker associated with FTSJ1 inhibitor sensitivity and a genetic marker associated with FTSJ1 inhibitor resistance.

[0159] These markers are used to determine the sensitivity of a patient to an FTSJ1 inhibitor based on whether they are detected in a sample (tissue, cells, etc.) taken from the patient (including humans and animals). When a genetic marker associated with FTSJ1 inhibitor sensitivity is detected in a sample, it is presumed that an FTSJ1 inhibitor will be effective in chemotherapy for that patient. On the other hand, when a genetic marker associated with FTSJ1 inhibitor resistance is detected in a sample, it is presumed that an FTSJ1 inhibitor will not be effective in chemotherapy for that patient.

[0160] These FTSJ1-related markers for determining the efficacy of anticancer drugs (gene markers associated with sensitivity to FTSJ1 inhibitors or gene markers associated with resistance to FTSJ1 inhibitors) are preferably FTSJ1 modified nucleic acid RNA.

[0161] In addition, the FTSJ1 inhibitor resistance-associated gene marker is preferably at least one selected from the group consisting of AHNAK2 (sequence number 14), ESYT1 (sequence number 15), SRGAP1 (sequence number 16), RHOF (sequence number 17), MIR4746 (sequence number 18), UBXN6 (sequence number 19), COX16 (sequence number 20), FTH1 (sequence number 21), LPAR1 (sequence number 22), ANKRD29 (sequence number 23), TWIST2 (sequence number 24), JKAMP (sequence number 25), PRKAA2 (sequence number 26), CSTF2T (sequence number 27), THSD4 (sequence number 28), MAGI1 (sequence number 29), UBE2L3 (sequence number 30), GPLD1 (sequence number 31), FRYL (sequence number 32), and MYO9A (sequence number 33).

[0162] The FTSJ1 inhibitor sensitivity-related gene markers are RBM15 (SEQ ID NO: 34), NASP (SEQ ID NO: 35), PRPF38A (SEQ ID NO: 36), C1orf50 (SEQ ID NO: 37), PEX16 (SEQ ID NO: 38), ZNF213 (SEQ ID NO: 39), FEM1B (SEQ ID NO: 40), RFXAP (SEQ ID NO: 41), SAP18 (SEQ ID NO: 42), AARS2 (SEQ ID NO: 43), RCC2 (SEQ ID NO: 44), YARS1 (SEQ ID NO: 45), RBM It is preferable that the gene is at least one selected from the group consisting of: 10 (sequence number 46), RPL5 (sequence number 47), ZNHIT2 (sequence number 48), OSGIN2 (sequence number 49), EGLN3 (sequence number 50), TRPTI (sequence number 51), CRACDL (sequence number 52), CAPG (sequence number 53), RAB11FIP3 (sequence number 54), CALHM5 (sequence number 55), BICD1 (sequence number 56) and FTSJ1 (sequence number 57).

[0163] 6. Kit for predicting efficacy of FTSJ1 inhibitors The present invention also encompasses a kit comprising the above-mentioned marker for determining the effectiveness of an anticancer drug. When at least one of the above-mentioned gene markers associated with resistance to an FTSJ1 inhibitor is detected in a sample, it is determined that an FTSJ1 inhibitor is ineffective in chemotherapy for the patient.

[0164] On the other hand, when at least one of the above-mentioned gene markers associated with sensitivity to an FTSJ1 inhibitor is detected in a sample, it is determined that an FTSJ1 inhibitor is effective for chemotherapy of the patient.

[0165] Such a kit is not particularly limited as long as it utilizes a mechanism for detecting the above-mentioned genetic markers in a sample. For example, a kit may be used in which cDNA is obtained from a sample and amplified by PCR to detect the genetic markers. In this case, the kit of the present invention preferably includes, for example, primers for each genetic marker for carrying out PCR.

[0166] Although the embodiment of the present invention has been described above, the present invention is not limited to these examples, and it is needless to say that the present invention can be embodied in various forms without departing from the gist of the present invention. EXAMPLES

[0167] Hereinafter, the embodiments of the present invention will be described more specifically based on examples, but the present invention is not limited to these.

[0168] (Experimental Example) screening Human gastric cancer cell line NUGC3 was cultured in DMEM medium (high glucose, L-glutamine, phenol red, Fujifilm Wako Pure Chemical) containing 10% fetal bovine serum (Thermo Fisher Scientific) and penicillin / streptomycin (Fujifilm Wako Pure Chemical) (hereinafter, the medium is simply referred to as "DMEM + 10% FBS + 1xP / S"). NUGC3 cells were then seeded on a 60 mm culture dish (BioLite) and allowed to reach 80% confluence after 24 hours. Next, 5 μg of reporter plasmid and 15 μL of lipofection reagent (TransIT-LT1, Mirus) were mixed in 500 μL of Opti-MEM (Thermo Fisher Scientific) medium to form a complex, which was then added to the medium of NUGC3 cells being cultured in a 60 mm culture dish. For the reporter plasmid, 5μg was introduced for the polyglutamine luciferase reporter (polyglutamine luciferase reporter is equipped with Renilla luciferase expressed by IRES as an internal standard downstream of the polyglutamine-tagged firefly luciferase sequence). For the YAP / TAZ activity reporter, 3μg of 8xGTIIC plasmid and 2μg of Renilla luciferase reporter as an internal standard were simultaneously introduced. After another 24 hours, the cells were detached with 0.05w / v% trypsin-0.53mmol / l EDTA·4Na solution (Fujifilm Wako Pure Chemical Industries, Ltd.) and re-seeded on a 96-well plate (BioLite) so that the cells were 80% confluent after 24 hours. 24 hours after seeding on the 96-well plate, the medium in each well was replaced with 100 μL of medium (DMEM + 10% FBS + antibiotics) containing 10 μM or 5 μM of the compound to be evaluated. After another 24 hours, the medium containing the compound was removed and the 96-well plate was transferred to ice. After washing with 100 μL of phosphate buffered buffer (PBS, Fujifilm Wako Pure Chemical Industries, Ltd.) per well, 20 μL of Passive Lysis Buffer (1X) contained in Dual-Luciferase Reporter Assay System (Promega) was added. The cells were then gently rocked at room temperature for 15 minutes to dissolve the cells.After confirming that the cells were lysed, 10 μL of the lysate was transferred from each well to the corresponding well of a white 96-well plate (Greiner). 100 μL of a mixture of Luciferase Assay Buffer II and Luciferase Assay Substrate contained in the Dual-Luciferase Reporter Assay System (Promega) was added to each well of the white 96-well plate to induce luminescence of firefly luciferase, and the luminescence intensity was detected using a microluminometer (Berthold). Next, 100 μL of a mixture of Stop & Glo Buffer and Stop & Glo Substrate contained in the Dual-Luciferase Reporter Assay System (Promega) was added to eliminate the luminescence of firefly luciferase and induce the luminescence of Renilla luciferase, and the luminescence intensity was similarly detected using a microluminometer (Berthold). The ratio of the luminescence intensity of firefly luciferase to that of Renilla luciferase was calculated, and the luminescence intensity ratio of the well to which DMSO (dimethyl sulfoxide, used as a solvent for compound solutions) was added was set as 100%, and the luminescence intensity ratio of the well to which each compound was added was calculated as a percentage. The inhibition results of each compound are shown in Table 1 below. Note that, with regard to the measured values ​​in the table, unless otherwise specified, they show the results of evaluation after adding 10 μM of the compound to be evaluated.

[0169] [Table 1]

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[0273] Screening Tests Human embryonic kidney cells (HEK293 cells) that constitutively express FLAG-tagged FTSJ1 were generated, and FLAG-FTSJ1 was adsorbed and separated from the cell lysate using anti-FLAG M2 antibody affinity gel (Sigma-Aldrich, cat#A2220-10ML), and eluted using FLAG peptide (Sigma-Aldrich, cat#F3290-25MG). After measuring the protein concentration of the eluate, it was serially diluted in the range of 0-20 ng / reaction to obtain 12 different enzyme dilutions. In addition, total RNA was extracted from HEK293-FTSJ1-KO cells in which FTSJ1 was knocked out, using TRIzol Reagent (ThermoFisher, cat# 15596018). To measure the activity of FLAG-FTSJ1 when it uses RNA as a substrate to cause a methyl group transfer reaction, we used the above-mentioned enzyme dilution solution, total RNA (1,000 ng / reaction), and a methyl group transferase activity measurement assay kit (Promega, cat#V7601). The conversion reaction from S-adenosyl methionine (SAM) to S-adenosyl homocysteine ​​(SAH) that occurs when FLAG-FTSJ1 in each dilution solution methylates 1,000 ng / reaction of total RNA was measured as luciferase luminescence value using MTase-Glo Reagent in the assay kit. The luminescence value at 0 ng of FLAG-FTSJ1 was used as the background value, and a graph was created using the values ​​obtained by subtracting the background value from the luminescence value at each dilution step. As shown in Figure 3A, a dose-dependent increase in luminescence value of FLAG-FTSJ1 was observed, confirming that the enzyme activity of FTSJ1 could be detected.

[0274] Using the above system, we confirmed the inhibitory effect of PVZF2001, an FTSJ1 inhibitor, on the methyl group transfer reaction. Using 10 ng / reaction of FLAG-FTSJ1, 1,000 ng / reaction of total RNA, and a methyl group transferase activity assay kit, we measured the luminescence intensity when different concentrations of PVZF2001 were mixed. As shown in Figure 3B, the luminescence intensity was observed to decrease in a concentration-dependent manner, confirming that PVZF2001 inhibits the methyl group transfer reaction catalyzed by FTSJ1.

[0275] Antitumor effect evaluation test A suspension of triple-negative breast cancer cell line MDA-MB-231 cells suspended in phosphate buffered saline (PBS, Fujifilm Wako Pure Chemical Industries, Ltd.) was injected subcutaneously at the lumbar region of immunodeficient mice (BALB / c-nu / nu, female, 6 weeks old, purchased from Shimizu Experimental Materials Co., Ltd.) at 1 × 10 6 The cancer cells were inoculated at 100 μL per cell. The cancer cells were subcutaneously implanted in the mice to form tumor tissue, and the tumor volume increased to 100 mm 3 After confirming that the tumor volume reached 100 mg / kg, the obtained tumor model mice were used in the following evaluation test. First, the compound to be evaluated was dissolved in corn oil (Sigma Aldrich) and administered intraperitoneally. PVZF0024 was administered at 100 mg / kg, and PVZF2001 was administered at 20 mg / kg to the tumor model mice every other day. After each administration, the tumor diameter was measured with a vernier caliper. The tumor volume was calculated as V=(3.14×D×d 2 ) / 6 (where V is tumor volume, D is tumor major axis, and d is tumor minor axis) (Wu. et al., Clin. Cancer Res., 2013 Oct 15;19(20):5699-5710).

[0276] The antitumor effects of PVZF0024 and PVZF2001 are shown in Figures 1 and 2. As shown in each figure, it was confirmed that both compounds significantly suppressed tumor growth, and no weight loss was observed due to administration.

[0277] A study to investigate genetic markers related to sensitivity to FTSJ1 inhibitors To extract genes that determine sensitivity and resistance to FTSJ1 inhibitors, we performed analysis of a cell line panel (JFCR39) using PVZF2001. Thirty-nine human cancer cell lines were treated with PVZF2001 at concentrations of 0.01 μM, 0.1 μM, 1 μM, 10 μM, and 100 μM for 48 hours, and cell proliferation was measured by colorimetry using sulforhodamine B. The Log GI50 values ​​shown in Figure 4A were obtained. The GI50 value is defined as the concentration that suppresses the increase in cell number due to drug treatment to 50%, when the increase in the cell number before drug exposure in the sample (negative control) cultured for 48 hours without drug treatment is taken as 100%. In order to extract the target gene group from this, first, a COMPARE analysis was performed using gene expression and Log GI50 values ​​in all cell lines, and the gene group shown in SEQ ID NO: 14 to 28 was identified as an FTSJ1 inhibitor resistance-related gene marker, and the gene group shown in SEQ ID NO: 34 to 47 was identified as an FTSJ1 inhibitor sensitivity-related gene marker. Furthermore, limited to malignant brain tumors and lung cancers in which sensitivity and resistance to PVZF2001 are clearly separated, gene groups whose expression is commonly enhanced in each were analyzed using gene expression data in highly sensitive cell lines (e.g., U251, SF-539, SNB-75, NCI-H522, DMS114) and highly resistant cell lines (e.g., SNB-78, NCI-H23). As a result, the gene group shown in SEQ ID NO: 29 to 33 was identified as an FTSJ1 inhibitor resistance-related gene marker, and the gene group shown in SEQ ID NO: 48 to 56 was identified as an FTSJ1 inhibitor sensitivity-related gene marker. Using these gene markers, a database of gene expression information (TCGA) obtained from patient samples was analyzed, and it was found that patients with high FTSJ1 gene expression levels had high expression of FTSJ1 inhibitor sensitivity-related gene markers, and conversely, patients with low FTSJ1 gene expression levels had high expression of FTSJ1 inhibitor resistance-related gene markers. In other words, it was found that the FTSJ1 gene expression level itself is a gene that determines sensitivity and resistance to FTSJ1 inhibitors (SEQ ID NO: 57).

[0278] To verify whether expression analysis of these gene groups contributes to predicting the anticancer effect of FTSJ1 inhibitors, we actually used the FTSJ1 gene as an example to analyze the anticancer effect of the FTSJ1 inhibitor PVZF2001 on human malignant brain tumor cell lines. Human malignant brain tumor cell lines MGG4, MGG8, MGG18, and MGG23 were treated with stem cell medium (Neurobasal, B-27, N-2, 20 ng / mL EGF, 20 ng / mL bFGF) containing different concentrations (0 nM, 200 nM, 500 nM, 1000 nM, 2000 nM, 5000 nM) of PVZF2001 for one week, and anchorage-independent cell proliferation was evaluated by sphere formation ability. As shown in Figure 4B, MGG4, MGG8, and MGG18, which have high FTSJ1 expression levels, showed growth inhibition at low concentrations of PVZF2001, whereas MGG23, which has low FTSJ1 expression levels, showed cell proliferation even at a high concentration of 2000 nM.

[0279] (Production Example 1) (E)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(2-hydroxyphenyl)prop-2-en-1-one (PVZF0024) 178 mg of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one and 122 mg of 2-hydroxybenzaldehyde were dissolved in 20 ml of ethanol. 0.5 mL of 40% sodium hydroxide solution was added and stirred at 60 degrees for 10 hours. After neutralization with acetic acid, it was extracted with chloroform and purified by silica gel chromatography to obtain (E)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(2-hydroxyphenyl)prop-2-en-1-one. 141 mg of the above compound was dissolved in 10 mL of ethanol, 121 μL of hydrazine monohydrate was added, and the mixture was stirred at 80 degrees for 5 hours. Ethanol was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain 31 mg of the target compound in a 31% yield. ESI (m / z): 297 (M+H) + 1H-NMR (400 MHz, DMSO-d6) δ 9.66 (d, J = 25.4 Hz, 1H), 7.25-7.27 (m, 1H), 7.05-7.12 (m, 3H), 6.74-6.86 (m, 3H), 4.95 (td, J = 10.5, 2.8 Hz, 1H), 4.25 (s, 4H), 3.32-3.38 (m, 1H), 2.66 (dd, J = 16.3, 10.5 Hz, 1H)

[0280] (Production Example 2) 2,4,6-Triisopropyl-N-(piperidin-4-yl)benzenesulfonamide (PVZF2005) 151 mg of 2,4,6-triisopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 50 mg of piperidin-4-amine and 120 μL of pyridine were added on an ice bath and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 158 mg of the target compound in 86% yield. ESI (m / z): 367 (M+H) + 1 H-NMR (400 MHz, DMSO-d6) δ 7.29-7.48 (s, 2H), 4.05 (td, J = 13.4, 6.7 Hz, 3 H), 3.43 (m, 8H), 1.91-1.95 (m, 1H), 1.44 (td, J = 11.8, 3.1 Hz, 1H), 1.05-1.38 (m, 18H)

[0281] (Production Example 3) 2,4,6-Triisopropyl-N-(piperidin-3-ylmethyl)benzenesulfonamide)PVZF2008) 151 mg of 2,4,6-triisopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 57 mg of piperidin-3-ylmethanamine and 120 μL of pyridine were added on an ice bath and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 129 mg of the target compound in 68% yield. ESI (m / z): 381 (M+H) + 1 H-NMR (400 MHz, DMSO-d6) δ 7.22-7.28 (m, 2H), 4.08 (td, J = 13.3, 6.7 Hz, 2H), 3.57-3.64 (m, 1H), 2.90-2.97 (m, 1H), 2.62-2.74 (m, 3H), 1.70-1.91 (m, 3H), 1.09-1.29 (m, 22H)

[0282] (Production Example 4) N-(2-(cyclohex-1-en-1-yl)ethyl)-[1,1'-biphenyl]-4-sulfonamide (PVZF2035) 126 mg of [1,1'-biphenyl]-4-sulfonyl chloride was dissolved in 10 mL of dichloromethane, and 62.5 mg of 2-(cyclohex-1-en-1-yl)ethan-1-amine and 120 μL of pyridine were added on an ice bath and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 123 mg of the target compound in 72% yield. ESI (m / z): 342 (M+H) + 1H-NMR (400 MHz, DMSO-d6) δ 7.85-7.90 (m, 4H), 7.74-7.76 (m, 2H), 7.64 (d, J = 23.2 Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H), 7.42-7.46 (m, 1H), 5.33 (s, 1H), 2.83 (t, J = 7.4 Hz, 2H), 2.01 (t, J = 7.2 Hz, 2H), 1.89 (s, 2H), 1.80 (s, 2H), 1.43-1.56 (m, 4H)

[0283] (Production Example 5) N-(2,2,6,6-tetramethylpiperidin-4-yl)-[1,1'-biphenyl]-4-sulfonamide (PVZF0036) 126 mg of [1,1'-biphenyl]-4-sulfonyl chloride was dissolved in 10 mL of dichloromethane, and 78 mg of 2,2,6,6-tetramethylpiperidin-4-amine and 120 μL of pyridine were added on an ice bath and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 153 mg of the target compound in 82% yield. ESI (m / z): 373 (M+H) + 1 H-NMR (400 MHz, DMSO-d6) δ 7.88-7.92 (m, 4H), 7.75 (t, J = 8.4 Hz, 2H), 7.49-7.55 (m, 2H), 7.42-7.47 (m, 1H), 3.46-3.57 (m, 1H), 1.54-1.61 (m, 2H), 1.39 (m, 2H), 1.13-1.37 (m, 12H)

[0284] (Production Example 6) N-Cyclohexyl-4-(tert-pentyl)benzenesulfonamide (PVZF0039) 123 mg of 4-(tert-pentyl)benzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 50 mg of cyclohexaneamine and 120 μL of pyridine were added on an ice bath and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 105 mg of the target compound in 68% yield. ESI (m / z): 310 (M+H) + 1 H-NMR (400 MHz, DMSO-d6) δ 7.72-7.81 (m, 2H), 7.56 (s, 1H), 7.53 (d, J = 8.0 Hz, 2H), 2.91 (s, 1H), 1.63 (q, J = 7.4 Hz, 2H), 1.55(d,J = 4.6Hz, 2H), 1.41-1.44 (m, 1H), 1.27 (s, 6H), 1.05-1.15 (m, 4H), 1.01 (d, J = 11.0 Hz, 2H), 0.58 (t, J = 7.3 Hz, 3H)

[0285] (Production Example 7) 4-Cyclohexyl-N-pentylbenzenesulfonamide (PVZF2065) 129 mg of 4-cyclohexylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 44 mg of pentan-1-amine and 120 μL of pyridine were added on an ice bath and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 121 mg of the target compound in 78% yield. ESI (m / z): 310 (M+H) + 1H-NMR (400 MHz, DMSO-d6) δ 7.67-7.70 (m, 2H), 7.47 (s, 1H), 7.43 (d, J = 8.0 Hz, 2H), 2.57-2.72 (m, 3H), 1.79 (d, J = 10.7 Hz, 4H), 1.71 (d, J = 12.7 Hz, 1H), 1.25-1.56 (m, 7H), 1.12-1.23 (m, 4H), 0.79 (dd, J = 7.0, 6.0 Hz, 3H)

[0286] (Production Example 8) N,4-Dicyclohexylbenzenesulfonamide (PVZF2066) 129 mg of 4-cyclohexylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 50 mg of cyclohexaneamine and 120 μL of pyridine were added on an ice bath and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 135 mg of the target compound in 84% yield. ESI (m / z): 322 (M+H) + 1 H-NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 8.3 Hz, 2H), 7.56 (s, 1H), 7.42 (d, J = 8.3 Hz, 2H), 2.91 (s, 1H), 2.56-2.67 (m, 1H), 1.78-1.85 (m, 4H), 1.71 (d, J = 12.4 Hz, 1H), 1.56 (d, J = 6.6 Hz, 4H), 1.32-1.43 (m, 5H), 1.25 (t, J = 12.2 Hz, 1H), 1.00-1.16 (m, 5H)

[0287] (Production Example 9) 4-Cyclohexyl-N-(cyclohexylmethyl)benzenesulfonamide (PVZF2069) 129 mg of 4-cyclohexylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 58 mg of cyclohexylmethanamine and 120 μL of pyridine were added on an ice bath and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 131 mg of the target compound in 78% yield. ESI (m / z): 336 (M+H) + 1 H-NMR (400 MHz, DMSO-d6) δ 7.68 (d, J = 8.3 Hz, 2H), 7.49 (s, 1H), 7.43 (d, J = 8.3 Hz, 2H), 2.53-2.67 (m, 6H), 1.77-1.84 (m, 3H), 1.71 (d, J = 12.4 Hz, 2H), 1.61 (d, J = 11.2 Hz, 3H), 1.35-1.46 (m, 2H), 1.22-1.32 (m, 1H), 1.07-1.15 (m, 3H), 0.74-0.82 (m, 2H)

[0288] (Production Example 10) 4-Bromo-2-isopropyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)benzenesulfonamide (PVZF2074) 148 mg of 4-bromo-2-isopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 78 mg of 2,2,6,6-tetramethylpiperidin-4-amine and 120 μL of pyridine were added on an ice bath and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 175 mg of the target compound in 85% yield. ESI (m / z): 417 (M+H) + 1H-NMR (400 MHz, DMSO-d6) δ 8.14 (bs, 1H), 7.78 (d, J = 8.5 Hz, 2H), 7.57-7.60 (m, 1H), 3.75-3.82 (m, 1H), 1.60 (s, 2H), 1.13-1.39 (m, 22H)

[0289] (Production Example 11) 2-(tert-butyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)benzenesulfonamide (PVZF2075) 116 mg of 2-(tert-butyl)benzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 78 mg of 2,2,6,6-tetramethylpiperidin-4-amine and 120 μL of pyridine were added on an ice bath and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 141 mg of the target compound PVZF2075 in 80% yield. ESI (m / z): 353 (M+H)+ 1 H-NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.53-7.56 (m, 1H), 7.43 (t, J = 7.7 Hz, 1H), 1.68-1.75 (m, 2H), 1.52 (s, 9H), 1.15-1.29 (m, 16H)

[0290] (Production Example 12) 2-Isopropyl-4-methoxy-5-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)benzenesulfonamide (PVZF2076) 131 mg of 2-isopropyl-4-methoxy-5-methylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 78 mg of 2,2,6,6-tetramethylpiperidin-4-amine and 120 μL of pyridine were added on an ice bath and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 145 mg of the target compound in 76% yield. ESI (m / z): 383 (M+H)+ 1 H-NMR (400 MHz, DMSO-d6) δ 7.77 (bs, 1H), 7.64 (s, 1), 7.03 (s, 1H), 3.88 (s, 3H), 3.76-3.83 (m, 1H), 2.20-2.08 (3H), 1.59 (d, J = 12.4Hz, 2H), 1.13-1.33 (m, 22H)

[0291] (Production Example 13) 2,5-Diisopropyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)benzenesulfonamide (PVZF2077) 130 mg of 2,5-diisopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 78 mg of 2,2,6,6-tetramethylpiperidin-4-amine and 120 μL of pyridine were added on an ice bath and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 164 mg of the target compound in 86% yield. ESI (m / z): 381 (M+H)+ 1 H-NMR (400 MHz, DMSO-d6) δ 7.93 (bs, 1H), 7.71-7.79 (m, 1H), 7.44-7.54 (m, 2H), 3.76-3.83 (m, 1H), 3.54 (d, J = 25.6 Hz, 1H), 3.05-2.86 (1H), 1.54 (d, J = 11.5 Hz, 2H), 1.03-1.39 (m, 26H)

[0292] (Production Example 14) 2-Cyclopropyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)benzenesulfonamide (PVZF2078) 108 mg of 2-cyclopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 78 mg of 2,2,6,6-tetramethylpiperidin-4-amine and 120 μL of pyridine were added on an ice bath and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 133 mg of the target compound in 79% yield. ESI (m / z): 337 (M+H)+ 1 H-NMR (400 MHz, DMSO-d6) δ 8.02-7.91 (1H), 7.89 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 3.51 (s, 2H), 2.64-2.70 (m, 1H), 1.60 (d, J = 10.0 Hz, 2H), 1.03-1.35 (m, 16H), 0.80-0.84 (m, 2H)

[0293] (Production Example 15) 5-Chloro-2-cyclopropyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)benzenesulfonamide (PVZF2079) 125 mg of 5-chloro-2-cyclopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 78 mg of 2,2,6,6-tetramethylpiperidin-4-amine and 120 μL of pyridine were added on an ice bath and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 152 mg of the target compound in 82% yield. ESI (m / z): 371 (M+H)+ 1H-NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 28.8 Hz, 1H), 7.86 (d, J = 1.2 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 2.60-2.68 (m, 1H), 1.72-1.47 (2H), 1.44-1.04 (18H), 0.91-0.74 (bs, 2H)

[0294] (Production Example 16) N-Benzhydryl-2,4,6-triisopropylbenzenesulfonamide (PVZF2082) 151 mg of 2,4,6-triisopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 92 mg of diphenylmethanamine and 120 μL of pyridine were added on an ice bath and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 101 mg of the target compound in 45% yield. ESI (m / z): 450 (M+H)+ 1 H-NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 9.3 Hz, 1H), 7.15-7.35 (m, 10H), 7.05-7.11 (m, 2H), 5.46 (d, J = 9.3 Hz, 1H), 4.07-4.13 (m, 2H), 2.84-2.92 (m, 1H), 1.14-1.24 (m, 6H), 1.05 (m, 12H)

[0295] (Production Example 17) 2,4,6-Triisopropyl-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)benzenesulfonamide (PVZF2085) 151 mg of 2,4,6-triisopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 85 mg of 1,2,2,6,6-pentamethylpiperidin-4-amine and 120 μL of pyridine were added on an ice bath and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 118 mg of the target compound in a yield of 54%. ESI (m / z): 437 (M+H) + 1 H-NMR (400 MHz, DMSO-d6) δ 7.23 (s, 2H), 3.94-4.08 (m, 3H), 2.89-2.96 (m, 1H), 2.60-2.62 (m, 3H), 1.29-1.41 (m, 5H), 1.20 (d, J = 6.8Hz, 18H), 0.96-1.06 (m, 12H)

[0296] (Example 18) 2,4,6-Triisopropyl-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)benzenesulfonamide (PVZF2086) 151 mg of 2,4,6-triisopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 85 mg of N,2,2,6,6-pentamethylpiperidin-4-amine and 120 μL of pyridine were added on an ice bath and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 50 mg of the target compound in a yield of 23%. ESI (m / z): 437 (M+H)+ 1 H-NMR (400 MHz, DMSO-d6) δ 7.27 (s, 2H), 4.02 (td, J = 13.4, 6.7 Hz, 3H), 2.93 (td, J = 13.6, 6.7 Hz, 1H), 2.64 (s, 3H), 1.49-1.63 (m, 3H)1.04-1.37 (m, 32H)

[0297] (Production Example 19) N-(2,6-Dimethylpiperidin-4-yl)-2,4,6-triisopropylbenzenesulfonamide (PVZF2132) 151 mg of 2,4,6-triisopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, 64 mg of 2,6-dimethylpiperidin-4-amine and 120 μL of pyridine were added and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 158 mg of the target compound in 80% yield. ESI (m / z): 395 (M+H) + 1 H-NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.25 (s, 2H), 4.13 (td, J = 13.3, 6.6 Hz, 2H), 3.30-3.21 (m, 2H)3.09-2.86 (m, 2H), 1.76-1.63 (bs, 1H), 1.36-1.09 (m, 28H)

[0298] (Example 20) 1-Ethyl-3-(trifluoromethyl)-N-(2-((2,4,6-triisopropylphenyl)sulfonamido)ethyl)-1H-pyrazole-5-carboxamide (PVZF2133) 151 mg of 2,4,6-triisopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, 64 mg of N-(2-aminoethyl)-1-ethyl-3-trifluoromethyl)-H-pyrazole-5-carboxamide and 120 μL of pyridine were added and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 139 mg of the target compound in 54% yield. ESI (m / z): 517 (M+H) + 1H-NMR (400 MHz, DMSO-d6) δ 8.40 (t, J = 5.9 Hz, 1H), 7.61 (s, 1H), 7.22 (s, 2H), 7.18 (s, 1H), 4.30 (q, J = 7.2 Hz, 2H), 4.16-4.06 (m, 2H), 3.45-3.26 (m, 2H), 2.95-2.85 (m, 3H), 1.43-1.32 (m, 3H), 1.27-1.01 (m, 18H)

[0299] (Production Example 21) 2,4,6-Triisopropyl-N-(1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)benzenesulfonamide (PVZF2134) 151 mg of 2,4,6-triisopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 123 mg of 1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-amine and 120 μL of pyridine were added and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 174 mg of the target compound in 68% yield. ESI (m / z): 512 (M+H) + 1 H-NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.75 (dd, J = 9.1, 2.3 Hz, 1H), 7.65 (d, J = 7.3 Hz, 1H), 7.25 (d, J = 12.4 Hz, 2H), 6.93 (d, J = 9.0 Hz, 1H), 4.33-4.12 (m, 4H), 3.01-2.87 (m, 3H), 1.69 (d, J = 10.5 Hz, 2H), 1.39-1.30 (m, 3H), 1.22-1.03 (m, 18H)

[0300] (Manufacturing Example 22) 2,4,6-Triisopropyl-N-(3-(3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)propyl)benzenesulfonamide (PVZF2135) 151 mg of 2,4,6-triisopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, 117 mg of 3-(3-(trifluoromethyl)-5,6-dihydrocyclopentane[c]pyrazol-1(4H)-yl)propan-1-amine and 120 μL of pyridine were added and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 155 mg of the target compound in a yield of 62%. ESI (m / z): 500 (M+H) + 1 H-NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1H), 7.22 (s, 2H), 4.12-3.99 (m, 4H), 2.95-2.85 (m, 1H), 2.76 (t, J = 6.2 Hz, 2H), 2.63-2.56 (m, 4H), 2.51-2.42 (m, 2H), 1.93-1.86 (m, 2H), 1.30-1.05 (m,18H)

[0301] (Production Example 23) 2,4,6-Triisopropyl-N'-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)benzenesulfonohydrazide (PVZF2136) 151 mg of 2,4,6-triisopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, 128 mg of 4-hydrazinyl-1-(3-(trifluoromethyl)benzyl)-1H-pyrazole and 120 μL of pyridine were added and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 91 mg of the target compound in a yield of 35%. ESI (m / z): 523 (M+H) + 1H-NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.72-7.46 (m, 5H), 7.15 (s, 2H), 7.09 (s, 1H), 5.31 (s, 2H), 3.94 (t, J = 6.5 Hz, 2H), 2.93-2.82 (m, 1H), 1.23-0.87 (m, 18H)

[0302] (Example 24) N-(6-(2,3-difluorophenoxy)pyridin-3-yl)-2,4,6-triisopropylbenzenesulfonamide (PVZF2137) 151 mg of 2,4,6-triisopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, 244 mg of 6-(2,3-difluorophenoxy)pyridin-3-amine and 120 μL of pyridine were added and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 142 mg of the target compound in a yield of 58%. ESI (m / z): 489 (M+H) + 1 H-NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.54-7.52 (m, 1H), 7.36-7.08 (m, 6H), 3.95 (s, 2H), 2.88 (td, J = 13.7, 6.8 Hz, 1H), 1.25-0.85 (m, 18H)

[0303] (Example 25) 2,4,6-Triisopropyl-N-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methyl)benzenesulfonamide (PVZF2138) 151 mg of 2,4,6-triisopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 123 mg of (1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methanamine and 120 μL of pyridine were added and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 200 mg of the target compound in a 78% yield. ESI (m / z): 513 (M+H) + 1 H-NMR (400 MHz, DMSO-d6) δ 7.65 (s, 1H), 7.24 (s, 1H), 7.23(s, 1H), 4.17-4.07 (m, 2H), 3.74 (d, J = 12.9 Hz, 2H), 3.10 (t, J = 12.4 Hz, 2H), 2.96-2.86 (m, 1H), 2.73-2.67 (m, 2H), 1.77-1.74 (m, 2H), 1.70-1.62 (m, 1H), 1.37-1.18 (m, 18H), 1.15-1.02 (m, 2H)

[0304] (Example 26) 2,4,6-Triisopropyl-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzenesulfonamide (PVZF2139) 151 mg of 2,4,6-triisopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 114 mg of 1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine and 120 μL of pyridine were added and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 69 mg of the target compound in a yield of 28%. ESI (m / z): 494 (M+H) + 1 H-NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.49 (s, 1H), 7.95-7.92 (m, 2H), 7.66 (t, J = 7.9 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.20 (s, 2H), 6.09 (d, J = 2.2 Hz, 1H), 4.27 (s, 2H), 2.93-2.83 (m, 1H), 1.16 (dd, J = 6.7, 2.3 Hz, 18H)

[0305] (Example 27) (E)-N'-Hydroxy-3-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)-N-((2,4,6-triisopropylphenyl)sulfonyl)propanimidamide (PVZF2140) 151 mg of 2,4,6-triisopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 118 mg of (E)-2-amino-4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)but-1-en-1-ol and 120 μL of pyridine were added and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 53 mg of the target compound in a yield of 21%. ESI (m / z): 503 (M+H) + 1 H-NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.23 (s, 2H), 6.82 (s, 2H), 6.55 (s, 1H), 4.15-4.06 (m, 4H), 3.57 (d, J = 1.2 Hz, 1H), 2.97-2.87 (m, 1H), 2.11 (s, 3H), 1.21-1.15 (m, 18H)

[0306] (Example 28) N-(3-(3-cyclopropyl-4,5-dihydroxy-2-oxo-2,3-dihydro-1H-imidazol-1-yl)phenyl)-2,4,6-triisopropylbenzenesulfonamide (PVZF2141) 151 mg of 2,4,6-triisopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, 137 mg of 1-(3-aminophenyl)-3-cyclopropyl-4,5-dihydroxy-1,3-dihydro-2H-imidazol-2-one and 120 μL of pyridine were added and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 108 mg of the target compound in a yield of 42%. ESI (m / z): 514 (M+H) + 1H-NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 7.49 (s, 1H), 7.28-7.07 (m, 5H), 6.79 (d, J = 8.0 Hz, 1H), 5.44 (d, J = 9.8 Hz, 1H), 4.20 (s, 2H), 3.57 (d, J = 1.2 Hz, 1H), 2.89 (td, J = 13.6, 6.6 Hz, 1H), 1.18-1.13 (m, 18H), 0.90-0.79 (m, 4H)

[0307] (Example 29) 2,4,6-Triisopropyl-N-(((2,2,6,6-tetramethylpiperidin-4-yl)methyl)benzenesulfonamide (PVZF2142) 151 mg of 2,4,6-triisopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 135 mg of (2,2,6,6-tetramethylpiperidin-4-yl)methanamine and 120 μL of pyridine were added and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 194 mg of the target compound in 89% yield. ESI (m / z): 437 (M+H) + 1 H-NMR (400 MHz, DMSO-d6) 1H-NMR (400 MHz, DMSO) δ 7.80-7.67 (m, 1H), 7.37-7.18 (m, 2H), 6.95 (s, 1H), 4.17-4.07 (m, 2H), 2.96-2.86 (m, 1H), 2.75 (t, J = 6.2 Hz, 2H), 1.91-1.86 (m, 1H), 1.61-1.43 (m, 2H), 1.26-1.15 (m, 32H)

[0308] (Example 29) 2,4,6-Triisopropyl-N-(1,2,3,4-tetrahydroquinolin-4-yl)benzenesulfonamide (PVZF2143) 151 mg of 2,4,6-triisopropylbenzenesulfonyl chloride was dissolved in 10 mL of dichloromethane, and 124 mg of 1,2,3,4-tetrahydroquinolin-4-amine and 120 μL of pyridine were added and stirred at room temperature for 4 hours. Methanol was added to terminate the reaction, and dichloromethane was distilled off under reduced pressure. The resulting residue was purified by silica chromatography to obtain 155 mg of the target compound in 75% yield. ESI (m / z): 415 (M+H) + 1 H-NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 8.8 Hz, 1H), 7.24 (s, 2H), 6.94-6.86 (m, 1H), 6.70 (d, J = 7.6 Hz, 1H), 6.47-6.32 (m, 2H), 5.84 (s, 1H), 4.34-4.30 (m, 1H), 4.22-4.10 (m, 2H), 3.22-3.17 (m, 1H), 3.06 (d, J = 12.0 Hz, 1H), 2.97-2.90 (m, 1H), 1.80-1.65 (m, 2H), 1.32-1.16 (m, 18H)

Claims

1. An RNA methyltransferase inhibitor comprising a sulfonamide compound represented by the following general formula (1): 【Chemistry 1】 [In formula (1), R 1 represents any one of the following groups (1-1) to (1-5). (1-1) a nitrogen-containing heterocyclic group which may have a substituent, (1-2) a cycloalkyl group which may have a substituent, (1-3) an alkyl group which may have a substituent; (1-4) a pyrazolylamino group, (1-5) phenyl group; R 2 represents (2-1) a hydrogen atom or (2-2) an alkyl group. R 3 represents the following group (3-1) or (3-2). (3-1) a phenyl group, (3-2) naphthyl group; The group represented by (3-1) further has 1 to 3 alkyl groups having 1 to 3 carbon atoms as substituents. Or, R 1 and R 2 may be bonded to the nitrogen atom to which they are bonded to form a ring.

2. The RNA methyltransferase inhibitor according to claim 1, wherein the substituent on the nitrogen-containing heterocyclic group represented by (1-1) is at least one selected from the group consisting of an alkyl group, a hydroxyl group, a cyclopropyl group, a phenylthiopropylcarbonyl group, a phenylsulfonyl group, an alkylsulfonyl group, a thienylsulfonyl group, an alkylcarbonyl group, an alkoxycarbonyl group, a phenylsulfonylamino group, an aminocarbonylalkyl group, a pyrazolylcarbonyl group, a cyclopropylcarbonyl group, a piperidylsulfonyl group, and a morpholinosulfonyl group.

3. The RNA methyltransferase inhibitor according to claim 1, wherein the substituent on the cycloalkyl group represented by (1-2) and the substituent on the alkyl group represented by (1-3) are at least one selected from the group consisting of a phenyl group, a biphenyl group, a cycloalkyl group, a cycloalkenyl group, a nitrogen-containing heterocyclic group, and a hydroxyl group.

4. The RNA methyltransferase inhibitor according to any one of claims 1 to 3, which is used in the treatment of cancer.

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