Ras / raf binding inhibitor compound

Abstract

The present invention addresses the problem of providing a Ras / Raf binding inhibitor compound that has the effect of inhibiting Ras / Raf signaling in drug-resistant cancer cells and in a wide range of Ras mutant cancers. A Ras / Raf binding inhibitor compound according to the present invention is represented by Formula (I) (A, B, X, and R1 to R4 are as defined in the specification).

Description

Ras / Raf binding inhibitor compound

[0001] The present invention relates to novel and excellent small molecule compounds that specifically inhibit Ras / Raf binding, pharmaceutical compositions containing the compounds, and methods for producing the pharmaceutical compositions using the compounds. Activation of the Ras / Raf / MEK / ERK signaling system (Ras / MAPK pathway) has been reported in many cancers, including leukemia (ALL, APL, AML), small cell lung cancer, colon cancer, pancreatic cancer, and melanoma. Therefore, the present compounds and pharmaceutical compositions also provide novel and excellent therapeutic methods for these cancers.

[0002] Ras, a small G protein consisting of three isoforms, H-Ras, K-Ras, and N-Ras, is one of the most frequently mutated oncogenes found in approximately 25% of human cancers and plays a major role in the development and progression of cancer (Non-Patent Documents 1 and 2). The oncogenic potential of Ras is activated by point mutations mainly involving codons 12, 13, and 61. These point mutations impair the inherent GTP hydrolysis activity of Ras, rendering it insensitive to the action of GAP (GTP hydrolysis accelerating factor), resulting in the abundant presence of Ras-GTP in cells. This abundant Ras-GTP induces conformational changes in and activates three major target proteins, namely, Raf kinases such as c-Raf-1 and B-Raf, PI3K, and RalGDS (Ral guanine nucleotide exchange factor) family proteins, through interactions with these proteins, leading to tumorigenesis in cells and tissues (Non-patent Documents 3, 4, and 5).

[0003] For several decades, vigorous research and development has been conducted on direct molecular targets of mutant Ras, which are frequently observed clinically. However, there have been no successful examples of the development of effective molecular-targeted cancer therapeutic drugs that can comprehensively suppress the activity of Ras with various mutations, particularly mutant Ras-GTP, which is significant in cancer (Non-Patent Documents 2, 6, and 7).

[0004] On the other hand, Shokat et al. partially overcame this obstacle by identifying an electrophilic compound that covalently binds to cysteine ​​12 of mutant K-RasG12C-GDP (inactive form) and prevents the generation of the GTP-bound active form mediated by the nucleotide exchange factor Sos located upstream of Ras (Non-Patent Document 8).

[0005] K-Ras G12C-GDP-specific inhibitors with improved physicochemical properties, such as AMG510 and MRTX849, are currently undergoing clinical trials as monotherapy or in combination with immune checkpoint inhibitors or other small molecule inhibitors (Non-Patent Documents 6 and 7), and some have even been launched on the market (https: / / www.fda.gov / news-events / pr ess-announcements / fda-approves-first-targeted-therapy-lung-cancer-mutation-previousl y-considered-resistant-drug) (https: / / www.nature.com / articles / d41573-021-00098-4; doi: https: / / doi.org / 10.1038 / d41573-021-00098-4).

[0006] Although K-Ras G12C-GDP-specific inhibitors have shown promising early signs in clinical trials of patients with advanced K-Ras G12C-mutated lung cancer, with clear responses observed in approximately half of the patients (https: / / investors.amgen.com / news-releases / news-release-details / amgen-announcements-new-clinical-data-evaluating-novel-0; https: / / ir.mirati.com / press-releases / press-release-details / 2021 / Mirati-Therapeutics-Reports-First-Quarter-2021-Financial-Results-and-Recent-Corporate-Updates / default.aspx), and as Aaron and Shaw noted, "drug resistance exists to these inhibitors."

[0007] Furthermore, it should be noted that even the most recent research and development efforts have not been able to comprehensively overcome clinically frequent Ras mutations such as G12D, G12V, and G13D. Taking these findings together, it is clear that there is an urgent need to develop broad-spectrum Ras inhibitors or effective strategies for more comprehensively inhibiting Ras signaling (Non-Patent Documents 9 to 11).

[0008] Simanshu DK, Nissley DV. McCormick F. RAS proteins and their regulators in human disease. Cell 2017 170:17-33Stephen AG, Esposito D, Bagni RK, McCormick F. Dragging ras back in the ring. Cancer cell. 2014 Mar 17;25(3):272-81Vetter IR, Wittinghofer A. The guanine nucleotide-binding switch in three dimensions. Science 2001 294:1299-1304Weinstein B. Addiction to oncogenes-the Achilles heel of cancer. Science 2002 297:63-64Knrnoub AE, Weinberg RA. Ras oncogenes: split personalities. Nat Rev Mol Cell Biol 2008 9:517-531Mullard A. Cracking KRas. Nat.Rev.Drug Discov. 2019 Dec:887-891Sheridan C. Grail of RAS cancer drugs within reach. Nature Biotech. 2020 38:6-8Ostrem JM, Peters U, Sos ML, Wells JA and Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 2013 503:548-551Merchant M, Moffat J, Schaefer G, Chan J, Wang X, Orr C, et al. Combined MEK and ERK inhibition overcomes therapy-mediated pathway reactivation in RAS mutant tumors. PLoS One 2017;12:e0185862 Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic-Huezo O, Serra V, et al. AKT inhibition receives feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 2011;19:58-71 Misale S, Fatherree JP, Cortez E, Li C, Bilton SJ, Timonina D, et al. KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition. Clin Cancer Res 2019;25:769-807;

[0009] As described above, there are Raf inhibitors that have already been clinically applied to cancers in which activation of the Ras / MAPK pathway is observed, and there are drugs under clinical development or approved that are effective against carcinomas with the RasG12C mutation, but these have problems such as the induction of drug resistance and their effectiveness being observed only in a small number of cancer types. An object of the present invention is to provide a compound that inhibits Ras / Raf binding, which exhibits an inhibitory effect on Ras / Raf signaling even against drug-resistant cancer cells and a wide range of Ras-mutated cancers.

[0010] The present inventors have conducted extensive research over many years into the synthesis and pharmacological activity of derivatives that specifically inhibit Ras / Raf signaling, and as a result have found that the compound represented by the following formula (I) has excellent inhibitory activity against Ras / Raf signaling, thereby completing the present invention.

[0011] (1) An embodiment of the present invention provides a compound represented by formula (I) or a pharmacologically acceptable salt thereof, or an isomer thereof. [wherein A represents a benzene ring or a pyridine ring, B represents C ６－１０an aryl group or a heteroaryl group containing 1 to 4 atoms selected from N, S and O, ５ - indicates R １ is H,NHCOCH ３ C optionally substituted with a group １－６ represents an alkyl group or a halogen; R ２ , R ３ and R ４ are the same or different (but at least one of them is not H), and: ● H; ● C １－６ Alkyl-SO ２ - (for example, mesyl); ● cyano; ● halogen; ● nitro; ● azide; ● -CO-R １１ group (in the formula, R １１ is, ・OH, ・R １２ Group (R １２ The group may have a substituent, such as N, S, SO, or SO ２ and O), NH ２ , N.H.R. １２ , or N(R １２ ) R １２ , or ・C ６－１０ arylamino, -O-CH ２ -CO-R １１ group; optionally substituted C １－６ Alkyl group (substituent is -CONH ２ , ・R １２ Group, ・OH, ・-NR １３ R １４ (R １３ is C １－６ Alkyl-SO ２ - (e.g., mesyl), C １－６ alkyl-CO- (preferably acetyl), or R １２ represents a group, and R １４ is H, C １－６ alkyl group, or R １２ represents a group), R １２ -CO-, or ・R １２ -C １－６ alkyl -CONH-); -OR １５Group (wherein, R １５ is H, optionally substituted C １－６ Alkyl group (substituents include OH, C １－６ Alkoxy, C ６－１０ Aryl, C ６－１０ Aryloxy, R １２ , Cyano, C １－６ Alkyl-SO ２ - (for example, mesyl, etc.) or methylsulfinyl), C １－６ Alkyl-SO ２ - (e.g., mesyl), or a heteroaryl group containing 1 to 4 atoms selected from N, S, and O; -NR １６ R １７ Group (wherein, R １６ and R １７ are the same or different, and are H, C １－６ alkyl-CO-, .R １２ group, or R １２ -C １－６ represents alkyl-CO- or R １６ and R １７ together with N, １２ a C group which may have a substituent; ６－１０ Aryl group (substituents are C ６－１０ aryloxy, an optionally substituted heteroaryl group containing 1 to 4 atoms selected from N, S and O, or R １２ a phenyl group optionally fused to a ring; an optionally substituted heteroaryl group containing 1 to 4 atoms selected from N, S, and O; or -(CH=CH)-R １８ (In the formula, R １８ is -CO-R １９ , or -SO ２ -R １９ indicates, R １９ is NH ２ , or R １２ represents a group); ５ is C １－６ Alkyl, -COR ６ , -COOR ６ , -CONR ６ R７ , -SO ｎ R ６ , or SO ｎ NR ６ R ７ n represents 0, 1 or 2; R ６ and R ７ are the same or different and are H, C １－６ alkyl group, or C ６－１０ The symbol ● and ・ may be placed at the beginning of each option within the same group when listing multiple options.

[0012] (2) A preferred embodiment of the present invention is a compound represented by formula (I) described in (1) above, or a pharmacologically acceptable salt thereof, or an isomer thereof, in which A represents a benzene ring.

[0013] (3) A preferred embodiment of the present invention is a compound represented by formula (I) described in (1) or (2) above, or a pharmacologically acceptable salt thereof, or an isomer thereof, in which B represents a heteroaryl group containing 1 to 4 atoms selected from N, S, and O.

[0014] (4) A further preferred embodiment of the present invention is a compound represented by formula (I) described in (1) or (2) above, or a pharmacologically acceptable salt thereof, or an isomer thereof, in which B represents pyridyl, quinolyl, indolyl, thiazolyl, pyrrolopyridinyl, benzothiazolyl, or furopyridinyl.

[0015] (5) A further preferred embodiment of the present invention is a compound represented by formula (I) described in (1) or (2) above, or a pharmacologically acceptable salt thereof, or an isomer thereof, wherein B is: However, one of the bonds corresponds to the wavy bond in formula (I), and the other bond corresponds to R ２ , R ３ and R ４ In this case, if there is another substituent, that substituent is substituted at the remaining position.

[0016] (6) A further preferred embodiment of the present invention is a compound represented by formula (I) described in (1) or (2) above, or a pharmacologically acceptable salt thereof, or an isomer thereof, in which B is quinolyl, thiazolyl, or benzothiazolyl.

[0017] (7) In one preferred embodiment of the present invention, R １ represents H, or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0018] (8) In one preferred embodiment of the present invention, R ２ , R ３ and R ４ -CO-R in １１ R in the group １１ is OH, or R １２ The compound is a compound represented by formula (I) described in any one of (1) to (7) above, or a pharmacologically acceptable salt thereof, or an isomer thereof, wherein R represents a group.

[0019] (9) In one preferred embodiment of the present invention, R ２ , R ３ and R ４ In the formula, —O—CH ２ -CO-R １１ R in the group １１ But, R １２ The compound is a compound represented by formula (I) described in any one of (1) to (7) above, or a pharmacologically acceptable salt thereof, or an isomer thereof, wherein R represents a group.

[0020] (10) A preferred embodiment of the present invention is ２ , R ３ and R ４ C which may have a substituent １－６ The substituent of the alkyl group is R １２ group, OH, -NR １３ R １４ (R １３ But C １－６ Alkyl-SO ２ - (e.g., mesyl), or R １２ group, and R１４ is H or C １－６ represents an alkyl group), R １２ -CO- or R １２ -C １－６ The compound is a compound represented by formula (I) according to any one of the above (1) to (7), or a pharmacologically acceptable salt thereof, or an isomer thereof, wherein the compound represents alkyl-CONH-.

[0021] (11) In a further preferred embodiment of the present invention, R ２ , R ３ and R ４ C which may have a substituent １－６ The alkyl group substituent is —NR １３ R １４ (R １３ But C １－６ Alkyl-SO ２ - (for example, mesyl), and R １４ represents H), or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0022] (12) In one preferred embodiment of the present invention, R ２ , R ３ and R ４ In the -OR １５ R in the group １５ But C １－６ an alkyl group (preferably methyl), or C １－６ Alkyl-SO ２ - (for example, mesyl) or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0023] (13) In one preferred embodiment of the present invention, R ２ , R ３ and R ４ In the -NR １６ R １７ R in the group １６ and R １７ are the same or different and are H or R １２ represents a group, or R １６ and R１７ Together, R １２ The compound is a compound represented by formula (I) according to any one of the above items (1) to (7), or a pharmacologically acceptable salt thereof, or an isomer thereof, wherein the compound represents a group (preferably acetylpiperazinyl or cyanopiperidino).

[0024] (14) In one preferred embodiment of the present invention, R ２ , R ３ and R ４ C which may have a substituent ６－１０ C of aryl group ６－１０ The aryl group is phenyl or naphthyl, and the substituent is a heteroaryl group containing 1 to 4 atoms selected from N, S, and O, which may have a substituent (preferably pyridyl, phenylpyridyl, quinolyl, indazolyl, pyrazolyl, or methylpyrazolyl; more preferably indazolyl, pyrazolyl, or methylpyrazolyl), or R １２ The compound is a compound represented by formula (I) according to any one of (1) to (7) above, or a pharmacologically acceptable salt thereof, or an isomer thereof, wherein the compound represents a phenyl (preferably phenyl) optionally fused with a group.

[0025] (15) In one preferred embodiment of the present invention, R ２ , R ３ and R ４ wherein the optionally substituted heteroaryl group containing 1 to 4 atoms selected from N, S and O represents pyridyl, phenylpyridyl, quinolyl, indazolyl, pyrazolyl, or methylpyrazolyl, or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0026] (16) In a further preferred embodiment of the present invention, R ２ , R ３ and R ４The compound represented by formula (I) described in (15) above, or a pharmacologically acceptable salt thereof, or an isomer thereof, is provided, wherein the optionally substituted heteroaryl group containing 1 to 4 atoms selected from N, S, and O is indazolyl, pyrazolyl, or methylpyrazolyl.

[0027] (17) In one preferred embodiment of the present invention, R ２ , R ３ and R ４ At least one of the groups is —(CH═CH)—R １８ (In the formula, R １８ is -CO-R １９ indicates R １９ is R １２ The compound is a compound represented by formula (I) according to any one of (1) to (7) above, or a pharmacologically acceptable salt thereof, or an isomer thereof, wherein

[0028] (18) In one preferred embodiment of the present invention, R １２ N, S, SO, SO ２ and N, S, SO, SO of a heterocyclyl group containing 1 to 2 atoms (groups) selected from O ２ and O, wherein the heterocyclyl group containing 1 to 2 atoms (groups) selected from morpholino, piperazinyl, thiomorpholino, dioxidethiomorpholino, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, dioxidetetrahydrothiopyranyl, or piperidinyl, or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0029] (19) In a further preferred embodiment of the present invention, R １２ N, S, SO, SO ２ and N, S, SO, SO of a heterocyclyl group containing 1 to 2 atoms (groups) selected from O ２and O, wherein the heterocyclyl group containing 1 to 2 atoms (groups) selected from morpholino, piperazinyl, piperidinyl, or tetrahydropyranyl, or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0030] (20) In one preferred embodiment of the present invention, R １２ N, S, SO, SO ２ and O, the substituents of "heterocyclyl containing 1 to 2 atoms (groups) selected from -CO-, -COOH, cyano, 1 or 2 C １－６ Alkyl groups (preferably heterocyclyl groups N, S, SO, SO ２ and O, more preferably 2,6-dimethyl for tetrahydropyranyl and morpholino), C １－６ alkyl-CO- (preferably acetyl), C １－６ Alkyl-SO ２ - (e.g., mesyl), C ６－１０ an aryl group (preferably phenyl), 3-methoxy-2-hydroxypropyl, R １２ group (preferably oxetanyl, morpholino), R １２ -CH ２ - (preferably methoxyoxetanylmethyl), R １２ -CH ２ CO—(preferably morpholinomethylcarbonyl), R １２ -CH ２ The compound is a compound represented by formula (I) according to any one of the above items (1) to (19), which represents OCO- (preferably methoxyoxetanylmethoxycarbonyl), or methoxyethyl, or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0031] (21) In one preferred embodiment of the present invention, R ５ But, -COR ６ indicates R ６ But C １－６The compound is a compound represented by formula (I) according to any one of the above items (1) to (20), or a pharmacologically acceptable salt thereof, or an isomer thereof, wherein R represents an alkyl group.

[0032] (22) Preferred embodiments of the compound (I) of the present invention or a pharmacologically acceptable salt thereof or an isomer thereof are compounds selected from the following:

[0033] (23) More preferred embodiments of compound (I) of the present invention are compounds selected from the following:

[0034] (24) A preferred embodiment of the present invention is a compound of formula (I) or a pharmacologically acceptable salt thereof according to any one of (1) to (23) above, wherein the wavy line portion of the compound of formula (I) is a Z-form.

[0035] (25) A preferred embodiment of the present invention is a compound represented by formula (I) or a pharmacologically acceptable salt thereof according to any one of the above (1) to (23), wherein the wavy line portion of the compound represented by formula (I) is an E-form.

[0036] (26) Another embodiment of the present invention provides a Ras / Raf binding inhibitor, comprising a compound represented by formula (I), a pharmacologically acceptable salt thereof, or an isomer thereof: [wherein A represents a benzene ring or a pyridine ring, B represents C ６－１０ an aryl group or a heteroaryl group containing 1 to 4 atoms selected from N, S and O, ５ - indicates R １is H,NHCOCH ３ C optionally substituted with a group １－６ represents an alkyl group or a halogen; R ２ , R ３ and R ４ are the same or different (but at least one of them is not H), and: ● H; ● C １－６ Alkyl-SO ２ - (for example, mesyl); ● cyano; ● halogen; ● nitro; ● azide; ● -CO-R １１ group (in the formula, R １１ is, ・OH, ・R １２ Group (R １２ The group may have a substituent, such as N, S, SO, or SO ２ and O), NH ２ , N.H.R. １２ , or N(R １２ ) R １２ , or ・C ６－１０ arylamino, -O-CH ２ -CO-R １１ group; optionally substituted C １－６ Alkyl group (substituent is -CONH ２ , ・R １２ Group, ・OH, ・-NR １３ R １４ (R １３ is C １－６ Alkyl-SO ２ - (e.g., mesyl), C １－６ alkyl-CO- (preferably acetyl), or R １２ represents a group, and R １４ is H, C １－６ alkyl, or R １２ indicates), ・R １２ -CO-, or ・R １２ -C １－６ alkyl -CONH-); -OR １５ Group (wherein, R １５ is H, optionally substituted C １－６ Alkyl group (substituents include OH, C １－６Alkoxy, C ６－１０ Aryl, C ６－１０ Aryloxy, R １２ , Cyano, C １－６ Alkyl-SO ２ - (for example, mesyl, etc.) or methylsulfinyl), C １－６ Alkyl-SO ２ - (e.g., mesyl), or a heteroaryl group containing 1 to 4 atoms selected from N, S, and O; -NR １６ R １７ Group (wherein, R １６ and R １７ are the same or different, and are H, C １－６ alkyl-CO-, .R １２ group, or R １２ -C １－６ alkyl-CO—, or R １６ and R １７ together with N, １２ a C group which may have a substituent; ６－１０ Aryl group (substituents are C ６－１０ aryloxy, a heteroaryl group having a substituent and containing 1 to 4 atoms selected from N, S and O, or R １２ a phenyl group optionally fused to a ring; an optionally substituted heteroaryl group containing 1 to 4 atoms selected from N, S, and O; or -(CH=CH)-R １８ (In the formula, R １８ is -CO-R １９ , or -SO ２ -R １９ indicates R １９ is NH ２ , or R １２ represents a group); ５ is C １－６ Alkyl, -COR ６ , -COOR ６ , -CONR ６ R ７ , -SO ｎ R ６ , or SO ｎ NR ６ R ７n represents 0, 1 or 2; R ６ and R ７ are the same or different and are H, C １－６ alkyl group, or C ６－１０ The wavy lines indicate geometric isomers.

[0037] (27) Another preferred embodiment of the present invention is a Ras / Raf binding inhibitor comprising the compound represented by formula (I) described in (26) above, or a pharmacologically acceptable salt thereof, or an isomer thereof, wherein A is a benzene ring.

[0038] (28) Another preferred embodiment of the present invention is a Ras / Raf binding inhibitor comprising the compound represented by formula (I) described in (26) or (27) above, or a pharmacologically acceptable salt thereof, or an isomer thereof, wherein B represents phenyl or a heteroaryl group containing 1 to 4 atoms selected from N, S, and O.

[0039] (29) Another preferred embodiment of the present invention is a Ras / Raf binding inhibitor comprising the compound represented by formula (I) described in (26) or (27) above, or a pharmacologically acceptable salt thereof, or an isomer thereof, wherein B represents phenyl, pyridyl, quinolyl, indolyl, thiazolyl, pyrrolopyridinyl, benzothiazolyl, or furopyridinyl.

[0040] (30) Another preferred embodiment of the present invention is a Ras / Raf binding inhibitor comprising a compound represented by formula (I) described in (26) or (27) above, or a pharmacologically acceptable salt thereof, or an isomer thereof, wherein B is: However, one of the bonds corresponds to the wavy bond in formula (I), and the other bond corresponds to R ２ , R ３ and R ４ In this case, if there is another substituent, that substituent is substituted at the remaining position.

[0041] (31) Another preferred embodiment of the present invention is a Ras / Raf binding inhibitor comprising the compound represented by formula (I) described in (26) or (27) above, or a pharmacologically acceptable salt thereof, or an isomer thereof, wherein B represents phenyl, quinolyl, thiazolyl, or benzothiazolyl.

[0042] (32) Another preferred embodiment of the present invention is １ is H, or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0043] (33) Another preferred embodiment of the present invention is ２ , R ３ and R ４ -CO-R in １１ R in the group １１ is OH, or R １２ The Ras / Raf binding inhibitor comprises a compound represented by formula (I) according to any one of the above items (26) to (32), or a pharmacologically acceptable salt thereof, or an isomer thereof, wherein R represents a group.

[0044] (34) Another preferred embodiment of the present invention is ２ , R ３ and R ４ In the formula, —O—CH ２ -CO-R １１ R in the group １１ But, R １２ The Ras / Raf binding inhibitor comprises a compound represented by formula (I) according to any one of the above items (26) to (32), or a pharmacologically acceptable salt thereof, or an isomer thereof, wherein R represents a group.

[0045] (35) Another preferred embodiment of the present invention is ２ , R ３ and R ４ C which may have a substituent １－６ The substituent of the alkyl group is R １２ group, OH, -NR １３ R １４ (R １３ But C１－６ Alkyl-SO ２ - (e.g., mesyl) or R １２ represents a group, and R １４ is H or C １－６ represents an alkyl group), R １２ -CO-, or R １２ -C １－６ The Ras / Raf binding inhibitor comprises a compound represented by formula (I) according to any one of (26) to (32) above, which represents alkyl-CONH-, or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0046] (36) Another preferred embodiment of the present invention is R ２ , R ３ and R ４ C which may have a substituent １－６ The alkyl group substituent is —NR １３ R １４ (R １３ But C １－６ Alkyl-SO ２ - (for example, mesyl), and R １４ represents H), or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0047] (37) Another preferred embodiment of the present invention is R ２ , R ３ and R ４ In the -OR １５ R in the group １５ But C １－６ an alkyl group (preferably methyl), or C １－６ Alkyl-SO ２ - (for example, mesyl) or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0048] (38) Another preferred embodiment of the present invention is R ２ , R ３ and R ４ In the -NR１６ R １７ R in the group １６ and R １７ are the same or different and are H or R １２ represents a group, or R １６ and R １７ Together, R １２ The Ras / Raf binding inhibitor comprises a compound represented by formula (I) according to any one of the above items (26) to (32), or a pharmacologically acceptable salt thereof, or an isomer thereof, wherein R represents a group (preferably, acetylpiperazinyl and cyanopiperidino).

[0049] (39) Another preferred embodiment of the present invention is R ２ , R ３ and R ４ C which may have a substituent ６－１０ C of aryl group ６－１０ The aryl group is phenyl or naphthyl, and the substituent is a heteroaryl group containing 1 to 4 atoms selected from N, S, and O, which may have a substituent (preferably pyridyl, phenylpyridyl, quinolyl, indazolyl, pyrazolyl, or methylpyrazolyl; more preferably indazolyl, pyrazolyl, or methylpyrazolyl), or R １２ a phenyl (preferably phenyl) optionally fused with a group, a compound represented by formula (I) according to any one of (26) to (32) above, or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0050] (40) Another preferred embodiment of the present invention is R ２ , R ３ and R ４ wherein the optionally substituted heteroaryl group containing 1 to 4 atoms selected from N, S and O represents pyridyl, phenylpyridyl, quinolyl, indazolyl, pyrazolyl, or methylpyrazolyl, or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0051] (41) Another preferred embodiment of the present invention is R ２ , R ３ and R ４ wherein the optionally substituted heteroaryl group containing 1 to 4 atoms selected from N, S and O represents indazolyl, pyrazolyl, or methylpyrazolyl, or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0052] (42) Another preferred embodiment of the present invention is R ２ , R ３ and R ４ In the formula, -(CH=CH)-R １８ (In the formula, R １８ is -CO-R １９ indicates R １９ is R １２ a compound represented by formula (I) according to any one of (26) to (32) above, or a pharmacologically acceptable salt thereof, or an isomer thereof, wherein R represents a 1- or 2-membered group;

[0053] (43) Another preferred embodiment of the present invention is R １２ N, S, SO, SO ２ and N, S, SO, SO of a heterocyclyl group containing 1 to 2 atoms (groups) selected from O ２ and O, wherein the heterocyclyl group containing 1 to 2 atoms (groups) selected from morpholino, piperazinyl, thiomorpholino, dioxidethiomorpholino, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, dioxidetetrahydrothiopyranyl, or piperidinyl, or a pharmacologically acceptable salt thereof, is a Ras / Raf binding inhibitor comprising the compound represented by formula (I) according to any one of (27) to (42) above, or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0054] (44) Another preferred embodiment of the present invention is R １２ N, S, SO, SO ２and N, S, SO, SO of a heterocyclyl group containing 1 to 2 atoms (groups) selected from O ２ and O, wherein the heterocyclyl group containing 1 to 2 atoms (groups) selected from morpholino, piperazinyl, piperidinyl, or tetrahydropyranyl, or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0055] (45) Another preferred embodiment of the present invention is R １２ N, S, SO, SO ２ and the substituents of the heterocyclyl group containing 1 to 2 atoms (groups) selected from -CO-, -COOH, cyano, 1 or 2 C １－６ Alkyl groups (preferably heterocyclyl groups N, S, SO, SO ２ and O, more preferably 2,6-dimethyl for tetrahydropyranyl and morpholino), C １－６ alkyl-CO- (preferably acetyl), C １－６ Alkyl-SO ２ - (e.g., mesyl), C ６－１０ aryl (preferably phenyl), 3-methoxy-2-hydroxypropyl, R １２ group (preferably oxetanyl, morpholino), R １２ -CH ２ - (preferably methoxyoxetanylmethyl), R １２ -CH ２ CO—(preferably morpholinomethylcarbonyl), R １２ -CH ２ The Ras / Raf binding inhibitor comprises a compound represented by formula (I) according to any one of (26) to (44) above, which represents OCO- (preferably methoxyoxetanylmethoxycarbonyl) or methoxyethyl, or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0056] (46) Another preferred embodiment of the present invention is R ５ But, -COR ６ indicates R６ But C １－６ The Ras / Raf binding inhibitor comprises a compound represented by formula (I) according to any one of (26) to (45) above, wherein R represents an alkyl group, or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0057] (47) Another preferred embodiment of the present invention is the Ras / Raf binding inhibitor according to (26) above, wherein the compound represented by formula (I) or a pharmacologically acceptable salt thereof, or an isomer thereof is a compound selected from compounds 1 to 214 listed in Table 1.

[0058] (48) Another preferred embodiment of the present invention is the Ras / Raf binding inhibitor according to (26) above, wherein the compound represented by formula (I) is a compound selected from the following:

[0059] (49) Another embodiment of the present invention is a method for treating a patient with a disease or condition associated with activation of the Ras / Raf / MEK / ERK signaling system (Ras / MAPK pathway), particularly a blood tumor such as leukemia (ALL, APL, AML) and / or myeloma; or a solid tumor such as small cell lung cancer, gastrointestinal cancer, colon cancer, rectal cancer, colorectal cancer, colon cancer, pancreatic cancer, melanoma, and / or ovarian cancer, comprising administering to the patient a therapeutically effective amount of a Ras / Raf binding inhibitor comprising at least one compound represented by formula (I) in (1) above or a pharmacologically acceptable salt thereof or an isomer thereof, or a compound represented by formula (I) in (26) above or a pharmacologically acceptable salt thereof or an isomer thereof.

[0060] (50) Another preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (2) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (27) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0061] (51) Another preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (3) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (28) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0062] (52) Another more preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (4) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (29) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0063] (53) Another more preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (5) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (30) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0064] (54) Another more preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (6) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (31) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0065] (55) Another preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (7) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (32) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0066] (56) Another preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (8) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (33) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0067] (57) Another preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (9) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (34) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0068] (58) Another preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (10) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (35) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0069] (59) Another more preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (11) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (36) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0070] (60) Another preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (12) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (37) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0071] (61) Another preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (13) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (38) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0072] (62) Another preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (14) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (39) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0073] (63) Another preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (15) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (40) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0074] (64) Another more preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (16) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (41) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0075] (65) Another preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (17) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (42) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0076] (66) Another preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (18) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (43) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0077] (67) Another more preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (19) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (44) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0078] (68) Another preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (20) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (45) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0079] (69) Another preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (21) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (46) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0080] (70) Another preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (22) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (47) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0081] (71) Another more preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which are involved in activation of the Ras / Raf / MEK / ERK signal transduction system (Ras / MAPK pathway), using a Ras / Raf binding inhibitor comprising the compound represented by formula (I) in (23) above, a pharmacologically acceptable salt thereof, or an isomer thereof, or the compound represented by formula (I) in (48) above, a pharmacologically acceptable salt thereof, or an isomer thereof.

[0082] (72) Another preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which is involved in activation of the Ras / Raf / MEK / ERK signaling system (Ras / MAPK pathway), using the compound represented by formula (I) in (24) above, or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0083] (73) Another preferred embodiment of the present invention is a method for treating leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, or melanoma, which is involved in activation of the Ras / Raf / MEK / ERK signaling system (Ras / MAPK pathway), using the compound represented by formula (I) in (25) above, or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0084] The present invention further provides a pharmaceutical comprising the compound represented by formula (I) or a pharmacologically acceptable salt thereof, or an isomer thereof. The present invention also provides an anticancer agent comprising the compound represented by formula (I) or a pharmacologically acceptable salt thereof, or an isomer thereof.

[0085] Definition "C" in the definition of B ６－１０ "aryl group", R １１ "C" in the definition of ６－１０ "C" in "arylamino" ６－１０ Aryl", R ２ , R ３ and R ４ "Optionally substituted C" in the definition of ６－１０"C" in "aryl group" ６－１０ "aryl group", R ６ and R ７ "C" in the definition of ６－１０ aryl group”, and R １５ "Optionally substituted C" in the definition of １－６ "C" in "Substituent" of "Alkyl group" ６－１０ aryl" and "C ６－１０ "C" of "aryloxy" ６－１０ The term "aryl" refers to a monocyclic or bicyclic 6- to 10-membered aromatic ring group, examples of which include phenyl, indenyl, and naphthyl, with a phenyl group being preferred. The above-mentioned "aryl group" may be condensed with a cycloalkyl group having 3 to 10 carbon atoms, examples of which include 2-indanyl. Phenyl or naphthyl is preferred.

[0086] R ２ , R ３ and R ４ "Optionally substituted C" in the definition of ６－１０ The "substituent" of the "aryl group" is the same as the "C ６－１０ aryl"oxy, "an optionally substituted heteroaryl group containing 1 to 4 atoms selected from N, S, and O," or "R １２ and preferably "a heteroaryl group containing 1 to 4 atoms selected from N, S, and O, which may have a substituent" (more preferably pyridyl, phenylpyridyl, quinolyl, indazolyl, pyrazolyl, or methylpyrazolyl; even more preferably indazolyl, pyrazolyl, or methylpyrazolyl), or "R １２ and (phenyl which may be fused with a group) (more preferably phenyl).

[0087] "a heteroaryl group containing 1 to 4 atoms selected from N, S, and O" in the definition of B, R １５ "a heteroaryl group containing 1 to 4 atoms selected from N, S and O" in the definition of R ２ , R ３ and R ４In the definition of "heteroaryl group containing 1 to 4 atoms selected from N, S, and O, which may have a substituent," the "heteroaryl group containing 1 to 4 atoms selected from N, S, and O" refers to an aromatic ring system containing carbon and at least one heteroatom. Heteroaryl groups may be monocyclic or polycyclic. Heteroaryl groups may have 1 to 4 heteroatoms in the ring. Polycyclic heteroaryl rings may contain fused, spiro, or bridged ring junctions; for example, a bicyclic heteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings may contain 8 to 12 ring member atoms. Monocyclic heteroaryl groups may contain 5 to 8 ring member atoms (carbon atoms and heteroatoms). Examples of such heteroaryl groups include, but are not limited to, pyridyl, phenylpyridyl, quinolyl, isoquinolyl, indazolyl, pyrazolyl, pyrazolyl, indolyl, thiazolyl, pyrrolopyridinyl, benzothiazolyl, furopyridinyl, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, thiadiazolyl, triazolyl, pyridazinyl, azaindolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzodisooxazolyl, benzoxazolyl, benzopyrazolyl, benzothiadiazolyl, benzotridiazolyl, benzotriazolyl, or adenyl. Preferred is quinolyl, indazolyl, pyrazolyl, indolyl, pyridyl, pyrrolopyridinyl, benzothiazolyl, furopyridinyl or thiazolyl, more preferred is quinolyl, pyridyl, benzothiazolyl or thiazolyl, or the following groups: However, one of the bonds corresponds to the wavy bond in formula (I), and the other bond corresponds to R ２ , R ３ and R ４ In this case, if there is another substituent, that substituent is substituted at the remaining position.

[0088] R ２ , R ３ and R ４The "substituent" in the "heteroaryl group containing 1 to 4 atoms selected from N, S and O, which may be substituted" in the definition of １－６ alkyl group," and preferably "C １－４ It is preferably an alkyl group, and more preferably methyl.

[0089] R １ "C" in the definition of １－６ alkyl group," R ２ , R ３ and R ４ "Optionally substituted C" in the definition of １－６ "C" of "Alkyl group" １－６ alkyl group," R ５ "C" in the definition of １－６ alkyl", R ６ and R ７ "C" in the definition of １－６ alkyl group," R １１ "R" in the definition of １２ -C １－６ "C" of "Alkyl-CONH-" １－６ alkyl", R １３ "C" in the definition of １－６ "C" of "Alkyl-CO-" １－６ alkyl", R １４ "C" in the definition of １－６ alkyl group," R １５ "Optionally substituted C" in the definition of １－６ "C" of "Alkyl group" １－６ alkyl group," and R １６ and R １７ "C" in the definition of １－６ alkyl-CO-" and "R １２ -C １－６ "C" of "Alkyl-CO-" １－６"Alkyl" means a saturated monovalent hydrocarbon radical of 1, 2, 3, 4, 5, or 6 carbon atoms in a linear or branched arrangement; for example, alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, and cyclohexyl; preferably, a linear or branched alkyl group having 1 to 4 carbon atoms; more preferably, methyl or ethyl.

[0090] R １ , R ２ , R ３ and R ４ "Halogen" in the definition of is fluoro, chloro, bromo or iodo, preferably F or Cl.

[0091] R １２ In the definition of "optionally substituted N, S, SO, SO ２ and O" in "a heterocyclyl group containing 1 to 2 atoms (groups) selected from N, S, SO, SO ２and O" refers to a monocyclic or polycyclic non-aromatic ring system containing one to two N, S, and O to form the ring. Preferred heteroatoms include N-oxides, sulfur oxides, and dioxides. Preferably, the ring is 3-10 membered and is fully saturated or exhibits one or more degrees of unsaturation. Multiple degrees of substitution, preferably 1, 2, or 3, are included in this definition. Examples of such heterocyclic groups include, but are not limited to, morpholino, piperazinyl, thiomorpholino, dioxidethiomorpholino, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, dioxidetetrahydrothiopyranyl, piperidinyl, azetidinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Preferably, morpholino, piperazinyl, piperidinyl, or tetrahydropyranyl.

[0092] R １２ "N, S, SO, SO which may have a substituent" ２ The "substituents" of "heterocyclyl containing 1 to 2 atoms (groups) selected from -CO-, -COOH, cyano, 1 or 2 C １－６ Alkyl (preferably heterocyclyl groups N, S, SO, SO ２ and O, more preferably 2,6-dimethyl for morpholino and tetrahydropyranyl), C １－６ alkyl-CO- (preferably acetyl), C １－６ Alkyl-SO ２ - (e.g., mesyl), C ６－１０ aryl (preferably phenyl), 3-methoxy-2-hydroxypropyl, R １２ (preferably oxetanyl, morpholino), R １２ CH ２- (preferably methoxyoxetanylmethyl), R １２ CH ２ CO—(preferably morpholinomethylcarbonyl), R １２ CH ２ OCO- (preferably methoxyoxetanylmethoxycarbonyl) or methoxyethyl.

[0093] R １５ "Optionally substituted C" in the definition of １－６ "C" in "Substituent" of "Alkyl group" １－６ The term "alkoxy" refers to the same as the above "C １－６ "Alkyl group" refers to a group bonded to an oxygen atom, and indicates a straight or branched chain alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, and 2,3-dimethylbutoxy, and is preferably a straight or branched chain alkoxy group having 1 to 4 carbon atoms.

[0094] R １５ "Optionally substituted C" in the definition of １－６ "C" in "Substituents" of "Alkyl" ６－１０ The term "aryloxy" refers to the same as the above "C ６－１０ An "aryl group" refers to a group bonded to an oxygen atom.

[0095] The group represented by the following formula (II) in formula (I) (wherein the wavy line represents a bond) is Particularly preferred are groups selected from the following:

[0096] The wavy line indicates an E or Z geometric isomer. As described above, the compounds of the present invention exist as geometric isomers, and the present invention encompasses the separated isomers or mixtures of these isomers in any proportion. Furthermore, the compounds of the present invention may have asymmetric carbon atoms, and based on this, diastereomers and (R) and (S) optical isomers may exist. The present invention encompasses all such mixtures and isolated optical isomers, possible diastereomers, as well as racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers, and pharmacologically acceptable salts thereof. During the course of synthetic procedures used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers.

[0097] Furthermore, when tautomers of the compound of formula (I) exist, the present invention includes any possible tautomers and pharmacologically acceptable salts thereof, as well as mixtures thereof, unless otherwise specified.

[0098] For use in medicine, the salts of the compounds of the present invention are non-toxic "pharmacologically acceptable salts". Pharmacologically acceptable salt forms include pharmacologically acceptable acidic / anionic or basic / cationic salts. When compound (I) of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. When compound (I) of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such salts are pharmaceutically acceptable salts, and preferred examples thereof include, but are not limited to, acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, and phosphoric acid; acid addition salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid, aspartic acid, glutamic acid, glycolic acid, benzoic acid, mandelic acid, hydroxyethanesulfonic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, salicylic acid, saccharinic acid, and trifluoroacetic acid; salts with inorganic bases such as sodium, lithium, potassium, magnesium, calcium, aluminum, and zinc; salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, chloroprocaine, choline, diethanolamine, and ethylenediamine; and ammonium salts.

[0099] When the compound of formula (I) and its pharmacologically acceptable salts exist in the form of solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent that forms the solvate is not particularly limited as long as it is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, etc. can be used.

[0100] The present invention includes within its scope prodrugs of the compounds of the present invention. Generally, such prodrugs are functional derivatives of the compounds that are readily converted in vivo into the required compound. Thus, in this invention, the term "compound" encompasses the treatment of the various disorders described with compounds that are specifically disclosed or compounds that are not specifically disclosed but that are converted into the specified compound in vivo after administration to a subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," edited by H. Bundgaard, Elsevier, 1985, the contents of which are incorporated herein.

[0101] The term "inhibitor" as used herein encompasses a product containing a specified amount of a specified component, as well as any product resulting directly or indirectly from the combination of the specified components in the specified amounts. Therefore, compositions containing the compound (I) of the present invention as an active ingredient, as well as methods for preparing the compound, are also part of the present invention. The pharmaceutical composition of the present invention comprises, as an active ingredient, a compound represented by formula (I) or a pharmaceutically acceptable salt (or isomer thereof), a pharmaceutically acceptable carrier, and optionally other therapeutic components or adjuvants.

[0102] The compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host and the nature and severity of the condition for which the active ingredient is being administered. The compositions can be conveniently provided in unit dosage form and prepared by any method well known in the art of pharmacy. In practice, the compound represented by Formula (I) of the present invention, or a prodrug or metabolite thereof, or a pharmaceutically acceptable salt thereof, as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, and the product can then be conveniently shaped into the desired form. The carrier can take a wide variety of forms, depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the compositions of the present invention can be provided as discrete units suitable for oral administration, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient. Additionally, the composition may be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion.

[0103] In addition to the common dosage forms set out above, the compounds represented by formula (I) or pharmaceutically acceptable salts thereof, etc., can also be administered by controlled release means and / or delivery devices.

[0104] The compounds of formula (I), or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[0105] The pharmaceutical carrier used can be for example solid or liquid.The example of solid carrier includes lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid.The example of liquid carrier is sugar syrup, peanut oil, olive oil and water.

[0106] The dosage form of Compound (I) of the present invention can be, for example, oral administration in the form of tablets, capsules, granules, powders, syrups, etc., or parenteral administration in the form of injections, suppositories, etc., and these preparations can be prepared by adding excipients (e.g., sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin; cellulose derivatives such as crystalline cellulose; organic excipients such as gum arabic; dextran; pullulan; and light anhydrous silicic acid, synthetic aluminum silicate, etc.). Examples of suitable excipients include inorganic excipients such as silicate derivatives such as calcium silicate and magnesium aluminometasilicate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate; lubricants (for example, stearic acid, metal stearates such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as Veegum and Gay wax; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; sodium fatty acids; Examples of suitable excipients include ammonium salts; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; and the above-mentioned starch derivatives.), binders (for example, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, macrogol, and compounds similar to the above-mentioned excipients.), disintegrants (for example, cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, and internally crosslinked sodium carboxymethyl cellulose; and chemically modified starches and celluloses such as carboxymethyl starch, carboxymethyl starch sodium, and crosslinked polyvinylpyrrolidone.), stabilizers (for example, parahydroxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.The composition is prepared by a known method using additives such as flavoring agents (for example, commonly used sweeteners, acidulants, fragrances, etc.), diluents, etc.

[0107] Tablets containing the compositions of the present invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant. Mold tablets can be produced by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0108] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and effectively fluid for easy injectability. Pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, they must preferably be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0109] Furthermore, the composition may be in a form suitable for use in transdermal devices. These preparations can be prepared by conventional processing methods using the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof.

[0110] The dosage varies depending on the symptoms, age, administration method, etc., but for example, in the case of oral administration, the lower limit is 0.01 mg / kg body weight (preferably 0.1 mg / kg body weight) and the upper limit is 300 mg / kg body weight (preferably 200 mg / kg body weight) per dose, and in the case of intravenous administration, the lower limit is 0.001 mg / kg body weight (preferably 0.01 mg / kg body weight) and the upper limit is 100 mg / kg body weight (preferably 30 mg / kg body weight) per dose, and it is desirable to administer it once to several times per day depending on the symptoms.

[0111] It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease being treated. In some embodiments, the compound is in a weight ratio to excipient ranging from about 0.0001 to about 10. In some embodiments, the compound is in a weight ratio to excipient ranging from about 0.0005 to about 0.25.

[0112] The compound of the present invention and a pharmaceutical composition containing the same exhibit an inhibitory effect on Ras / Raf signaling even against drug-resistant cancer cells and a wide range of Ras-mutated cancers, and therefore specifically inhibit Ras / Raf binding, thereby exhibiting novel and excellent effects against many cancers including leukemia (ALL, APL, AML), small cell lung cancer, colon cancer, pancreatic cancer, and melanoma.

[0113] The present invention also provides novel and excellent small molecular weight compounds that specifically inhibit Ras / Raf binding, pharmaceutical compositions containing the compounds, methods for producing the pharmaceutical compositions using these compounds, and novel and excellent therapies for many cancers involving activation of the Ras / Raf / MEK / ERK signaling system (Ras / MAPK pathway), including leukemia (ALL, APL, AML), small cell lung cancer, colorectal cancer, pancreatic cancer, and melanoma.

[0114] (Preparation Methods) The compounds of the present invention and their pharmaceutically acceptable salts, as well as their isomers, can be prepared using various known synthetic methods well within the skill of those in the art of organic synthesis, as described below, unless otherwise specified. Compounds of formula (I) can be synthesized by reference to the following methods. Preferred methods are not limited to those described below. The references cited herein are incorporated by reference in their entirety. The synthetic methods described below are intended as examples of the present invention and do not limit the scope of the subject matter and the compounds claimed by these examples. Where the preparation of starting compounds is not described, they are commercially available or can be prepared analogously to known compounds or methods described herein. Materials described in the literature are prepared according to published synthetic methods. As shown herein, the final compound is a product having the structural formula shown as formula (I). It is understood that any compound of formula (I) can be prepared by selecting reagents with appropriate substitutions. Solvents, temperatures, pressures, and other reaction conditions can be readily selected by those skilled in the art. In each step, the desired compound can be obtained by protecting and deprotecting functional groups as necessary. Protection and deprotection of functional groups can be carried out by known methods, for example, the methods described in Wuts, "Green's Protective Groups in Organic Synthesis", 5th edition.

[0115] The present invention will be explained in more detail below with reference to examples, production examples and test examples.

[0116] (Examples) The present invention will be more readily understood by reference to the following examples. It should be understood that the following examples are further defined, but these examples are merely used to illustrate specific aspects and embodiments of the present invention. Those skilled in the art can reliably determine the essential features of the present invention and can make various modifications to adapt the present invention to various uses and conditions without departing from the spirit and scope of the present invention. Therefore, the present invention is not limited by the illustrative examples described below in this specification, but rather is defined by the claims appended hereto.

[0117] The methods for producing the raw material compounds used in the examples are explained as Production Examples.

[0118] In the following examples, the following abbreviations may be used. mCPBA: metachloroperbenzoic acid; THF: tetrahydrofuran; DMF: N,N-dimethylformamide; DMA: N,N-dimethylacetamide; DIPEA: N,N-diisopropylethylamine; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; TFA: 2,2,2-trifluoroacetic acid; WSCD·HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; DCE: 1,2-dichloroethane; BINAP: (1,1'-binaphthalene-2,2'-diyl)bis(diphenylphosphane); X-Phos: 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl 1H NMR: Proton nuclear magnetic resonance MS: Mass spectrometry using electrospray ionization (M+H), (M+Na), (M+H ２ O+H): molecular ion peak M: molar concentration Tr: trityl group SEM: (2-(trimethylsilyl)ethoxy)methyl group

[0119] Production Example 1 A mixture of N-((3-formyl-1H-indol-4-yl)methyl)acetamide (manufactured by Aurora Fine Chemicals, 601 mg) and acetic anhydride (5.85 ml) was stirred at 145° C. for 4 hours, and then the solvent was removed from the reaction mixture under a nitrogen stream. The resulting residue was crystallized from methanol to give N-acetyl-N-((1-acetyl-3-formyl-1H-indol-4-yl)methyl)acetamide (518 mg) as a pale brown solid. A mixture of N-acetyl-N-((1-acetyl-3-formyl-1H-indol-4-yl)methyl)acetamide (485 mg), dichloromethane (7 ml), and 70% mCPBA (478 mg) was stirred at room temperature for 22 hours and 50 minutes, and then 70% mCPBA (119 mg) was added to the reaction mixture, followed by stirring at room temperature for an additional 2 hours and 30 minutes. Chloroform was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and methanol (6 ml) and potassium carbonate (12 mg) were added to the resulting residue, followed by stirring at room temperature for 2 minutes. The solvent in the reaction mixture was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane-chloroform-methanol) to obtain N-acetyl-N-((1-acetyl-3-oxoindolin-4-yl)methyl)acetamide (86 mg) as a pale brown solid.

[0120] Preparation Example 2 A mixture of N-acetyl-N-((1-acetyl-3-oxoindolin-4-yl)methyl)acetamide (Preparation Example 1, 86 mg), ethanol (4 ml), THF (2 ml), water (2 ml), and sodium hydrogen carbonate (30 mg) was stirred at room temperature for 28 hours. Sodium hydrogen carbonate (16 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for an additional 2 days. The solvent of the reaction mixture was evaporated under reduced pressure, and then toluene was added, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give N-((1-acetyl-3-oxoindolin-4-yl)methyl)acetamide (15 mg) as a pale brownish yellow solid.

[0121] Production Example 3: A mixture of 4-bromo-3-methoxybenzaldehyde (AstaTech, 215 mg), acetonitrile (5 ml), triethylamine (5 ml), acrylamide (78 mg), and tris(2-methylphenyl)phosphine (61 mg) was degassed by repeatedly reducing the pressure and replacing the atmosphere with nitrogen. Palladium acetate (22 mg) was then added, and the mixture was stirred under reflux for 3 hours and 30 minutes. 2M hydrochloric acid was added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (E)-3-(4-formyl-2-methoxyphenyl)acrylamide (97 mg) as a pale yellow solid.

[0122] Production Example 4 A mixture of 6-bromo-2-methylbenzo[d]thiazole (Combi-Blocks, 200 mg), DMA (4 ml), triethylamine (0.367 ml), 4-(vinylsulfonyl)morpholine (Organic Letters, 22(13), 4970-4973; 2020, 311 mg), and tris(2-methoxyphenyl)phosphine (53 mg) was degassed by repeatedly reducing the pressure and replacing the atmosphere with nitrogen, and then palladium acetate (20 mg) was added and the mixture was stirred at 100° C. for 20 hours. Triethylamine (0.367 ml), 4-(vinylsulfonyl)morpholine (311 mg), and tris(2-methoxyphenyl)phosphine (133 mg) were added to the reaction mixture, which was then degassed by repeatedly reducing the pressure and replacing the atmosphere with nitrogen. Palladium acetate (49 mg) was then added, and the mixture was stirred at 100° C. for 26 hours. The solvent was removed from the reaction mixture under a nitrogen stream, and the resulting residue was purified by silica gel column chromatography (eluent: hexane-chloroform-ethyl acetate) to give (E)-4-((2-(2-methylbenzo[d]thiazol-6-yl)vinyl)sulfonyl)morpholine (32 mg) as a brown solid.

[0123] Production Example 5: To a mixture of 28% aqueous ammonia (4.3 ml) and chloroform (5 ml), 2-chloroethanesulfonyl chloride (1.62 ml) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Toluene was added to the reaction mixture, and the solvent was evaporated under reduced pressure. A mixture of the resulting residue and THF (100 ml) was stirred at 60°C for 30 minutes, after which the resulting solid was removed by filtration, and the solvent in the filtrate was evaporated under reduced pressure. To the resulting residue, 4-bromo-3-methoxybenzaldehyde (manufactured by AstaTech, 100 mg), DMA (2 ml), triethylamine (0.194 ml), and tris(2-methoxyphenyl)phosphine (28 mg) were added, and the mixture was degassed by repeatedly vacuum-purging and purging with nitrogen. Palladium acetate (11 mg) was then added, and the mixture was stirred at 100°C for 5 hours. The solvent was removed from the reaction mixture under a nitrogen stream, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (E)-2-(4-formyl-2-methoxyphenyl)ethene-1-sulfonamide (69 mg) as a yellow oil.

[0124] Preparation Example 6: A mixture of (E)-3-(4-formyl-2-methoxyphenyl)acrylamide (Preparation Example 3, 105 mg), ethanol (2 ml), THF (1 ml), and 5% palladium on carbon (14 mg) was stirred at room temperature for 3 hours under a hydrogen atmosphere at 1 atmosphere pressure. Insoluble matter in the reaction mixture was removed by filtration, and the solvent in the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give 3-(4-formyl-2-methoxyphenyl)propanamide (76 mg) as a pale yellow solid.

[0125] Production Example 7: A mixture of (E)-3-(2-methylquinolin-6-yl)-1-morpholinoprop-2-en-1-one (Production Example 18, 116 mg), ethanol (2.3 ml), water (0.23 ml), and 20% palladium hydroxide on carbon (23 mg) was stirred at room temperature for 22 hours under a hydrogen atmosphere at 1 atmosphere pressure. Insoluble matter in the reaction mixture was removed by filtration, and the solvent in the filtrate was evaporated under reduced pressure. Toluene was added to the resulting residue, and the solvent was evaporated again under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane-chloroform-methanol) to give 3-(2-methylquinolin-6-yl)-1-morpholinopropan-1-one (107 mg) as a pale yellow solid.

[0126] Production Example 8: To a mixture of 3-methoxy-4-((methylthio)methoxy)benzaldehyde (Tetrahedron Letters, 18(6), 533-534, 1977, 139 mg) and dichloromethane (3 ml), 70% mCPBA (226 mg) was added under ice-cooling, and the mixture was stirred under ice-cooling for 40 minutes. Dichloromethane was added to the reaction mixture, and the mixture was washed with an aqueous sodium carbonate solution. The organic layer was then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain the less polar 3-methoxy-4-((methylsulfonyl)methoxy)benzaldehyde (89 mg) that had been eluted earlier as a colorless solid.

[0127] Production Example 9 In the silica gel column chromatography obtained in Production Example 8, highly polar 3-methoxy-4-((methylsulfinyl)methoxy)benzaldehyde (57 mg) was eluted later as a colorless solid.

[0128] Preparation Example 10: A mixture of 4-hydroxy-3-isopropoxybenzaldehyde (WO2011125006, 352 mg), DMF (10 ml), potassium carbonate (810 mg), and 2-chloroacetamide (438 mg) was stirred at 80°C for 17 hours, and then the solvent of the reaction mixture was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to yield 2-(4-formyl-2-isopropoxyphenoxy)acetamide (251 mg) as a colorless solid.

[0129] Production Example 14 Using 6-(chloromethyl)-2-methylquinoline hydrochloride (manufactured by BLD Pharmatech), acetonitrile, potassium carbonate, and thiomorpholine 1,1-dioxide, 4-((2-methylquinolin-6-yl)methyl)thiomorpholine 1,1-dioxide was obtained as a colorless solid in the same manner as in Production Example 10.

[0130] Preparation Example 16: A mixture of 4-amino-3-methoxybenzaldehyde (Sigma-Aldrich, 39 mg), 2-morpholinoacetic acid hydrochloride (Tokyo Chemical Industry, 70 mg), DMF (0.5 ml), DIPEA (0.157 ml), and HATU (196 mg) was stirred at 60°C for 20 hours, and then the solvent was removed from the reaction mixture under a nitrogen stream. The resulting residue was purified sequentially by silica gel column chromatography (eluent: hexane-ethyl acetate, then chloromethyl-methanol) to give N-(4-formyl-2-methoxyphenyl)-2-morpholinoacetamide (35 mg) as a pale yellow solid.

[0131] Production Example 18 A mixture of (E)-3-(2-methylquinolin-6-yl)acrylic acid (Organic Letters, 14(21), 5420-5423; 2012, 100 mg), dichloromethane (4 ml), morpholine (0.0615 ml), DIPEA (0.147 ml), and HATU (214 mg) was stirred at room temperature for 16 hours, and the reaction mixture was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (E)-3-(2-methylquinolin-6-yl)-1-morpholinoprop-2-en-1-one (121 mg) as a colorless solid.

[0132] Preparation Example 30 A mixture of 4-([1,1'-biphenyl]-2-yl)-2-methylquinoline-6-carboxylic acid (Preparation Example 94, 66 mg), 1-(oxetan-3-yl)piperidin-4-amine bis(2,2,2-trifluoroacetate) (Enamine, 75 mg), dichloromethane (1.3 ml), DIPEA (0.119 ml), and HATU (89 mg) was stirred at room temperature for 25 hours, and then ethyl acetate was added to the reaction solution, and the mixture was washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was then purified by silica gel column chromatography (eluent: hexane-chloroform-methanol) and gel permeation chromatography (eluent: chloroform) successively to give 4-([1,1'-biphenyl]-2-yl)-2-methyl-N-(1-(oxetan-3-yl)piperidin-4-yl)quinoline-6-carboxamide (76 mg) as a colorless oil.

[0133] Preparation 31: A mixture of 4-amino-2-methylquinoline-6-carboxylic acid dihydrochloride (Preparation Example 93, 51 mg), morpholine (0.0274 ml), DMF (2 ml), DIPEA (0.109 ml), and HATU (95 mg) was stirred at room temperature for 16 hours, and then the solvent was removed from the reaction mixture under a nitrogen stream. The resulting residue was purified by aminopropyl silica gel column chromatography (eluent: chloroform-methanol) to give (4-amino-2-methylquinolin-6-yl)(morpholino)methanone (63 mg) as a pale brown foam.

[0134] Preparation Example 33: A mixture of 4-chloro-2-methylquinoline-6-carboxylic acid (Preparation Example 92, 93 mg), DMF (1.9 ml), morpholine (0.0546 ml), DIPEA (0.130 ml), and HATU (190 mg) was stirred at room temperature for 18 hours, and the solid that precipitated in the reaction mixture was collected by filtration. The resulting solid was washed successively with DMF and then hexane to give (4-((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)-2-methylquinolin-6-yl)(morpholino)methanone (144 mg) as a colorless solid.

[0135] Preparation 34: A mixture of 4-chloro-2-methylquinoline-6-carboxylic acid (Preparation Example 92, 34 mg), dichloromethane (0.68 ml), morpholine (0.0201 ml), and WSCD·HCl (35 mg) was stirred at room temperature for 16 hours. The reaction mixture was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (4-chloro-2-methylquinolin-6-yl)(morpholino)methanone (40 mg) as a colorless solid.

[0136] Production Example 45 N-((2-methylquinolin-6-yl)methyl)-2-morpholinoacetamide was obtained as a pale yellow oil in the same manner as in Production Example 34 using (2-methylquinolin-6-yl)methanamine (manufactured by Enamine), 2-morpholinoacetic acid hydrochloride (manufactured by Tokyo Chemical Industry Co., Ltd.), dichloromethane, triethylamine, and WSCD.HCl.

[0137] Preparation Example 47: A mixture of methyl 2-(hydroxymethyl)-1-methyl-1H-indole-5-carboxylate (Azepine, 61 mg), methanol (1.2 ml), and 1M aqueous sodium hydroxide solution (1.2 ml) was stirred at room temperature for 5 hours, and then 1,4-dioxane (0.5 ml) was added to the reaction mixture, followed by stirring at room temperature for an additional 19 hours. 1M hydrochloric acid (1 ml) was added to the reaction mixture, and the solvent was evaporated under reduced pressure. Toluene was then added, and the solvent was again evaporated under reduced pressure. To the resulting residue, dichloromethane (1.2 ml), morpholine (0.0365 ml), and WSCD·HCl (80 mg) were added, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was then purified by silica gel column chromatography (eluent: chloroform-methanol) to give (2-(hydroxymethyl)-1-methyl-1H-indol-5-yl)(morpholino)methanone (60 mg) as a pale yellow oil.

[0138] Production Example 48: To a mixture of (2-methylquinolin-6-yl)methanamine (Enamine, 212 mg), dichloromethane (4 ml), and triethylamine (0.243 ml) was added acetic anhydride (0.132 ml) under ice-cooling, and the mixture was stirred at room temperature for 17 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give N-((2-methylquinolin-6-yl)methyl)acetamide (136 mg) as a pale yellow solid.

[0139] Preparation Example 50: A mixture of (4-amino-2-methylquinolin-6-yl)(morpholino)methanone (Preparation Example 31, 114 mg), dichloromethane (2.3 ml), DMF (0.23 ml), triethylamine (0.0701 ml), and acetic anhydride (0.038 ml) was stirred at room temperature for 21 hours, and then DMF (0.92 ml) and acetic anhydride (0.112 ml) were added to the reaction mixture, which was stirred at room temperature for 20 hours. DMF (1.15 ml) and triethylamine (0.140 ml) were added to the reaction mixture, which was stirred at room temperature for an additional 4 days, and then the solvent was removed from the reaction mixture under a nitrogen stream. The resulting residue was purified by aminopropyl silica gel column chromatography (eluent: chloroform-methanol) to give N-(2-methyl-6-(morpholine-4-carbonyl)quinolin-4-yl)acetamide (56 mg) as a colorless oil.

[0140] Preparation Example 51: To a mixture of 6-hydroxy-[1,1'-biphenyl]-3-carbaldehyde (Enamine, 125 mg), 2-hydroxy-1-morpholinoethan-1-one (AstaTech, 92 mg), THF (2.5 ml), and triphenylphosphine (248 mg), diisopropyl azodicarboxylate (0.186 ml) was added under ice-cooling and the mixture was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform-ethyl acetate, then hexane-chloroform-ethyl acetate) to give 6-(2-morpholino-2-oxoethoxy)-[1,1'-biphenyl]-3-carbaldehyde (126 mg) as a pale yellow oil.

[0141] Preparation Example 54: To a mixture of 6-fluoro-5-hydroxypicolinaldehyde (Milestone Pharma Tech, 47 mg), dichloromethane (1 ml), triethylamine (0.0696 ml), and N,N-dimethylpyridin-4-amine (4.1 mg), methanesulfonic anhydride (70 mg) was added under ice-cooling and the mixture was stirred at room temperature for 3 hours. Dichloromethane was then added to the reaction mixture, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give 2-fluoro-6-formylpyridin-3-yl methanesulfonate (56 mg) as a colorless oil.

[0142] Preparation Example 56: To a mixture of methyl 1H-pyrrolo[3,2-b]pyridine-5-carboxylate (Bioorganic & Medicinal Chemistry Letters, 20(1), 413-417; 2010, 147 mg) and DMF (1.47 ml), 60% sodium hydride (44 mg) was added under ice-cooling and stirred at 0°C for 30 minutes. Methanesulfonyl chloride (0.071 ml) was then added to the reaction mixture and stirred at room temperature for 21 hours. Water was added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was then washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was then purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain methyl 1-(methylsulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylate (135 mg) as a pale yellow solid.

[0143] Preparation Example 57: To a mixture of methyl 1-(methylsulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylate (Preparation Example 56, 135 mg) and THF (16.8 ml), diisobutylaluminum hydride (1 M toluene solution, 3.2 ml) was added dropwise while maintaining the internal temperature below −63°C, and the mixture was stirred at −78°C for 1 hour. The reaction mixture was poured into a mixture of water, 1 M aqueous sodium hydroxide, and saturated brine. The mixture was stirred at room temperature for 10 minutes, and the product was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give 1-(methylsulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-carbaldehyde (113 mg) as a colorless solid.

[0144] Production Example 58: To a mixture of (3-methoxyoxetan-3-yl)methanol (Tetrahedron Letters, 55(30), 4117-4119; 2014, 631 mg), tetrabutylammonium iodide (124 mg), and toluene (7 ml), 30% aqueous sodium hydroxide solution (1.42 g) and 4-methylbenzenesulfonyl chloride (1.53 g) were added successively while maintaining the internal temperature at 1°C or below in an ice-methanol bath, and the mixture was stirred at 0°C for 1 hour and then at room temperature for 29 hours. Ice water was added to the reaction mixture, and the product was extracted with dichloromethane. The organic layer was then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain (3-methoxyoxetan-3-yl)methyl 4-methylbenzenesulfonate (1.267 g) as pale yellow needles.

[0145] Preparation Example 59: To a mixture of (2-methylquinolin-6-yl)methanamine (Enamine, 209 mg), dichloromethane (4 ml), and triethylamine (0.24 ml) was added methanesulfonic anhydride (240 mg) under ice-cooling, and the mixture was stirred at room temperature for 17 hours. Ethyl acetate was then added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give N-((2-methylquinolin-6-yl)methyl)methanesulfonamide (182 mg) as a pale yellow solid.

[0146] Production Example 60: To a mixture of N-((2-methylquinolin-6-yl)methyl)tetrahydro-2H-pyran-4-amine (Aurora Fine Chemicals, 116 mg), dichloromethane (2.3 ml), and triethylamine (0.0946 ml) was added methanesulfonyl chloride (0.042 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water, a saturated aqueous solution of sodium bicarbonate, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give N-((2-methylquinolin-6-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)methanesulfonamide (122 mg) as a colorless solid.

[0147] Preparation Example 61: To a mixture of (5-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)(morpholino)methanone (Preparation Example 44, 168 mg) and chloroform (5 ml), 70% mCPBA (169 mg) was added under ice-cooling and stirred at room temperature for 23 hours. The reaction mixture was purified by silica gel column chromatography (eluent: chloroform-methanol) to give 5-methyl-2-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridine 4-oxide (205 mg) as a pale brown foam.

[0148] PREPARATION EXAMPLE 62 Using (5-methylfuro[3,2-b]pyridin-2-yl)(morpholino)methanone (Preparation Example 20), dichloromethane, and 70% mCPBA, and following the procedure of Preparation Example 61, 5-methyl-2-(morpholine-4-carbonyl)furo[3,2-b]pyridine 4-oxide was obtained as a colorless solid.

[0149] Preparation Example 64: A mixture of 5-methyl-2-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridine 4-oxide (Preparation Example 61, 196 mg) and acetic anhydride (10 ml) was stirred at 120°C for 3 hours, and then the solvent was removed from the reaction mixture under a nitrogen stream. Ethanol (10 ml) and 1M aqueous sodium hydroxide solution (10 ml) were added to the resulting residue, and the mixture was stirred at room temperature for 5 hours. The solvent was then distilled off under reduced pressure. Toluene was added to the resulting residue, and the solvent was again distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (5-(hydroxymethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)(morpholino)methanone (43 mg) as a pale yellow solid.

[0150] Preparation Example 65: A mixture of 5-methyl-2-(morpholine-4-carbonyl)furo[3,2-b]pyridine 4-oxide (Preparation Example 62, 106 mg) and acetic anhydride (1 ml) was stirred at 110°C for 20 minutes, and then the solvent was removed from the reaction mixture under a nitrogen stream. Methanol (2 ml) and potassium carbonate (112 mg) were added to the resulting residue, and the mixture was stirred at room temperature for 30 minutes. Water was then added to the reaction mixture, and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (5-(hydroxymethyl)furo[3,2-b]pyridin-2-yl)(morpholino)methanone (65 mg) as a pale yellow solid.

[0151] Production Example 66: To a mixture of 6-(ethoxycarbonyl)-2-methylquinoline 1-oxide (Production Example 63, 563 mg) and dichloromethane (11.3 ml), phosphorus oxychloride (3.15 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 18 hours and then at 50°C for 1 hour and 30 minutes. The solvent from the reaction mixture was evaporated under reduced pressure, and then a saturated aqueous solution of sodium bicarbonate and a 2M aqueous solution of sodium hydroxide were added to the resulting residue, and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified sequentially by silica gel column chromatography (eluent: hexane-ethyl acetate, then chloroform-methanol) to give ethyl 4-chloro-2-methylquinoline-6-carboxylate (322 mg) as a pale brown solid.

[0152] Production Example 67: To a mixture of N-((2-methylquinolin-6-yl)methyl)tetrahydro-2H-pyran-4-amine (Aurora Fine Chemicals, 159 mg) and dichloromethane (5.6 ml), 37% formalin (0.69 ml) and sodium triacetoxyborohydride (1.315 g) were added in five equal portions, respectively, while stirring at room temperature for 3 days. A saturated aqueous sodium hydrogen carbonate solution and sodium hydrogen carbonate were added to the reaction mixture, and the product was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give N-methyl-N-((2-methylquinolin-6-yl)methyl)tetrahydro-2H-pyran-4-amine (140 mg) as a pale yellow solid.

[0153] Preparation Example 68: A mixture of 2-methylbenzo[d]thiazole-6-carbaldehyde (BLD Pharmatech, 201 mg), tetrahydro-2H-pyran-4-amine (Apollo Scientific, 0.129 ml), and toluene (6.8 ml) was stirred under reflux for 6 hours, and then the solvent of the reaction mixture was distilled off under reduced pressure. To a mixture of the obtained residue and methanol (4 ml), sodium borohydride (86 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 6 hours and 30 minutes. After that, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the product was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was then purified by silica gel column chromatography (eluent: chloroform-methanol) to give N-((2-methylbenzo[d]thiazol-6-yl)methyl)tetrahydro-2H-pyran-4-amine (270 mg) as a pale yellow oil.

[0154] Production Example 70: To a mixture of tert-butyl (1-(oxetan-3-yl)piperidin-4-yl)carbamate (WO2019210828, 100 mg) and dichloromethane (1 ml), TFA (1 ml) was added under ice-cooling, and the mixture was stirred at 0°C for 2 hours and 30 minutes. The solvent of the reaction mixture was then evaporated under reduced pressure. To the resulting residue, toluene was added, and the solvent was evaporated again under reduced pressure. To the resulting residue, 2-methylquinoline-6-carbaldehyde (Kanto Chemical, 67 mg), toluene (5 ml), and triethylamine (0.163 ml) were added, and the mixture was stirred under reflux for 6 hours. The solvent of the reaction mixture was evaporated under reduced pressure, and to a mixture of the resulting residue and methanol (2 ml), sodium borohydride (30 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was treated in a similar manner to Preparation 68 to give N-((2-methylquinolin-6-yl)methyl)-1-(oxetan-3-yl)piperidin-4-amine (46 mg) as a pale yellow oil.

[0155] Preparation Example 71 To a mixture of tert-butyl 4-(4-([1,1'-biphenyl]-2-yl)-2-methylquinoline-6-carbonyl)piperazine-1-carboxylate (Preparation Example 22, 936 mg) and dichloromethane (5 ml), TFA (2 ml) was added and the mixture was stirred at room temperature for 2 hours and 30 minutes, and then the solvent of the reaction mixture was evaporated under reduced pressure. To the resulting residue were successively added saturated aqueous sodium hydrogen carbonate solution, sodium hydrogen carbonate, and sodium chloride, and the product was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to give (4-([1,1'-biphenyl]-2-yl)-2-methylquinolin-6-yl)(piperazin-1-yl)methanone (884 mg) as a pale yellow foam.

[0156] Preparation Example 72: A mixture of (2-methylquinolin-6-yl)(piperazin-1-yl)methanone (Aurora Fine Chemicals, 484 mg), oxetan-3-one (Tokyo Chemical Industry, 0.146 ml), DCE (9.7 ml), and acetic acid (1.09 ml) was stirred at room temperature for 3 hours, and sodium triacetoxyborohydride (804 mg) was added under ice-cooling, followed by stirring at room temperature for 1 hour and 30 minutes. A saturated aqueous solution of sodium hydrogen carbonate and sodium hydrogen carbonate were added to the reaction mixture, and the product was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (2-methylquinolin-6-yl)(4-(oxetan-3-yl)piperazin-1-yl)methanone (277 mg) as a pale yellow solid.

[0157] PREPARATION EXAMPLE 73 2-methylquinoline-6-carbaldehyde (manufactured by Kanto Chemical), 1-(oxetan-3-yl)piperazine bis(2,2,2-trifluoroacetate) (manufactured by Enamine), triethylamine, DCE, acetic acid, and sodium triacetoxyborohydride were used to obtain 2-methyl-6-((4-(oxetan-3-yl)piperazin-1-yl)methyl)quinoline as a pale yellow solid in the same manner as in Preparation Example 72.

[0158] Preparation Example 74 A mixture of (4-([1,1'-biphenyl]-2-yl)-2-methylquinolin-6-yl)(piperazin-1-yl)methanone (Preparation Example 71, 161 mg), oxetan-3-one (Tokyo Chemical Industry Co., Ltd., 0.038 ml), dichloromethane (3.2 ml), and acetic acid (0.226 ml) was stirred at room temperature for 2 hours, and sodium triacetoxyborohydride (167 mg) was added under ice-cooling, followed by stirring at room temperature for 17 hours. A saturated aqueous solution of sodium hydrogen carbonate and sodium hydrogen carbonate were added to the reaction mixture, and the product was extracted with chloroform. The organic layer was then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane-chloroform) to give (4-([1,1'-biphenyl]-2-yl)-2-methylquinolin-6-yl)(4-(oxetan-3-yl)piperazin-1-yl)methanone (160 mg) as a pale yellow oil.

[0159] Preparation Example 75: A mixture of (2-methylquinolin-6-yl)methanamine (Enamine, 200 mg), 2,6-dimethyltetrahydro-4H-pyran-4-one (Combi-Blocks, 0.17 ml), DCE (4 ml), and acetic acid (0.665 ml) was stirred at room temperature for 6 hours, and sodium triacetoxyborohydride (492 mg) was added under ice-cooling, followed by stirring at room temperature for 19 hours. Aqueous sodium hydrogen carbonate solution and sodium hydrogen carbonate were added to the reaction mixture, and the product was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give the less polar (2SR,6SR)-2,6-dimethyl-N-((2-methylquinolin-6-yl)methyl)tetrahydro-2H-pyran-4-amine (121 mg) that had been eluted earlier as a pale yellow solid.

[0160] PREPARATION EXAMPLE 76 In the silica gel column chromatography used to obtain Preparation Example 75, highly polar (2SR,6RS)-2,6-dimethyl-N-((2-methylquinolin-6-yl)methyl)tetrahydro-2H-pyran-4-amine (123 mg) was eluted later and obtained as a pale yellow solid. The relative configuration of the methyl groups in Preparation Example 75 and Preparation Example 76 was determined by comparing the chemical shift values ​​of the two methine carbons in the pyran ring. That is, compared with Preparation Example 76 (53.5, 72.0 ppm), Preparation Example 75 (50.5, 67.7 ppm) was shifted upfield due to the gamma gauche effect of the methyl group. From the above, it was determined that Preparation Example 76 is a (2SR,6RS) isomer in which both methyl groups occupy the equatrile position, and Preparation Example 75 is a (2SR,6SR) isomer in which one methyl group occupies the axial position and the other occupies the equatrile position.

[0161] Production Example 77: A mixture of 6-bromo-2-methylquinoline (Combi-Blocks, 1 g), tert-butyl piperazine-1-carboxylate (Kanto Chemical, 1.01 g), toluene (20 ml), BINAP (280 mg), and sodium tert-butoxide (649 mg) was degassed by repeatedly reducing the pressure and replacing the atmosphere with nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (206 mg) was then added and the mixture was stirred at 110°C for 24 hours. Ethyl acetate was added to the reaction mixture, and the precipitated insoluble matter was removed by filtration. The solvent in the filtrate was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-ethyl acetate) to give tert-butyl 4-(2-methylquinolin-6-yl)piperazine-1-carboxylate (952 mg) as a brown solid.

[0162] Preparation Example 78: A mixture of tert-butyl 4-(2-methylquinolin-6-yl)piperazine-1-carboxylate (Preparation Example 77, 191 mg), 1,4-dioxane (2 ml), methanol (2 ml), and a 4 M solution of hydrogen chloride in 1,4-dioxane (4 ml) was stirred at room temperature for 4 hours, and the solvent of the reaction mixture was evaporated under reduced pressure. Toluene was then added to the resulting residue, and the solvent was again evaporated under reduced pressure. Using the obtained residue, oxetan-3-one (Tokyo Chemical Industry Co., Ltd., 0.066 ml), triethylamine (0.325 ml), DCE (3.9 ml), acetic acid (0.334 ml), and sodium triacetoxyborohydride (247 mg), 2-methyl-6-(4-(oxetan-3-yl)piperazin-1-yl)quinoline (99 mg) was obtained as a pale yellow solid, in the same manner as in Preparation Example 72.

[0163] Production Example 79: A mixture of 2-methylbenzo[d]thiazole-5-carbaldehyde (BLD Pharmatech, 117 mg), methanesulfonamide (75 mg), toluene (2.4 ml), and titanium(IV) ethoxide (0.152 ml) was stirred at 110°C for 6 hours. The solvent was evaporated from the reaction mixture under reduced pressure, and methanol (1.2 ml) and THF (1.2 ml) were added to the resulting residue. Sodium borohydride (50 mg) was then added under ice-cooling, and the mixture was stirred at room temperature for 1 hour and 30 minutes. The solvent was evaporated from the reaction mixture under reduced pressure, and saturated aqueous sodium bicarbonate and chloroform were added to the resulting residue. The precipitated insoluble matter was removed by filtration. The filtrate was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain N-((2-methylbenzo[d]thiazol-5-yl)methyl)methanesulfonamide (153 mg) as a pale yellow solid.

[0164] Production Example 81: A mixture of (2-methylquinolin-6-yl)(piperazin-1-yl)methanone (Aurora Fine Chemicals, 376 mg), ethanol (7.6 ml), potassium carbonate (305 mg), and 2-(methoxymethyl)oxirane (Tokyo Chemical Industry, 0.157 ml) was stirred at 80°C for 3 hours, and then 2-(methoxymethyl)oxirane (0.0655 ml) was added to the reaction mixture, followed by stirring at 80°C for 1 hour. The solvent from the reaction mixture was evaporated under reduced pressure, and toluene was added to the resulting residue, and the solvent was evaporated again under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (4-(2-hydroxy-3-methoxypropyl)piperazin-1-yl)(2-methylquinolin-6-yl)methanone (376 mg) as a pale yellow oil.

[0165] Preparation Example 83: A mixture of ethyl 4-chloro-2-methylquinoline-6-carboxylate (Preparation Example 66, 145 mg), DMF (6.1 ml), and sodium azide (189 mg) was stirred at 120°C for 6 hours under a nitrogen atmosphere, and then the solvent of the reaction mixture was distilled off under reduced pressure. Ice water was added to the resulting residue, and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane-chloroform) to give ethyl 4-amino-2-methylquinoline-6-carboxylate (48 mg) as a pale brown solid.

[0166] Preparation Example 84: A mixture of ethyl 4-chloro-2-methylquinoline-6-carboxylate (Preparation Example 66, 102 mg), DMF (4.3 ml), and sodium azide (133 mg) was stirred at 120°C for 1 hour and 30 minutes under a nitrogen atmosphere, and then ice water was added to the reaction mixture, followed by stirring at room temperature for 1 hour. The product was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, after which the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to yield ethyl 4-azido-2-methylquinoline-6-carboxylate (90 mg) as a pale brown solid.

[0167] Production Example 85: A mixture of 2-methylquinoline-6-carboxylic acid (Tokyo Chemical Industry Co., Ltd., 770 mg), DMF (6 ml), and 1,1'-carbonyldiimidazole (670 mg) was stirred at 40°C for 1 hour, and then tert-butanol (0.787 ml) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.62 ml) were added to the reaction mixture, followed by stirring at 80°C for 4 hours. Water was added to the reaction mixture, and the product was extracted with tert-butyl methyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform) to give tert-butyl 2-methylquinoline-6-carboxylate (733 mg) as a yellow solid.

[0168] Preparation Example 87: A mixture of ethyl 4-chloro-2-methylquinoline-6-carboxylate (Preparation Example 66, 137 mg), DMF (1.4 ml), zinc cyanide (129 mg), and triphenylphosphine (63 mg) was stirred under microwave irradiation at 160° C. for 30 minutes. The solvent was removed from the reaction mixture under a nitrogen stream, and the resulting residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give ethyl 4-cyano-2-methylquinoline-6-carboxylate (110 mg) as a pale brown solid.

[0169] Preparation Example 89: A mixture of 1-acetyl-2-(3-methoxy-4-(2-morpholino-2-oxoethoxy)benzylidene)indolin-3-one (Example 2, 129 mg), methanol (13 ml), and potassium carbonate (123 mg) was stirred at room temperature for 1 hour and 30 minutes. Chloroform and water were added to the reaction mixture, and the product was extracted with chloroform. The organic layer was then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give 2-(3-methoxy-4-(2-morpholino-2-oxoethoxy)benzylidene)indolin-3-one (125 mg) as an orange foam.

[0170] Preparation Example 90: A mixture of ethyl 4-azido-2-methylquinoline-6-carboxylate (Preparation Example 84, 36 mg), ethanol (1 ml), and 1 M aqueous sodium hydroxide solution (0.281 ml) was stirred at room temperature for 5 hours and 30 minutes. 1 M hydrochloric acid (0.281 ml) was added to the reaction mixture, and the solvent was evaporated under reduced pressure. Toluene was added to the resulting residue, and the solvent was evaporated again under reduced pressure to give crude 4-azido-2-methylquinoline-6-carboxylic acid as a pale brown solid.

[0171] Preparation Example 93: A mixture of ethyl 4-amino-2-methylquinoline-6-carboxylate (Preparation Example 83, 48 mg) and 6 M hydrochloric acid (2 ml) was stirred at 100° C. for 26 hours, and then the solvent was evaporated under reduced pressure from the reaction mixture. Toluene was added to the resulting residue, and the solvent was evaporated again under reduced pressure to give 4-amino-2-methylquinoline-6-carboxylic acid dihydrochloride (51 mg) as a pale brown solid.

[0172] Preparation Example 94: A mixture of ethyl 4-([1,1'-biphenyl]-2-yl)-2-methylquinoline-6-carboxylate (Preparation Example 106, 1.568 g), ethanol (16 ml), THF (8 ml), and 1M aqueous sodium hydroxide solution (5.2 ml) was stirred at room temperature for 3 hours, and then 1M aqueous sodium hydroxide solution (2.6 ml) was added and stirred at room temperature for 19 hours. Water was added to the reaction solution, and the ethanol and THF were evaporated under reduced pressure, followed by washing with chloroform. 1M hydrochloric acid (7.8 ml) was added to the resulting solution, and the mixture was stirred at room temperature for 22 hours. The resulting solid was collected by filtration and washed successively with water and hexane to give 4-([1,1'-biphenyl]-2-yl)-2-methylquinoline-6-carboxylic acid (1.317 g) as a pale brown powder.

[0173] Preparation Example 95: A mixture of (4-chloro-2-methylquinolin-6-yl)(morpholino)methanone (Preparation Example 34, 102 mg), phenylboronic acid (51 mg), butanol (2 ml), 1.2 M aqueous cesium carbonate solution (0.497 ml), and X-Phos (20 mg) was degassed by repeatedly reducing the pressure and replacing the atmosphere with nitrogen. Palladium acetate (8 mg) was then added and the mixture was stirred at room temperature for 1 hour. The solvent was removed from the reaction mixture under a nitrogen stream, and ethyl acetate was added to the resulting residue, which was then washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (2-methyl-4-phenylquinolin-6-yl)(morpholino)methanone (97 mg) as a pale yellow oil.

[0174] Preparation Example 96: A mixture of (4-chloro-2-methylquinolin-6-yl)(morpholino)methanone (Preparation Example 34, 81 mg), 3-pyridylboronic acid (41 mg), butanol (1.6 ml), 1.2 M aqueous cesium carbonate solution (0.395 ml), and X-Phos (16 mg) was degassed by repeatedly reducing the pressure and replacing the atmosphere with nitrogen. Palladium acetate (6 mg) was then added and the mixture was stirred at room temperature for 1 hour and then at 80°C for 3 hours. The solvent was removed from the reaction mixture under a nitrogen stream, and ethyl acetate was added to the resulting residue, which was then washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give the less polar (4-butoxy-2-methylquinolin-6-yl)(morpholino)methanone (37 mg) as a colorless oil.

[0175] Production Example 97 In the silica gel column chromatography used to obtain Production Example 96, highly polar (2-methyl-4-(pyridin-3-yl)quinolin-6-yl)(morpholino)methanone (36 mg) was eluted later as a colorless oil.

[0176] Preparation Example 98: A mixture of (4-chloro-2-methylquinolin-6-yl)(morpholino)methanone (Preparation Example 34, 65 mg), [1,1'-biphenyl]-2-ylboronic acid (53 mg), 1,2-dimethoxyethane (1.6 ml), 3 M aqueous sodium carbonate solution (0.224 ml), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (18 mg) was stirred under a nitrogen atmosphere at 90°C for 6 hours and then at room temperature for 5 days. The reaction mixture was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (4-([1,1'-biphenyl]-2-yl)-2-methylquinolin-6-yl)(morpholino)methanone (93 mg) as a pale brown oil.

[0177] Preparation Example 107: To a mixture of sodium borohydride (67 mg) and methanol (4 ml) was added a methanol solution (4 ml) of 4-chloro-6-(morpholine-4-carbonyl)quinoline-2-carbaldehyde (Preparation Example 153, 399 mg) under ice-cooling, and the mixture was stirred at 0°C for 30 minutes. Water was added to the reaction mixture, and the methanol was evaporated under reduced pressure. The product was then extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (4-chloro-2-(hydroxymethyl)quinolin-6-yl)(morpholino)methanone (227 mg) as a colorless solid.

[0178] Preparation Example 108: A mixture of (4-chloro-2-(hydroxymethyl)quinolin-6-yl)(morpholino)methanone (Preparation Example 107, 168 mg), DMF (1.7 ml), tert-butyldimethylchlorosilane (99 mg), and imidazole (93 mg) was stirred at room temperature for 4 hours and 30 minutes. The solvent was removed from the reaction mixture under a nitrogen stream, and the resulting residue was purified by silica gel column chromatography (eluent: hexane-chloroform-methanol) to give (2-(((tert-butyldimethylsilyl)oxy)methyl)-4-chloroquinolin-6-yl)(morpholino)methanone (205 mg) as a pale blue solid.

[0179] Preparation Example 109: A mixture of (4-chloro-2-methylquinolin-6-yl)(morpholino)methanone (Preparation Example 34, 151 mg), piperidine-4-carbonitrile (Enamine, 0.0927 ml), toluene (3 ml), BINAP (129 mg), cesium carbonate (254 mg), and palladium acetate (23 mg) was stirred under a nitrogen atmosphere at 100° C. for 18 hours. The reaction mixture was purified by silica gel column chromatography (eluent: chloroform-methanol) to give 1-(2-methyl-6-(morpholine-4-carbonyl)quinolin-4-yl)piperidine-4-carbonitrile (160 mg) as a pale brown solid.

[0180] PREPARATION EXAMPLE 111 A mixture of 1-(4-(2-(((tert-butyldimethylsilyl)oxy)methyl)-6-(morpholine-4-carbonyl)quinolin-4-yl)piperazin-1-yl)ethan-1-one (Preparation Example 110, 103 mg) and tetrabutylammonium fluoride (1 M THF solution, 0.5 ml) was stirred at room temperature for 30 minutes, and then the solvent of the reaction mixture was evaporated under reduced pressure. Water was added to the resulting residue, and the product was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give 1-(4-(2-(hydroxymethyl)-6-(morpholine-4-carbonyl)quinolin-4-yl)piperazin-1-yl)ethan-1-one (67 mg) as a pale yellow oil.

[0181] Preparation Example 112: A mixture of N-((2-methylquinolin-6-yl)methyl)tetrahydro-2H-pyran-4-amine (Aurora Fine Chemicals, 99 mg), dichloromethane (4 ml), and di-tert-butyl dicarbonate (146 mg) was stirred at room temperature for 3 hours, and then the solvent of the reaction mixture was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give tert-butyl ((2-methylquinolin-6-yl)methyl)(tetrahydro-2H-pyran-4-yl)carbamate (112 mg) as a pale yellow oil.

[0182] A mixture of (2-methylquinolin-6-yl)(morpholino)methanone (Preparation Example 19, 527 mg), 1,4-dioxane (10 ml), and selenium dioxide (251 mg) was stirred at 80° C. for 3 hours, and then insoluble matter in the reaction mixture was removed by filtration, and the solvent in the filtrate was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give 6-(morpholine-4-carbonyl)quinoline-2-carbaldehyde (434 mg) as a pale brown solid.

[0183] PREPARATION EXAMPLE 181 A mixture of N-(2-methyl-6-(morpholine-4-carbonyl)quinolin-4-yl)acetamide (Preparation Example 50, 52 mg), 1,4-dioxane (1 ml), and selenium dioxide (37 mg) was stirred at 80° C. for 4 hours, and then DMF (0.5 ml) was added to the reaction mixture, and the mixture was stirred at 80° C. for 2 hours. The solvent was removed from the reaction mixture under a nitrogen stream, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give N-(2-formyl-6-(morpholine-4-carbonyl)quinolin-4-yl)acetamide (27 mg) as a pale brown solid.

[0184] Preparation Example 182: A mixture of 2-methyl-6-(morpholine-4-carbonyl)quinoline-4-carboxamide (Preparation Example 32, 35 mg), 1,4-dioxane (1.4 ml), and selenium dioxide (30 mg) was stirred at 80° C. for 2 hours, and then insoluble matter in the reaction mixture was removed by filtration, and the solvent in the filtrate was evaporated under reduced pressure. The resulting residue was triturated in a mixed solvent of methanol and chloroform to give crude 2-formyl-6-(morpholine-4-carbonyl)quinoline-4-carboxamide as a pale brown solid.

[0185] Preparation Example 185: A mixture of (2-methylthiazol-4-yl)(morpholino)methanone (Aurora Fine Chemicals, 75 mg), 1,4-dioxane (1.5 ml), and selenium dioxide (40 mg) was stirred under microwave irradiation at 150°C for 20 minutes, and then selenium dioxide (118 mg) was added to the reaction mixture, and the mixture was stirred under microwave irradiation at 150°C for 8 hours. Insoluble matter in the reaction mixture was removed by filtration, and the solvent in the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give 4-(morpholine-4-carbonyl)thiazole-2-carbaldehyde (28 mg) as a pale yellow oil.

[0186] Preparation Example 188: A mixture of (6-(hydroxymethyl)naphthalen-2-yl)(morpholino)methanone (Preparation Example 36, 184 mg), chloroform (2.7 ml), and manganese dioxide (460 mg) was stirred at 60°C for 2 hours and 30 minutes, and then insoluble matter in the reaction mixture was removed by filtration, and the solvent in the filtrate was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane-chloroform-methanol) to give 6-(morpholine-4-carbonyl)-2-naphthalenaldehyde (164 mg) as a colorless solid.

[0187] PREPARATION EXAMPLE 190 Using (5-(hydroxymethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)(morpholino)methanone (Preparation Example 64), 2-propanol, and manganese dioxide, 2-(morpholine-4-carbonyl)-1H-pyrrolo[3,2-b]pyridine-5-carbaldehyde was obtained as a colorless solid in the same manner as in Preparation Example 188.

[0188] PREPARATION EXAMPLE 192 A mixture of (2-(hydroxymethyl)-1H-indol-5-yl)(morpholino)methanone (Preparation Example 40, 100 mg), dichloromethane (1 ml), and manganese dioxide (167 mg) was stirred at room temperature for 6 hours and 30 minutes, and the reaction mixture was purified by silica gel column chromatography (eluent: chloroform-methanol) to give 5-(morpholine-4-carbonyl)-1H-indole-2-carbaldehyde (73 mg) as a pale yellow solid.

[0189] PREPARATION EXAMPLE 194 A mixture of 6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)quinoline-2-carbaldehyde (Preparation Example 166, 287 mg), 1-acetylindolin-3-one (Combi-Blocks, 167 mg), toluene (5 ml), molecular sieves 4A (1 g), and piperidine (0.0188 ml) was stirred at 80°C for 3 hours, and the reaction mixture was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give (Z)-1-acetyl-2-((6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)quinolin-2-yl)methylene)indolin-3-one (227 mg) as a brown oil.

[0190] Preparation Example 199: A mixture of tert-butyl 2-formylquinoline-6-carboxylate (Preparation Example 164, 171 mg), 1-acetylindolin-3-one (Combi-Blocks, 140 mg), toluene (5 ml), molecular sieves 4A (1 g), and piperidine (0.0131 ml) was stirred at 80°C for 3 hours, and then the solvent of the reaction mixture was distilled off under reduced pressure. The resulting residue was purified sequentially by silica gel column chromatography (eluent: hexane-ethyl acetate) and gel permeation chromatography (eluent: chloroform) to give tert-butyl (Z)-2-((1-acetyl-3-oxoindolin-2-ylidene)methyl)quinoline-6-carboxylate (191 mg) as a pale brown oil.

[0191] Preparation Example 205 A mixture of tert-butyl ((2-formylbenzo[d]thiazol-5-yl)methyl) (tetrahydro-2H-pyran-4-yl)carbamate (Preparation Example 167, 120 mg), 1-acetylindolin-3-one (Combi-Blocks, 56 mg), toluene (3 ml), molecular sieves 4A (1 g), and piperidine (0.0063 ml) was stirred at 80°C for 3 hours, and the reaction mixture was purified by silica gel column chromatography (eluent: chloroform-methanol). The less polar fractions eluted earlier were collected, and the solvent was evaporated under reduced pressure. The resulting residue was then purified by gel permeation chromatography (eluent: chloroform) to give tert-butyl (Z)-((2-((1-acetyl-3-oxoindolin-2-ylidene)methyl)benzo[d]thiazol-5-yl)methyl)(tetrahydro-2H-pyran-4-yl)carbamate (22 mg) as a yellow oil.

[0192] PREPARATION EXAMPLE 206 In the silica gel column chromatography used to obtain Preparation Example 205, the later-eluted highly polar fractions were collected, and the solvent was distilled off under reduced pressure. The resulting residue was then purified by gel permeation chromatography (eluent: chloroform) to give tert-butyl (E)-((2-((1-acetyl-3-oxoindolin-2-ylidene)methyl)benzo[d]thiazol-5-yl)methyl)(tetrahydro-2H-pyran-4-yl)carbamate (23 mg) as a yellow solid.

[0193] Preparation Example 209: To a mixture of 4-([1,1'-biphenyl]-2-yl)-2-methylquinoline-6-carboxylic acid (Preparation Example 94, 100 mg), dichloromethane (2 ml), and DMF (0.0023 ml) was added oxalyl chloride (0.126 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours, and then the solvent of the reaction mixture was evaporated under reduced pressure. THF (10 ml) was added to the resulting residue, and the solvent was evaporated under reduced pressure. Then, THF (3 ml) and then 28% aqueous ammonia (0.1 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The solvent of the reaction mixture was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give 4-([1,1'-biphenyl]-2-yl)-2-methylquinoline-6-carboxamide (98 mg) as a colorless solid.

[0194] Preparation Example 211: A mixture of tert-butyl 6-(2-methyl-6-(morpholine-4-carbonyl)quinolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Preparation Example 337, 819 mg), dichloromethane (4 ml), and TFA (4 ml) was stirred at room temperature for 2 hours, and then saturated aqueous sodium hydrogen carbonate and sodium hydrogen carbonate were added to the reaction mixture, and the product was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give (2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)quinolin-6-yl)(morpholino)methanone (767 mg) as a pale brown foam.

[0195] Preparation Example 212: To a mixture of 4-([1,1'-biphenyl]-2-yl)-2-methyl-N-(tetrahydro-2H-pyran-4-yl)quinoline-6-carboxamide (Preparation Example 400, 128 mg) and THF (13 ml), lithium aluminum hydride (115 mg) was added under a nitrogen stream, and the mixture was stirred at 70°C for 30 minutes and then at room temperature for 17 hours. Sodium sulfate hydrate, THF, and ethyl acetate were added to the reaction mixture under ice-cooling, and then insoluble matter was removed by filtration, and the solvent in the filtrate was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give N-((4-([1,1'-biphenyl]-2-yl)-2-methylquinolin-6-yl)methyl)tetrahydro-2H-pyran-4-amine (69 mg) as a colorless oil.

[0196] Preparation Example 214: To a mixture of ethyl 4-(1H-indazol-4-yl)-2-methylquinoline-6-carboxylate (Preparation Example 338, 247 mg), ethanol (2.5 ml), and THF (1.3 ml), 1 M aqueous sodium hydroxide solution (1.34 ml) was added and stirred at room temperature for 17 hours. 1 M hydrochloric acid was added to the reaction mixture, and the solvent was evaporated under reduced pressure. Water (20 ml) was then added to the resulting residue, and the mixture was stirred at room temperature for 2 hours and 15 minutes. The resulting solid was collected by filtration and dried under reduced pressure to give 4-(1H-indazol-4-yl)-2-methylquinoline-6-carboxylic acid (183 mg) as a yellow solid.

[0197] Preparation Example 220: To a mixture of (4-(1H-indazol-4-yl)-2-methylquinolin-6-yl)(morpholino)methanone (Preparation Example 413, 184 mg) and THF (4 ml) was added 60% sodium hydride (39 mg) under ice-cooling, and the mixture was stirred for 1 hour and 30 minutes under ice-cooling. Trityl chloride (269 mg) was then added to the reaction mixture, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture, and the product was extracted successively with dichloromethane and chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (2-methyl-4-(N-tritylindazol-4-yl)quinolin-6-yl)(morpholino)methanone (52 mg) as a colorless solid.

[0198] PREPARATION EXAMPLE 223 Ethyl 3-chloro-2-methylquinoline-6-carboxylate, which was eluted earlier than Preparation Example 66 in silica gel column chromatography using hexane-ethyl acetate as an eluent during the synthesis of Preparation Example 66, was obtained as a colorless solid.

[0199] PREPARATION EXAMPLE 224: tert-Butyl 4-([1,1'-biphenyl]-3-yl)-2-methylquinoline-6-carboxylate (Preparation Example 432), 1,2-dimethoxyethane, and selenium dioxide were used to obtain tert-butyl 4-([1,1'-biphenyl]-3-yl)-2-formylquinoline-6-carboxylate (344.2 mg) as a pale orange solid in the same manner as in Preparation Example 119.

[0200] Preparation Example 237: A mixture of 4-(3-bromophenyl)-1-trityl-1H-pyrazole (Preparation Example 221, 1.687 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.17 g), 1,4-dioxane (17 ml), potassium acetate (605 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (252 mg) was stirred under a nitrogen atmosphere at room temperature for 5 hours and 30 minutes, and then at 80° C. for 16 hours. The solvent from the reaction mixture was evaporated under reduced pressure, and then toluene (20 ml) was added to the resulting residue, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-trityl-1H-pyrazole (1.618 g) as a pale yellow oil.

[0201] Preparation Example 238 A mixture of (4-chloro-2-methylquinolin-6-yl)(morpholino)methanone (Preparation Example 34, 209 mg), (1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)boronic acid (Apollo Scientific, 305 mg), 1,4-dioxane (24 ml), water (2.4 ml), cesium carbonate (703 mg), and tetrakis(triphenylphosphine)palladium(0) (42 mg) was stirred under a nitrogen atmosphere at 80° C. for 16 hours. The solvent from the reaction mixture was evaporated under reduced pressure, and then toluene (10 ml) was added to the resulting residue, and the solvent was evaporated under reduced pressure. Dichloromethane (2 ml) and TFA (2 ml) were added to the resulting residue, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Saturated aqueous sodium bicarbonate and sodium bicarbonate were then added to the reaction mixture, and the product was extracted successively with chloroform and chloroform-isopropanol (4:1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (2-methyl-4-(1H-pyrazol-4-yl)quinolin-6-yl)(morpholino)methanone (146 mg) as a pale yellow foam.

[0202] Preparation Example 239: A mixture of ethyl 4-chloro-2-methylquinoline-6-carboxylate (Preparation Example 66, 1.46 g), propionitrile (44 ml), and bromotrimethylsilane (1.52 ml) was stirred at 100°C for 6 hours and 30 minutes. The reaction mixture was poured into a mixture of 2 M aqueous sodium hydroxide solution (44 ml) and ice (110 ml). The product was extracted with diethyl ether, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane-chloroform) to give ethyl 4-bromo-2-methylquinoline-6-carboxylate (1.236 g) as a pale brown solid.

[0203] Preparation Example 240 A mixture of ethyl 4-bromo-2-methylquinoline-6-carboxylate (Preparation Example 239, 58 mg), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (65 mg), 1,4-dioxane (1.2 ml), potassium acetate (29 mg), tricyclohexylphosphine (11 mg), and tris(dibenzylideneacetone)dipalladium(0) (18 mg) was stirred under a nitrogen atmosphere at 90°C for 3 hours, and after the insoluble matter in the reaction mixture was removed by filtration, the solvent in the filtrate was evaporated under reduced pressure. To the obtained residue were added 5-bromopyrimidine (32 mg), 1,2-dimethoxyethane (1.2 ml), 3 M aqueous sodium carbonate solution (0.131 ml), and tetrakis(triphenylphosphine)palladium(0) (12 mg), and the mixture was stirred at 90°C under a nitrogen atmosphere for 3 hours. The reaction mixture was then purified by silica gel column chromatography (eluent: chloroform-methanol) to give ethyl 2-methyl-4-(pyrimidin-5-yl)quinoline-6-carboxylate (49 mg) as a pale brown solid.

[0204] Preparation Example 248: To a mixture of 4-([1,1'-biphenyl]-4-yl)-2-methyl-N-(tetrahydro-2H-pyran-4-yl)quinoline-6-carboxamide (Preparation Example 277, 1.24 g), dodecacarbonyltriruthenium 203.4 mg, and toluene (12 ml), 1,1,3,3-tetramethyldisiloxane (2.6 ml) was added, and the mixture was stirred at 55° C. for 8 hours under an argon atmosphere. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give N-((4-([1,1'-biphenyl]-4-yl)-2-methylquinolin-6-yl)methyl)tetrahydro-2H-pyran-4-amine (1.51 g) as a red-black oil.

[0205] Preparation Example 252 A mixture of tert-butyl 5-(2-methyl-6-(morpholine-4-carbonyl)quinolin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Preparation Example 358, 225 mg), 5% Pd / C PE type (water-containing, manufactured by N.E. Chemcat, 23 mg), and methanol (10 ml) was stirred under a hydrogen atmosphere of 0.3 MPa for 17 hours. Insoluble matter in the reaction mixture was removed by filtration, and the solvent in the filtrate was distilled off under reduced pressure. The resulting residue was purified by gel permeation chromatography (eluent: chloroform) to give tert-butyl 3-(2-methyl-6-(morpholine-4-carbonyl)quinolin-4-yl)piperidine-1-carboxylate (157 mg) as a brown oil.

[0206] Preparation Example 253 A mixture of tert-butyl 3-(2-methyl-6-(morpholine-4-carbonyl)quinolin-4-yl)piperidine-1-carboxylate (Preparation Example 252, 150 mg), dichloromethane (3 ml), and TFA (1 ml) was stirred at room temperature for 4 hours, and then the solvent of the reaction mixture was evaporated under reduced pressure. Dichloromethane (10 ml) was added to the resulting residue, and the pH was adjusted to 10 or higher with triethylamine. Then, acetic anhydride (70 mg) was added, and the mixture was stirred at room temperature for 2 hours. The solvent of the reaction mixture was evaporated under reduced pressure, and the resulting residue was purified sequentially by aminopropyl silica gel column chromatography (eluent: ethyl acetate) and gel permeation chromatography (eluent: chloroform) to give 1-(3-(2-methyl-6-(morpholine-4-carbonyl)quinolin-4-yl)piperidin-1-yl)ethan-1-one (73 mg) as a colorless solid.

[0207] Production Example 255: To a mixture of 3-bromo-1H-1,2,4-triazole (504 mg) and DMF (7.8 ml), 60% sodium hydride (164 mg) was added under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. After that, (2-(chloromethoxy)ethyl)trimethylsilane (0.741 ml) was added, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture, and the product was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give 3-bromo-N-((2-(trimethylsilyl)ethoxy)methyl)-1,2,4-triazole (821 mg) as a colorless oil.

[0208] PREPARATION EXAMPLE 256 2-Methyl-4-(1H-pyrazol-4-yl)quinoline Using (Preparation Example 360), THF, 60% sodium hydride, and (2-(chloromethoxy)ethyl)trimethylsilane, and following the procedure of Preparation Example 255, 2-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)quinoline was obtained as a pale brown oil.

[0209] Preparation Example 257: To a mixture of (5-hydroxy-2-methylquinolin-6-yl)(morpholino)methanone (Preparation Example 282, 102 mg), dichloromethane (4.1 ml), and pyridine (0.0543 ml), trifluoromethanesulfonic anhydride (0.0922 ml) was added under ice-cooling, and the mixture was stirred under ice-cooling for 3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the product was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give 2-methyl-6-(morpholin-4-carbonyl)quinolin-5-yl trifluoromethanesulfonate (129 mg) as a pale yellow solid.

[0210] Preparation Example 260: A mixture of 2-methyl-6-(morpholine-4-carbonyl)quinolin-5-yl trifluoromethanesulfonate (Preparation Example 257, 59 mg), naphthalen-1-ylboronic acid (38 mg), THF (1.2 ml), water (0.3 ml), sodium carbonate (46 mg), and tetrakis(triphenylphosphine)palladium(0) (17 mg) was stirred under a nitrogen atmosphere at 30° C. for 3 hours. The solvent was evaporated under reduced pressure from the reaction mixture, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (2-methyl-5-(naphthalen-1-yl)quinolin-6-yl)(morpholino)methanone (62 mg) as a pale brown oil.

[0211] Preparation Example 262 (4-chloro-2-methylquinolin-6-yl)(morpholino)methanone A mixture of (Preparation Example 34, 97 mg), 1-methyl-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (Angewandte Chemie, International Edition, 53(45), 12077-12080; 2014, 114 mg), 1,2-dimethoxyethane (1.9 ml), 3 M aqueous sodium carbonate solution (0.334 ml), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (27 mg) was stirred under a nitrogen atmosphere at 80°C for 7 hours. Chloroform was added to the reaction mixture, and the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified sequentially by silica gel column chromatography (eluent: chloroform-methanol) and gel permeation chromatography (eluent: chloroform) to give (2-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)quinolin-6-yl)(morpholino)methanone (54 mg) as a colorless oil.

[0212] Preparation Example 263: To a mixture of 2-methyl-3-(naphthalen-1-yl)quinoline-6-carboxamide (Preparation Example 210, 380 mg) and chloroform (20 ml), trifluoroacetic anhydride (0.422 ml) was added under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling and then at room temperature for 30 minutes. A saturated aqueous solution of sodium carbonate was added to the reaction mixture, and the product was extracted with ethyl acetate, after which the solvent in the organic layer was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give 2-methyl-3-(naphthalen-1-yl)quinoline-6-carbonitrile (299 mg) as a yellow solid.

[0213] Preparation Example 264: A mixture of 2-methyl-3-(naphthalen-1-yl)quinoline-6-carbonitrile (Preparation Example 263, 299 mg), trimethylsilyl azide (0.199 ml), and tetrabutylammonium fluoride hydrate (160 mg) was stirred at 85°C for 1 hour and 30 minutes. Trimethylsilyl azide (0.199 ml) and tetrabutylammonium fluoride (160 mg) were added to the reaction mixture, and the mixture was stirred at 85°C for 17 hours. 1M hydrochloric acid was then added to the reaction mixture, and the product was extracted with ethyl acetate. The solid precipitated from the organic layer was collected by filtration, suspended in 1M hydrochloric acid (30 ml), and stirred at room temperature for 30 minutes. The resulting solid was collected by filtration and dried under reduced pressure to give 2-methyl-3-(naphthalen-1-yl)-6-(1H-tetrazol-5-yl)quinoline (150 mg) as a yellow solid.

[0214] Preparation Example 265: To a mixture of 2-methyl-3-(naphthalen-1-yl)-6-(2H-tetrazol-5-yl)quinoline (Preparation Example 264, 150 mg), DMF (5 ml), and triethylamine (0.136 ml), 2-(chloromethoxy)ethyltrimethylsilane (0.086 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, and then the solvent in the organic layer was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give 2-methyl-3-(naphthalen-1-yl)-6-(N-((2-(trimethylsilyl)ethoxy)methyl)tetrazol-5-yl)quinoline (168 mg) as a yellow oil.

[0215] Production Example 266: 2-Picoline borane (94 mg) was added to a mixture of 2-methylquinoline-4-carbaldehyde (Combi-Blocks, 150 mg), morpholine (0.075 ml), methanol (4.55 ml), and acetic acid (0.45 ml), and the mixture was stirred at room temperature for 2 days. 1 M hydrochloric acid (5 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The pH of the reaction mixture was then adjusted to approximately 9 with a saturated aqueous solution of sodium carbonate. The product was extracted with ethyl acetate, and the solvent in the organic layer was evaporated under reduced pressure. The resulting residue was purified sequentially by silica gel column chromatography (eluent: hexane-ethyl acetate) and aminopropyl silica gel column chromatography (eluent: hexane-ethyl acetate) to give 4-((2-methylquinolin-4-yl)methyl)morpholine (171 mg) as a colorless oil.

[0216] Production Example 267: A mixture of 2-methylquinoline-4-carbaldehyde (Combi-Blocks, 150 mg), methyl 2-(2-aminoethoxy)acetate hydrochloride (BLD Pharmatech, 236 mg), sodium triacetoxyborohydride (394 mg), triethylamine (0.324 ml), and trifluoroethanol (10 ml) was stirred at room temperature for 4 days. The solvent was evaporated from the reaction mixture under reduced pressure, and then 1 M hydrochloric acid (5 ml) was added to the resulting residue, followed by stirring at room temperature for 30 minutes. A saturated aqueous solution of sodium carbonate was added to the reaction mixture, and the product was extracted with ethyl acetate. The organic layer was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol) and washed with diisopropyl ether to give 4-((2-methylquinolin-4-yl)methyl)morpholin-3-one (78 mg) as a colorless solid.

[0217] Preparation Example 269 tert-Butyl ((4-chloro-2-methylquinolin-6-yl)methyl (tetrahydro-2H-pyran-4-yl)carbamate (Preparation Example 420, 100 mg), 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Enamine, 116 mg), toluene (0.77 ml), tripotassium phosphate (109 mg), 2-dicyclohexylphosphino-2',6'-di A mixture of methoxybiphenyl (26 mg) and palladium(II) acetate (5.7 mg) was stirred under a nitrogen atmosphere at 100° C. for 3 hours. The reaction mixture was purified by silica gel column chromatography (eluent: chloroform-methanol) to give tert-butyl ((4-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methylquinolin-6-yl)methyl) (tetrahydro-2H-pyran-4-yl)carbamate (68 mg) as a slightly brown oil.

[0218] Preparation Example 440: To a mixture of ethyl 4-chloro-2-methylquinoline-6-carboxylate (Preparation Example 66, 349 mg) and THF (17.5 ml), diisobutylaluminum hydride (1 M toluene solution, 8.4 ml) was added dropwise while maintaining the internal temperature below -65°C, and the mixture was stirred at -78°C for 2 hours. The reaction mixture was poured into ice water (100 ml), and the product was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (4-chloro-2-methylquinolin-6-yl)methanol (217 mg) as a pale yellow solid.

[0219] In Production Examples 11 to 13, 15, 17, 19 to 29, 32, 35 to 44, 46, 49, 52, 53, 55, 63, 69, 80, 82, 86, 88, 91, 92, 99 to 106, 110, 113 to 118, 120 to 180, 183, 184, 186, 187, 189, 191, 193, 195 to 198, 200 to 204, 207, 208, 210, 213, 215 to 219, 221, 222, 225 to 236, 241 to 247, 249 to 251, 254, 258, 259, 261, 268, 270 to 439, and 441, compounds were synthesized by the above-mentioned methods or methods similar thereto. The compound names, structural formulas, examples of synthesis methods, raw material compounds, and physical property data (H NMR chemical shift values, MS molecular ion peaks) of the compounds of the production examples are shown in the following table. The solvent used for H NMR measurements was deuterated chloroform unless otherwise specified.

[0220]

[0221] Example 1 A mixture of 2-(4-formyl-2-methoxyphenoxy)acetamide (European Journal of Medicinal Chemistry, 81, 1-14; 2014, 1.80 g), 1-acetylindolin-3-one (Combi-Blocks, 1.51 g), toluene (50 ml), molecular sieves 4A (10 g), and piperidine (0.17 ml) was stirred at 110°C for 17 hours and then at room temperature for 2 hours. The reaction mixture was filtered, and the resulting solid was washed with toluene, then suspended in chloroform (300 ml), and stirred at 50°C for 1 hour. Insoluble matter in the mixture was removed by filtration, and the solvent in the filtrate was evaporated under reduced pressure. Ethyl acetate was then added to the resulting residue, and the solvent was evaporated again. The obtained residue was triturated with ethyl acetate and hexane, and the obtained solid was washed with ethyl acetate to give (Z)-2-(4-((1-acetyl-3-oxoindolin-2-ylidene)methyl)-2-methoxyphenoxy)acetamide (2.526 g) as a yellow solid.

[0222] Example 2 A mixture of 3-methoxy-4-(2-morpholino-2-oxoethoxy)benzaldehyde (Enamine, 95 mg), 1-acetylindolin-3-one (Combi-Blocks, 60 mg), toluene (3 ml), molecular sieves 4A (1 g), and piperidine (1 drop) was stirred under reflux for 16 hours, and the reaction mixture was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (Z)-1-acetyl-2-(3-methoxy-4-(2-morpholino-2-oxoethoxy)benzylidene)indolin-3-one (50 mg) as a yellow oil.

[0223] Example 47 A mixture of 5-(morpholine-4-carbonyl)benzo[d]thiazole-2-carbaldehyde (Preparation Example 131, 55 mg), 1-acetylindolin-3-one (Combi-Blocks, 35 mg), toluene (3 ml), molecular sieves 4A (1 g), and piperidine (0.0039 ml) was stirred at 80° C. for 3 hours. The reaction mixture was purified by silica gel column chromatography (eluent: chloroform-methanol) to give the less polar (Z)-1-acetyl-2-((5-(morpholine-4-carbonyl)benzo[d]thiazol-2-yl)methylene)indolin-3-one (25 mg) as a brown oil.

[0224] Example 48 In the silica gel column chromatography used to obtain Example 47, highly polar (E)-1-acetyl-2-((5-(morpholine-4-carbonyl)benzo[d]thiazol-2-yl)methylene)indolin-3-one (15 mg) was eluted later as a yellow solid.

[0225] Example 49 Using 2-(4-formyl-2-methoxyphenoxy)acetamide (European Journal of Medicinal Chemistry, 81, 1-14; 2014), 1-benzoylindolin-3-one (Heterocycles, 92(6), 1063-1074, 2016), toluene, molecular sieves 4A, and piperidine, 2-(4-((1-benzoyl-3-oxoindolin-2-ylidene)methyl)-2-methoxyphenoxy)acetamide was obtained as a yellow oil in the same manner as in Example 2.

[0226] Example 50 Using 3-methoxy-4-(2-morpholino-2-oxoethoxy)benzaldehyde (manufactured by Enamine), 1-acetyl-5-fluoroindolin-3-one (manufactured by Aurora Fine Chemicals), toluene, molecular sieves 4A, and piperidine, 1-acetyl-5-fluoro-2-(3-methoxy-4-(2-morpholino-2-oxoethoxy)benzylidene)indolin-3-one was obtained as a yellow oil in the same manner as in Example 2.

[0227] Example 51 Using 3-methoxy-4-(2-morpholino-2-oxoethoxy)benzaldehyde (manufactured by Enamine), 1-acetyl-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-one (manufactured by Aurora Fine Chemicals), toluene, molecular sieves 4A, and piperidine, 1-acetyl-2-(3-methoxy-4-(2-morpholino-2-oxoethoxy)benzylidene)-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-one was obtained as a pale brown oil in the same manner as in Example 2.

[0228] Example 52 Using (E)-2-(4-formyl-2-methoxyphenyl)ethene-1-sulfonamide (Preparation Example 5), 1-acetylindolin-3-one (Combi-Blocks), toluene, DMF, molecular sieves 4A, and piperidine, (1E)-2-(4-((1-acetyl-3-oxoindolin-2-ylidene)methyl)-2-methoxyphenyl)ethene-1-sulfonamide was obtained as a yellow oil in the same manner as in Example 2.

[0229] Example 53 A mixture of N-((2-formylbenzo[d]thiazol-5-yl)methyl)methanesulfonamide (Preparation Example 141, 61 mg), 1-acetylindolin-3-one (Combi-Blocks, 40 mg), toluene (3 ml), molecular sieves 4A (1 g), and piperidine (0.0045 ml) was stirred at 80° C. for 4 hours. The reaction mixture was purified by silica gel column chromatography (eluent: chloroform-methanol) and then crystallized from chloroform to give (E)-N-((2-((1-acetyl-3-oxoindolin-2-ylidene)methyl)benzo[d]thiazol-5-yl)methyl)methanesulfonamide (40.9 mg) as a yellow solid.

[0230] Example 56 Using N-((2-formylbenzo[d]thiazol-6-yl)methyl)methanesulfonamide (Preparation Example 145), 1-acetylindolin-3-one (Combi-Blocks), toluene, THF, molecular sieves 4A, and piperidine, (E)-N-((2-((1-acetyl-3-oxoindolin-2-ylidene)methyl)benzo[d]thiazol-6-yl)methyl)methanesulfonamide was obtained as a yellow solid in the same manner as in Example 53.

[0231] Example 57 A mixture of 2-(4-formyl-2-methoxyphenoxy)acetic acid (Enamine, 68 mg), 1-acetylindolin-3-one (Combi-Blocks, 57 mg), toluene (3 ml), molecular sieves 4A (1 g), and piperidine (1 drop) was stirred under reflux for 24 hours. The reaction mixture was purified sequentially by silica gel column chromatography (eluent: chloroform-methanol-acetic acid) and preparative silica gel thin-layer plate (developing solvent: chloroform-methanol) to give 2-(4-((1-acetyl-3-oxoindolin-2-ylidene)methyl)-2-methoxyphenoxy)acetic acid (32 mg) as a yellow solid.

[0232] Example 58 A mixture of 6-(morpholine-4-carbonyl)benzo[d]thiazole-2-carbaldehyde (Preparation Example 126, 572 mg), 1-acetylindolin-3-one (Combi-Blocks, 363 mg), toluene (20 ml), molecular sieve 4A (1 g), and piperidine (0.0409 ml) was stirred at 80°C for 40 minutes, and the reaction mixture was filtered. The obtained filtrate was used in Example 59. Chloroform and methanol were added to the obtained solid, and the molecular sieve 4A was removed by filtration. The solvent in the filtrate was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (E)-1-acetyl-2-((6-(morpholine-4-carbonyl)benzo[d]thiazol-2-yl)methylene)indolin-3-one (506 mg) as a yellow solid.

[0233] Example 59 The filtrate obtained by filtering the reaction mixture of Example 58 was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (Z)-1-acetyl-2-((6-(morpholine-4-carbonyl)benzo[d]thiazol-2-yl)methylene)indolin-3-one (27 mg) as a brown oil.

[0234] Example 60 A mixture of 6-(1,1-dioxidothiomorpholine-4-carbonyl)quinoline-2-carbaldehyde (Preparation Example 132, 42 mg), 1-acetylindolin-3-one (Combi-Blocks, 21 mg), toluene (3 ml), molecular sieves 4A (1 g), and piperidine (0.0118 ml) was stirred at 80° C. for 1 hour and 45 minutes, and the reaction mixture was purified sequentially by silica gel column chromatography (eluent: chloroform-methanol) and gel permeation chromatography (eluent: chloroform) to give (Z)-1-acetyl-2-((6-(1,1-dioxidothiomorpholine-4-carbonyl)quinolin-2-yl)methylene)indolin-3-one (28 mg) as a brown oil.

[0235] Example 98 A mixture of 5-(2,6-dimethylmorpholine-4-carbonyl)benzo[d]thiazole-2-carbaldehyde (Preparation Example 142, 245 mg), 1-acetylindolin-3-one (Combi-Blocks, 141 mg), toluene (5 ml), molecular sieves 4A (1.5 g), and piperidine (0.0159 ml) was stirred at 80° C. for 1 hour and 30 minutes, and the reaction mixture was purified by silica gel column chromatography (eluent: chloroform-methanol). The less polar fractions eluted earlier were collected, and the solvent was distilled off under reduced pressure. The resulting residue was purified by gel permeation chromatography (eluent: chloroform) to give (Z)-1-acetyl-2-((5-(2,6-dimethylmorpholine-4-carbonyl)benzo[d]thiazol-2-yl)methylene)indolin-3-one (37 mg) as a brown oil.

[0236] Example 99 In the silica gel column chromatography used to obtain Example 98, the later-eluted highly polar fractions were collected, and the solvent was distilled off under reduced pressure. The resulting residue was purified by gel permeation chromatography (eluent: chloroform) to give (E)-1-acetyl-2-((5-(2,6-dimethylmorpholine-4-carbonyl)benzo[d]thiazol-2-yl)methylene)indolin-3-one (86 mg) as a brown oil.

[0237] Example 102 Using 5-(2-morpholino-2-oxoethoxy)picolinaldehyde (manufactured by Aurora Fine Chemicals), 1-acetyl-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-one (manufactured by Aurora Fine Chemicals), toluene, molecular sieves 4A, and piperidine, 1-acetyl-2-((5-(2-morpholino-2-oxoethoxy)pyridin-2-yl)methylene)-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-one was obtained as a yellow oil in the same manner as in Example 60.

[0238] Example 103 Using 3-methoxy-4-(2-morpholino-2-oxoethoxy)benzaldehyde (manufactured by Enamine), 1-acetyl-6-fluoroindolin-3-one (manufactured by Aurora Fine Chemicals), toluene, molecular sieves 4A, and piperidine, 1-acetyl-6-fluoro-2-(3-methoxy-4-(2-morpholino-2-oxoethoxy)benzylidene)indolin-3-one was obtained as a yellow oil in the same manner as in Example 60.

[0239] Example 104 Using 3-methoxy-4-(2-morpholino-2-oxoethoxy)benzaldehyde (manufactured by Enamine), 1-acetyl-4-fluoroindolin-3-one (manufactured by Aurora Fine Chemicals), toluene, molecular sieves 4A, and piperidine, 1-acetyl-4-fluoro-2-(3-methoxy-4-(2-morpholino-2-oxoethoxy)benzylidene)indolin-3-one was obtained as a yellow oil in the same manner as in Example 60.

[0240] Example 105 Using 3-methoxy-4-(2-morpholino-2-oxoethoxy)benzaldehyde (manufactured by Enamine), 1-acetyl-7-fluoroindolin-3-one (manufactured by Aurora Fine Chemicals), toluene, molecular sieves 4A, and piperidine, 1-acetyl-7-fluoro-2-(3-methoxy-4-(2-morpholino-2-oxoethoxy)benzylidene)indolin-3-one was obtained as a yellow oil in the same manner as in Example 60.

[0241] Example 106 Using 6-(morpholine-4-carbonyl)quinoline-2-carbaldehyde (Preparation Example 119), N-((1-acetyl-3-oxoindolin-4-yl)methyl)acetamide (Preparation Example 2), toluene, molecular sieves 4A, and piperidine, (Z)—N-((1-acetyl-2-((6-(morpholine-4-carbonyl)quinolin-2-yl)methylene)-3-oxoindolin-4-yl)methyl)acetamide was obtained as a yellow oil in the same manner as in Example 60.

[0242] Example 107 Using 6-((1,1-dioxidethiomorpholino)methyl)quinoline-2-carbaldehyde (Preparation Example 133), 1-acetylindolin-3-one (Combi-Blocks), toluene, THF, molecular sieves 4A, and piperidine, (Z)-1-acetyl-2-((6-((1,1-dioxidethiomorpholino)methyl)quinolin-2-yl)methylene)indolin-3-one was obtained as a brown oil in the same manner as in Example 60.

[0243] Example 108 Using (E)-6-(3-morpholino-3-oxoprop-1-en-1-yl)benzo[d]thiazole-2-carbaldehyde (Preparation Example 148), 1-acetylindolin-3-one (Combi-Blocks), toluene, DMF, molecular sieves 4A, and piperidine, (E)-1-acetyl-2-((6-((E)-3-morpholino-3-oxoprop-1-en-1-yl)benzo[d]thiazol-2-yl)methylene)indolin-3-one was obtained as a yellow solid in the same manner as in Example 60.

[0244] Example 109 A mixture of (E)-5-(3-morpholino-3-oxoprop-1-en-1-yl)benzo[d]thiazole-2-carbaldehyde (Preparation Example 139, 79 mg), 1-acetylindolin-3-one (Combi-Blocks, 47 mg), toluene (6 ml), DMF (1 ml), molecular sieves 4A (1 g), and piperidine (0.0258 ml) was stirred at 80°C for 3 hours and 30 minutes, and the reaction mixture was purified by silica gel column chromatography (eluent: hexane-chloroform-methanol). The less polar fractions eluted earlier were collected, and the solvent was distilled off under reduced pressure. The resulting residue was purified by gel permeation chromatography (eluent: chloroform) to give (Z)-1-acetyl-2-((5-((E)-3-morpholino-3-oxoprop-1-en-1-yl)benzo[d]thiazol-2-yl)methylene)indolin-3-one (25 mg) as a brown oil.

[0245] Example 110 In the silica gel column chromatography used to obtain Example 109, the later-eluted highly polar fractions were collected, and the solvent was distilled off under reduced pressure. The resulting residue was then purified by gel permeation chromatography (eluent: chloroform) to give (E)-1-acetyl-2-((5-((E)-3-morpholino-3-oxoprop-1-en-1-yl)benzo[d]thiazol-2-yl)methylene)indolin-3-one (24 mg) as a brown oil.

[0246] Example 111 Using 2-formyl-6-(morpholine-4-carbonyl)quinoline-4-carboxamide (Preparation Example 182), 1-acetylindolin-3-one (Combi-Blocks), DMF, molecular sieves 4A, and piperidine, (Z)-2-((1-acetyl-3-oxoindolin-2-ylidene)methyl)-6-(morpholine-4-carbonyl)quinoline-4-carboxamide was obtained as a brown solid in the same manner as in Example 60.

[0247] Example 114 A mixture of 6-(4-phenylpiperidine-1-carbonyl)quinoline-2-carbaldehyde (Preparation Example 128, 104 mg), 1-acetylindolin-3-one (Combi-Blocks, 47 mg), toluene (3 ml), molecular sieves 4A (1 g), and piperidine (0.0052 ml) was stirred at 80° C. for 3 hours, and the reaction mixture was purified sequentially by silica gel column chromatography (eluent: hexane-chloroform), gel permeation chromatography (eluent: chloroform), and a preparative silica gel thin-layer plate (developing solvent: chloroform-methanol) to give (Z)-1-acetyl-2-((6-(4-phenylpiperidine-1-carbonyl)quinolin-2-yl)methylene)indolin-3-one (19 mg) as a yellow oil.

[0248] Example 115 A mixture of 6-(4-morpholinopiperidine-1-carbonyl)quinoline-2-carbaldehyde (Preparation Example 129, 95 mg), 1-acetylindolin-3-one (Combi-Blocks, 48 ​​mg), toluene (3 ml), molecular sieves 4A (1 g), and piperidine (0.0053 ml) was stirred at 80° C. for 3 hours, and the reaction mixture was purified sequentially by silica gel column chromatography (eluent: chloroform-methanol), gel permeation chromatography (eluent: chloroform), and silica gel column chromatography (eluent: chloroform-methanol) to give (Z)-1-acetyl-2-((6-(4-morpholinopiperidine-1-carbonyl)quinolin-2-yl)methylene)indolin-3-one (62 mg) as a brown oil.

[0249] Example 117 A mixture of (2-methyl-[4,4'-biquinolin]-6-yl)(morpholino)methanone (Preparation Example 102, 19 mg), 1,4-dioxane (0.76 ml), and selenium dioxide (11 mg) was stirred at 80°C for 2 hours, and then the insoluble matter in the reaction mixture was removed by filtration, and the solvent in the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol), and then using the resulting crude 6-(morpholine-4-carbonyl)-[4,4'-biquinoline]-2-carbaldehyde, 1-acetylindolin-3-one (manufactured by Combi-Blocks), toluene, molecular sieves 4A, and piperidine, (E)-1-acetyl-2-((6-(morpholine-4-carbonyl)-[4,4'-biquinoline]-2-yl)methylene)indolin-3-one as a brown solid was obtained in the same manner as in Example 60.

[0250] Example 119 A mixture of (2-methylquinolin-6-yl)(piperazin-1-yl)methanone (Aurora Fine Chemicals, 206 mg), (3-methoxyoxetan-3-yl)methyl 4-methylbenzenesulfonate (Preparation Example 58, 222 mg), acetonitrile (4 ml), and potassium carbonate (141 mg) was stirred at 80°C for 24 hours, and the solvent of the reaction mixture was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol). Fractions containing (4-((3-methoxyoxetan-3-yl)methyl)piperazin-1-yl)(2-methylquinolin-6-yl)methanone were collected, and the solvent was then distilled off under reduced pressure. A mixture of the obtained residue, selenium dioxide (74 mg), and 1,4-dioxane (2.4 ml) was stirred at 80°C for 3 hours and 30 minutes, insoluble matter was removed by filtration, and the solvent in the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol), and fractions containing 6-(4-((3-methoxyoxetan-3-yl)methyl)piperazine-1-carbonyl)quinoline-2-carbaldehyde were collected, and the solvent was evaporated under reduced pressure. A mixture of the obtained residue and 1-acetylindolin-3-one (Combi-Blocks, 37 mg), toluene (3 ml), molecular sieves 4A (1 g), and piperidine (0.0041 ml) was stirred at 80°C for 1 hour and 30 minutes, and the reaction mixture was purified sequentially by silica gel column chromatography (eluent: chloroform-methanol) and gel permeation chromatography (eluent: chloroform) to give (Z)-1-acetyl-2-((6-(4-((3-methoxyoxetan-3-yl)methyl)piperazine-1-carbonyl)quinolin-2-yl)methylene)indolin-3-one (37 mg) as a brown oil.

[0251] Example 120 In the gel permeation chromatography used to obtain Example 119, the high molecular weight fractions that eluted first were collected, and the solvent was distilled off under reduced pressure to give (3-methoxyoxetan-3-yl)methyl (Z)-4-(2-((1-acetyl-3-oxoindolin-2-ylidene)methyl)quinoline-6-carbonyl)piperazine-1-carboxylate (15 mg) as a brown oil.

[0252] Example 122 A mixture of 2-(3-methoxy-4-(2-morpholino-2-oxoethoxy)benzylidene)indolin-3-one (Preparation Example 89, 30 mg), DMF (0.3 ml), 60% sodium hydride (6 mg), and methyl iodide (0.0095 ml) was stirred at room temperature for 1 hour. The solvent was removed from the reaction mixture under a nitrogen stream, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give 2-(3-methoxy-4-(2-morpholino-2-oxoethoxy)benzylidene)-1-methylindolin-3-one (7 mg) as a red oil.

[0253] Example 123 A mixture of 2-(3-methoxy-4-(2-morpholino-2-oxoethoxy)benzylidene)indolin-3-one (Preparation Example 89, 30.1 mg), DMF (0.3 ml), and 60% sodium hydride (6.1 mg) was stirred at room temperature for 30 minutes, and then diethyl dicarbonate (0.0169 ml) was added under ice cooling, and the mixture was stirred at room temperature for 16 hours. The solvent was removed from the reaction mixture under a nitrogen stream, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give ethyl 2-(3-methoxy-4-(2-morpholino-2-oxoethoxy)benzylidene)-3-oxoindoline-1-carboxylate (9 mg) as a yellow oil.

[0254] Example 124 A mixture of 2-(3-methoxy-4-(2-morpholino-2-oxoethoxy)benzylidene)indolin-3-one (Preparation Example 89, 35 mg), DMF (0.35 ml), and 60% sodium hydride (7.1 mg) was stirred at room temperature for 40 minutes, and then methanesulfonic anhydride (23 mg) was added under ice cooling and stirred at room temperature for 17 hours. The solvent was removed from the reaction mixture under a nitrogen stream, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give 2-(3-methoxy-4-(2-morpholino-2-oxoethoxy)benzylidene)-1-(methylsulfonyl)indolin-3-one (9 mg) as a yellow oil.

[0255] Example 125 A mixture of 1-acetyl-2-(3-methoxy-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzylidene)indolin-3-one (Preparation Example 195, 123 mg), THF (0.984 ml), water (0.492 ml), and acetic acid (1.968 ml) was stirred at 45° C. for 1 hour and 40 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated brine. The organic layer was then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give 1-acetyl-2-(4-(2-hydroxyethoxy)-3-methoxybenzylidene)indolin-3-one (75 mg) as a brown oil.

[0256] Example 126 A mixture of (Z)-1-acetyl-2-((6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)quinolin-2-yl)methylene)indolin-3-one (Preparation Example 194, 227 mg), THF (1.8 ml), water (0.9 ml), and acetic acid (3.6 ml) was stirred at 45° C. for 19 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified sequentially by silica gel column chromatography (eluent: chloroform-methanol) and gel permeation chromatography (eluent: chloroform) to give (Z)-1-acetyl-2-((6-(2-hydroxyethoxy)quinolin-2-yl)methylene)indolin-3-one (36 mg) as a brown oil.

[0257] Example 127: To a mixture of tert-butyl (Z)-2-((1-acetyl-3-oxoindolin-2-ylidene)methyl)quinoline-6-carboxylate (Preparation Example 199, 46 mg) and dichloromethane (1 ml), TFA (1 ml) was added under ice-cooling, and the mixture was stirred at 0°C for 2 hours and 30 minutes. Dichloromethane was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (Z)-2-((1-acetyl-3-oxoindolin-2-ylidene)methyl)quinoline-6-carboxylic acid (17 mg) as a brown solid.

[0258] Example 129 To a mixture of tert-butyl (Z)-1-(2-((1-acetyl-3-oxoindolin-2-ylidene)methyl)quinoline-6-carbonyl)piperidine-4-carboxylate (Preparation Example 200, 51 mg), dichloromethane (1 ml), and thioanisole (0.0227 ml), TFA (1 ml) was added under ice-cooling and the mixture was stirred at 0°C for 4 hours. Toluene was then added to the reaction mixture, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (Z)-1-(2-((1-acetyl-3-oxoindolin-2-ylidene)methyl)quinoline-6-carbonyl)piperidine-4-carboxylic acid (42 mg) as a brown oil.

[0259] Example 130 To a mixture of tert-butyl (E)-((2-((1-acetyl-3-oxoindolin-2-ylidene)methyl)benzo[d]thiazol-5-yl)methyl)(tetrahydro-2H-pyran-4-yl)carbamate (Preparation Example 206, 23 mg) and dichloromethane (0.46 ml), TFA (0.46 ml) was added under ice-cooling, and the mixture was stirred at 0° C. for 40 minutes. A saturated aqueous solution of sodium hydrogen carbonate and sodium hydrogen carbonate were added to the reaction mixture, and the product was extracted with chloroform. The organic layer was then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give (E)-1-acetyl-2-((5-(((tetrahydro-2H-pyran-4-yl)amino)methyl)benzo[d]thiazol-2-yl)methylene)indolin-3-one (16 mg) as a light brown solid.

[0260] Example 138 To a mixture of tert-butyl (Z)-((2-((1-acetyl-3-oxoindolin-2-ylidene)methyl)quinolin-6-yl)methyl)(1-(oxetan-3-yl)piperidin-4-yl)carbamate (Preparation Example 203, 17 mg) and dichloromethane (0.34 ml), TFA (0.34 ml) was added under ice-cooling, and the mixture was stirred at 0° C. for 2 hours. A saturated aqueous solution of sodium hydrogen carbonate and sodium hydrogen carbonate were added to the reaction mixture, and the product was extracted with chloroform. The organic layer was then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by gel permeation chromatography (eluent: chloroform) to give (Z)-1-acetyl-2-((6-(((1-(oxetan-3-yl)piperidin-4-yl)amino)methyl)quinolin-2-yl)methylene)indolin-3-one (12 mg) as a yellow oil.

[0261] Example 139 A mixture of tert-butyl (Z)-4-(2-((1-acetyl-3-oxoindolin-2-ylidene)methyl)quinoline-6-carbonyl)piperazine-1-carboxylate (Preparation Example 202, 100 mg), 1,4-dioxane (1 ml), and 4 M hydrogen chloride in 1,4-dioxane (1 ml) was stirred at room temperature for 1 hour and 30 minutes, and the solvent of the reaction mixture was evaporated under reduced pressure. To the obtained residue was added ethyl acetate, and the mixture was stirred at room temperature for 40 minutes. The resulting solid was collected by filtration to give 1-acetyl-2-((6-(piperazine-1-carbonyl)quinolin-2-yl)methylene)indolin-3-one dihydrochloride (76 mg) as a brown solid.

[0262] Example 177 A mixture of 4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carbaldehyde (Preparation Example 302, 178 mg), 1-acetylindolin-3-one (Combi-Blocks, 132 mg), toluene (5 ml), molecular sieves 4A (2 g), and piperidine (0.0074 ml) was stirred at 80° C. for 2 hours. The reaction mixture was purified sequentially by silica gel chromatography (eluent: dichloromethane-methanol) and gel permeation chromatography (eluent: chloroform) and then washed with a mixed solvent of diisopropyl ether and chloroform (10:1) to give (Z)-1-acetyl-2-((4-(1-methyl-1H-pyrazol-4-yl)quinolin-2-yl)methylene)indolin-3-one (77 mg) as a yellow solid.

[0263] In Examples 3 to 46, 54, 55, 61 to 97, 100, 101, 112, 113, 116, 118, 128, 131 to 137, 140 to 149, 152, 153, 155 to 159, 162 to 164, 167 to 176, and 178 to 214, compounds were synthesized by the above-mentioned methods or methods similar thereto. The compound names, structural formulas, double bond configurations, synthetic method examples, raw material compounds, and physical property data (H NMR chemical shift values, MS molecular ion peaks) of the example compounds are shown in the table below. The solvent used for H NMR measurements was deuterated chloroform unless otherwise specified.

[0264]

[0265] Where the following synthesis literature is mentioned in the text and tables, the compounds were synthesized according to the literature description. Synthesis Reference 1 Wozniak et al., Organic Letters, 22(13), 4970-4973; 2020 Synthesis Reference 2 Holton et al., Tetrahedron Letters, 18(6), 533-534, 1977 Synthesis Reference 3 Brodney et al., WO2011125006 Synthesis Reference 4 Li et al., Organic Letters, 14(21), 5420-5423; 2012 Synthesis Reference 5 Kim et al., Bioorganic & Medicinal Chemistry Letters, 20(1), 413-417; 2010 Synthesis Reference 6 Boyd et al., Tetrahedron Letters, 55(30), 4117-4119; 2014 Synthesis Reference 7 Guo et al., WO2019210828 Synthesis Reference 8 Maccari et al., European Journal of Medicinal Chemistry, 81, 1-14; 2014. Synthesis Reference 9: Kobayashi et al., Heterocycles, 92(6), 1063-1074, 2016. Synthesis Reference 10: Mrozek-Wilczkiewicz et al., Bioorganic & Medicinal Chemistry, 18, 2664-26; 2010. Synthesis Reference 11: Fyfe et al., Angewandte Chemie, International Edition, 53(45), 12077-12080; 2014. Synthesis Reference 12: Wang et al., WO2015026792. Synthesis Reference 13: Deiters et al., WO2020123482. Commercially available raw materials were obtained from the reagent suppliers listed in the text. In addition, when the following reagent suppliers are listed in the table, the compounds were purchased from those suppliers and synthesized.Reagent Supplier 1 Aurora Fine Chemicals Reagent Supplier 2 Asta Tech Reagent Supplier 3 Combi-Blocks Reagent Supplier 4 Tokyo Chemical Industry Co., Ltd. Reagent Supplier 5 BLD Pharmatech Reagent Supplier 6 Sigma-Aldrich Reagent Supplier 7 Kanto Chemical Reagent Supplier 8 Santa Cruz Biotechnology Reagent Supplier 9 Enamine Reagent Supplier 10 Fujifilm Wako Pure Chemical Reagent Supplier 11 Azepine Reagent Supplier 12 Milestone Pharma Tech Reagent Supplier 13 Apollo SCIENTIFIC Reagent Supplier 14 Chemieliva Pharmaceutical Reagent Supplier 15 Fluorochem Reagent Supplier 16 Matrix Scientific Reagent Supplier 17 Aurum Pharmatech Reagent Supplier 18 Oakwood Chemical Reagent Supplier 19 ChemBridge Corporation Reagent Supplier 20 PharmaBlock.

[0266] Test Example 1 Purification of Ras and Raf for Detection of Ras-Raf Binding Inhibitory Activity The in vitro Ras-Raf binding inhibitory activity of the compounds of the present invention was evaluated by the ELISA method (Enzyme-Linked Immunosorbent Assay) shown below. Ras and Raf used for the evaluation were purified and activated by the following method. Human HRasG12V (full length, amino acid residues 1-189) and human c-Raf-1 Ras binding domain (RBD) (amino acid residues 50-131) were each expressed as a fusion with glutathione S-transferase (GST) in Escherichia coli using the pGEX6P-1 vector (GE Healthcare). GST-HRasG12V was incubated in a buffer containing 50 mM Tris-HCl pH 7.4, 150 mM NaCl, 5 mM MgCl ２The supernatant was collected after sonication in a buffer containing 1 mM ethylenediaminetetraacetic acid (EDTA), 1 mM dithiothreitol (DTT), 10% glycerol, and 1% Triton-X100, and then centrifuged at 100,000 × g for 30 minutes. HRasG12V in the supernatant was immobilized on glutathione-agarose resin and purified by cleaving the GST with PreScission protease (GE Healthcare). The resulting HRasG12V was reacted with 1000-fold concentrated guanosine 5'-O-[gamma-thio]triphosphate, trisodium salt (GTPγS) in the presence of 10 mM EDTA at 30°C for 1 hour, and then diluted with 20 mM MgCl ２ (final concentration) to prepare GTPγS-type (active) HRasG12V. On the other hand, GST-c-Raf-1 RBD was prepared by sonicating the expressing cells in the above buffer, centrifuging at 100,000 × g for 30 minutes, and collecting the supernatant.

[0267] Detection of Ras-Raf Binding Inhibitory Activity The in vitro Ras-Raf binding inhibitory activity of the compounds of the present invention was evaluated by the following ELISA method. A 96-well plate (Thermo Fisher Scientific) coated with glutathione was filled with Ras-Raf binding buffer (50 mM Tris-HCl pH 7.4, 150 mM NaCl, 5 mM MgCl ２GST-c-Raf-1 RBD diluted in 1% Triton-X100 (1 mM EDTA, 1% Triton-X100) was added to the wells and incubated at 30°C for 1 hour to immobilize Raf to the wells. Excess Raf was removed by washing the wells three times with the Ras-Raf binding buffer. Next, GTPγS-type HRasG12V diluted in Ras-Raf binding buffer and individual compound solutions (final DMSO concentration: 10%) were added to each well and incubated at 30°C for 1 hour to allow binding of Ras and Raf. The plate was then washed twice with Ras-Raf binding buffer and blocked with TBS-Tween (10 mM Tris-HCl pH 7.4, 150 mM NaCl, 0.05% (w / v) Tween-20)-5% (w / v) bovine serum albumin (BSA) for 20 minutes at room temperature. Anti-HRas antibody (C-20, Santa Cruz) or anti-HRas antibody (259, Santa Cruz) diluted 1:1000 in TBS-Tween-5% BSA was then added and incubated for 1 hour at room temperature. After primary antibody treatment, the plate was washed three times with TBS-Tween-5% BSA, and then horseradish peroxidase-labeled secondary antibody against rabbit immunoglobulin G (GE Healthcare) diluted 1:1000 with TBS-Tween-5% BSA was added and incubated at room temperature for 1 hour. After secondary antibody treatment, the plate was washed three times with TBS-Tween-5% BSA, and color development was achieved by adding substrate solution (TMB) and incubating at room temperature for 15 minutes. Finally, 2M H ２ SO ４ The color reaction was stopped by adding (color reaction kit: Nacalai Tesque), and the OD ４５０ The color intensity was quantified by measuring the absorbance at 0°C. The inhibition of the test compound was determined by the following formula: Inhibition (%) = (OD ４５０・ control-OD ４５０・ compound) / (OD ４５０・ control-OD ４５０・ Blank) * 100 The inhibitory effect of the test compound at each compound concentration was calculated using the above formula, and the concentration showing 50% of the maximum inhibition (IC ５０The results are shown in the table below. IC using anti-HRas antibody (259, Santa Cruz) ５０ (*)

[0268]

[0269] The results of inhibition (%) by the test compounds at 1 μM, 10 μM (*) or 100 μM (**) are shown in the table below.

[0270] Test Example 2 Detection of Cell Proliferation Inhibitory Activity The proliferation inhibitory activity of the compounds of the present invention in cultured human cancer cells having an activating mutation in Ras was evaluated by the method described below using suspension cancer cells {acute lymphoblastic leukemia cells CCRF-CEM (K-RasG12D), promyelocytic leukemia cells HL60 (N-RasQ61L), acute lymphoblastic leukemia cells MOLT4 (N-RasG12C), small cell lung cancer cells SHP77 (K-RasG12V)} and adherent cancer cells {colon cancer cells SW480 (K-RasG12V), colon cancer cells SW620 (K-RasG12V)}. (For suspension cells) Cells suspended in a medium containing 0.5% (v / v) fetal bovine serum (FBS) were seeded (2-4 x 10 cells) onto a 96-well plate together with individual compound solutions (final DMSO concentration: 1%). ４ cells / well), 37°C 5% CO ２ (For adhesive cells) Cells (1-2 x 10) suspended in a medium containing 10% FBS were cultured for 72 hours. ４ The cells (100 cells / well) were seeded in a 96-well plate and incubated at 37°C, 5% CO ２ The cells were cultured overnight in the presence of DMSO. After that, the medium was replaced with a 0.5% FBS-containing medium supplemented with individual compound solutions (final DMSO concentration: 1%), and the cells were incubated at 37°C in 5% CO ２The cells were cultured in the presence of 1000 mg / mL ... ４５０・ control-OD ４５０・ compound) / (OD ４５０・ control-OD ４５０・ Blank) * 100 The results are shown in the table below.

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277] Test Example 3: Detection of cell growth inhibitory effect on drug-resistant melanoma. Human melanoma cell lines A375 and HTT144 carrying the BRafV600E mutation were cultured in a medium containing 10% FBS at 37°C in 5% CO. ２ When the cells became confluent, 1 μM of vemurafenib, a BRaf inhibitor, was added to the medium, and the cells were cultured in the presence of vemurafenib for one month or more (the medium was changed once a week during this period), thereby obtaining vemurafenib-resistant malignant melanoma A375R and HTT144R. The obtained cells were suspended in a medium containing 10% FBS, and 1-2 × 10 ４ The cells were seeded onto a 96-well plate at 100 cells / well and incubated at 37°C in 5% CO ２The cells were cultured overnight in the presence of DMSO. After that, the medium was replaced with a 0.5% FBS-containing medium supplemented with individual compound solutions (final DMSO concentration: 1%) and 1 μM Vemurafenib, and incubated at 37°C in 5% CO ２ The cells were cultured in the presence of 1000 mg / mL ... ４５０・ control-OD ４５０・ compound) / (OD ４５０・ control-OD ４５０・ Blank) * 100

[0278] The inhibition (%) at 3.3 μM compound is shown below.

[0279]

[0280] Test Example 4: Detection of Ras-Raf signaling inhibitory activity at the cultured cell level The Ras-Raf signaling inhibitory activity of the compounds of the present invention at the cultured cell level was evaluated by the method described below. HL60 cells described in Test Example 2 were suspended in a medium containing 0.5% (v / v) FBS, and seeded (2-4 × 10 cells) onto a 12-well plate together with individual compound solutions (final DMSO concentration: 1%). ５ cells / well), 37°C 5% CO ２The cells were incubated for 3 hours in the presence of ATP. After incubation, proteins were extracted from the cells using RIPA buffer (Nacalai Tesque) containing a mixture of protease and phosphatase inhibitors. Equal amounts of protein were separated by standard SDS-PAGE and transferred to a PVDF membrane. To detect the activation (phosphorylation) of MEK and ERK, which are downstream of the Ras-Raf signaling pathway, the membrane was probed with 1:1000 dilution of primary antibodies (phosphorylated MEK (pMEK: #9121), phosphorylated ERK (pERK: #9101), total MEK (tMEK: #9122), and total ERK (tERK: #9102), all from Cell Signaling) followed by 1:1000 dilution of horseradish peroxidase-conjugated secondary antibody against rabbit immunoglobulin G. Immunoreactive signals were developed with EzWestLumi One (ATTO) and detected with Fusion FX (Vilber). Signal intensity was quantified by pixel count. Inhibition by test compounds was determined by the following formula: Inhibition (%) = (control p / tMEK or ERK signal intensity - compound p / tMEK or ERK signal intensity) / (control p / tMEK or ERK signal intensity - blank p / tMEK or ERK signal intensity) * 100. The inhibition (%) results by 1 μM test compound are shown in the table below.

[0281]

[0282] [Test Example 5] Detection of Ras-Raf signaling inhibitory effect at the individual level Detection of Ras-Raf signaling inhibitory effect at the individual level was evaluated by the following method. ６ The tumors were transplanted into the right flank of female athymic nude mice (6-8 weeks old; CLEA Japan, Inc.). The tumor size was approximately 50 mm on average. ３After the tumors reached a mass index of 100, 30-160 mg / kg of the compound suspended in a compound dilution solution (HCO-40 (8.75%), Cremophor EL (17.5%), EtOH (8.75%), DMSO (15%), and phosphate-buffered saline (50%)) was intraperitoneally administered five days a week for 21 consecutive days. 24 hours after the final compound administration, the tumors were excised and weighed. The inhibition of the test compound was determined by the following formula: Inhibition (%) = (1 - compound-administered tumor weight / vehicle-administered tumor weight) * 100. The results are shown in the table below.

[0283]

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof or an isomer thereof: 【Chemical 1】 [wherein, A represents a benzene ring or a pyridine ring, B is C ６－１０ represents an aryl group or a heteroaryl group containing 1 to 4 atoms selected from N, S, and O, X represents -NR ５ and indicates R １ represents a C ３ alkyl group which may be substituted with an H, NHCOCH １－６ group, or a halogen. R ２ , R ３ and R ４ are the same or different (provided that at least one of them is not H), ● H; ● C １－６ alkyl-SO ２ -; ● Cyano; ● Halogen; ● Nitro; ● Azide; ●-CO-R １１ group (wherein, R １１ is ・ OH, - R １２ group (R １２ group is a heterocyclyl group containing 1 to 2 atoms (groups) selected from N, S, SO, SO ２ and O, and may have a substituent). ・NH ２ 、NHR １２ 、 or N(R １２ )R １２ 、 or ・C ６－１０ Aryl amino, represents); ●-O-CH ２ -CO-R １１ group; ● Optionally substituted C １－６ alkyl group (The substituent is ・-CONH ２ , ・R １２ group ・ OH, ・ - NR １３ R １４ (R １３ is C １－６ alkyl - SO ２ -, C １－６ alkyl - CO -, or R １２ group, and, R １４ is H, C １－６ alkyl group, or R １２ group) ・R １２ -CO-, or ・R １２ -C １－６ alkyl-CONH- represents); ● - OR １５ group (wherein, R １５ is ・ H, ・Optionally substituted C １－６ alkyl group (The substituent represents OH, C １－６ alkoxy, C ６－１０ aryl, C ６－１０ aryloxy, R １２ , cyano, C １－６ alkyl - SO ２ -, or methylsulfinyl). ・C １－６ alkyl-SO ２ -, or ・ A heteroaryl group containing 1 to 4 atoms selected from N, S and O represents); ●-NR １６ R １７ group (wherein, R １６ and R １７ are the same or different and ・ H, - C １－６ alkyl - CO - ・R １２ group, or ・R １２ -C １－６ Alkyl-CO- represents or R １６ and R １７ may, together with N, form an R １２ group); ● Optionally substituted C ６－１０ aryl group (The substituent is C ６－１０ aryloxy, a heteroaryl group containing 1 to 4 atoms selected from N, S and O which may have a substituent, or R １２ and phenyl which may be condensed). ● Optionally having a substituent, a heteroaryl group containing 1 to 4 atoms selected from N, S and O; or ●-(CH=CH)-R １８ (In the formula, R １８ represents -CO-R １９ or -SO ２ -R １９ is shown, R １９ represents NH ２ or R １２ group); represents, R ５ represents C １－６ alkyl, -COR ６ , -COOR ６ , -CONR ６ R ７ , -SO ｎ R ６ , or SO ｎ NR ６ R ７ ; n represents 0, 1, or 2, R ６ and R ７ are the same or different and are H, C １－６ alkyl group, or C ６－１０ aryl group, and The wavy line represents a geometric isomer.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein B represents a heteroaryl group containing 1 to 4 atoms selected from N, S and O.

3. B is Pyridyl, Quinolyl, Indolyl, Thiazolyl, Pyrrolopyridinyl, Benzothiazolyl, or Furopyridinyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof or an isomer thereof.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof or an isomer thereof, wherein B represents the following. 【Chemical Formula 2】 However, one of the above-mentioned linking groups is for the wavy bond of formula (I), and the other linking group is a bond to any one substituent other than hydrogen among R ２ , R ３ and R ４ and represents a bond to any one substituent other than hydrogen. In that case, when there are other substituents, the substituents are substituted at the remaining positions described above.

5. B is Quinolyl, Thiazolyl, or Benzothiazolyl The compound according to claim 1, or a pharmaceutically acceptable salt thereof or an isomer thereof.

6. R ２ 、 R ３ and R ４ in which the optionally substituted C ６－１０ aryl group of the C ６－１０ aryl group represents phenyl or naphthyl, and the substituent represents a heteroaryl group having 1 to 4 atoms selected from N, S and O which may have a substituent, or R １２ phenyl which may be condensed with a group, the compound according to claim 1 or a pharmaceutically acceptable salt thereof or an isomer thereof.

7. R ２ , R ３ and R ４ in which the heteroaryl group having 1 to 4 atoms selected from N, S and O which may have a substituent represents pyridyl, phenylpyridyl, quinolyl, indazolyl, pyrazolyl, or methylpyrazolyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof or an isomer thereof.

8. R １２ A heterocyclic group having 1 to 2 atoms (groups) selected from N, S, SO, SO ２ and O and having an optional substituent, and the N, S, SO, SO ２ and a heterocyclic group having 1 to 2 atoms (groups) selected from O contain Morpholino, Piperazinyl, Thiomorpholino, Dioxidothiomorpholino, Tetrahydropyranyl, Tetrahydrothiopyranyl, Pyrrolidinyl, Dioxidotetrahydrothiopyranyl, or Piperidinyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof or an isomer thereof.

9. R １２ wherein the substituent of the heterocyclyl group having 1 to 2 atoms (groups) selected from N, S, SO, SO ２ and O may have a substituent ・ -CO-, ・ -COOH, ・ Cyano, ・ one or two C １－６ alkyl groups, ・C １－６ alkyl-CO- ・C １－６ Alkyl - SO ２ - ・C ６－１０ aryl group, ・ 3-Methoxy-2-hydroxypropyl, ・R １２ group, ・R １２ -CH ２ -, ・R １２ -CH ２ CO-, ・R １２ -CH ２ OCO-, or ・ Methoxyethyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof or an isomer thereof.

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the wavy line portion of the compound represented by formula (I) is the Z isomer.

11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the wavy line portion of the compound represented by formula (I) is the E isomer.

12. The group represented by the following formula (II) in formula (I) (wherein the wavy line represents a bond) is [Chemical Formula 3] ​ [Chemical Formula 4] 【Chem.】 The compound according to claim 1, or a pharmaceutically acceptable salt or isomer thereof, which represents a group selected from

13. A Ras / Raf binding inhibitor comprising the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or isomer thereof.

14. A medicament comprising the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or isomer thereof.

15. An anti-cancer agent comprising the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or isomer thereof.

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