G9a inhibitors

Abstract

This invention provides compounds for the treatment, prevention, or suppression of various pathological conditions (such as proliferative disorders like cancer, β-globin disorders, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy, and autism) by inhibiting G9a. [Solution] The following general formula (I) TIFF2026062914000401.tif2449 A compound represented by or a pharmacoposly acceptable salt thereof is provided.

Description

[Technical Field]

[0001] The present invention relates to a derivative having histone methyltransferase G9a inhibitory activity useful as a pharmaceutical, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and its pharmaceutical uses. [Background technology]

[0002] Histone lysine methylation is a biochemical reaction in which a methyl group is added to the ε-amino group of a histone lysine residue using S-adenosylmethionine (SAM) as a methyl group donor. Histone lysine methylation plays an important role in transcriptional regulation and is crucial in various biological processes, including cell proliferation and cell differentiation. Histone methyltransferases (also known as lysine methyltransferases) are known enzymes that catalyze the histone lysine methylation reaction (Non-patent Literature 1).

[0003] G9a and GLP (G9a-like protein) are the major enzymes that catalyze the mono- and dimethylation of the 9th lysine residue of histone H3 (H3K9me1 and H3K9me2). They are also known as EHMT2 and EHMT1 (euchromatin histone-lysine N-methyltransferases 2 and 1).

[0004] H3K9me2 is an epigenetic marker involved in transcriptional repression. G9a and GLP are involved in epigenetic transcriptional repression by activating H3K9me2.

[0005] Therefore, inhibition of G9a is thought to be useful in regulating biological processes such as cell proliferation and cell differentiation, which are mediated by transcriptional repression by H3K9me2. Diseases in which G9a inhibitors may be effective include β-globin disorders such as sickle cell anemia, gastric cancer, hepatocellular carcinoma, leukemias such as acute myeloid leukemia and chronic myeloid leukemia, cervical cancer, neuroblastoma, glioma, pancreatic cancer, colorectal cancer, head and neck squamous cell carcinoma, breast cancer, lung cancer, ovarian cancer, melanoma, fibrosis such as pulmonary fibrosis and renal fibrosis, pain, neurodegenerative diseases such as Alzheimer's disease, Prader-Willi syndrome, viral infections such as malaria, foot-and-mouth disease, and vesicular stomatitis, cardiomyopathy, myopathy, and autism. Furthermore, inhibition of G9a has been suggested to be effective in suppressing cancer metastasis. In addition, inhibition of G9a has been shown to be effective in sex reassignment (Non-Patent Literature 1-24).

[0006] Known compounds possessing G9a inhibitory activity include BIX-01294 (Patent Document 1), quinazolines (Patent Document 2), 2-aminoindoles (Patent Document 3), heteroaryls (Patent Document 4), and tricyclic compounds (Patent Document 5), but their structures differ from those of the compound of the present invention. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International Publication No. 2012 / 023285 [Patent Document 2] International Publication No. 2013 / 140148 [Patent Document 3] US2015274660 [Patent Document 4] Japanese Patent Publication No. 2019-513778 [Patent Document 5] Japanese Patent Publication No. 2019-511472 [Non-patent literature]

[0008] [Non-Patent Document 1] Krivega I. et al., Blood. Vol.126, No.5, pp. 665-672, 2015

Non-licensed Document 2

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed Document 8

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

[0009] The present invention has been made in view of the problems of the prior art described above, and aims to provide compounds having excellent G9a inhibitory activity, which are useful for treating β-globin disorders such as sickle cell anemia, and also useful for treating other proliferative disorders such as cancer, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy, autism, etc., as well as pharmacoacceptable salts thereof, and G9a inhibitors and pharmaceutical compositions containing them. Furthermore, the present invention aims to provide a method for producing the compounds and pharmacoacceptable salts thereof, and intermediate compounds useful for the production thereof.

[0010] Currently, no compound has been identified that possesses excellent G9a inhibitory activity and can be considered a sufficiently satisfactory pharmaceutical product for the prevention and treatment of the various disease conditions mentioned above. The object of the present invention is to provide a compound having G9a inhibitory activity. [Means for solving the problem]

[0011] As a result of intensive studies, the present inventors have found that a compound represented by the following general formula (I) (hereinafter sometimes referred to as compound (I)) or a pharmacologically acceptable salt thereof has a G9a inhibitory effect and is sufficiently satisfactory as a medicine, thereby completing the present invention.

[0012] That is, the present invention is as follows.

[0013] [1] General formula (I):

[0014]

Chemical formula

[0015]

Chemical formula

[0016] [ka] R 15 and R 16 Each of these is independently a hydrogen atom, a C1-C6 alkyl group, or a hydroxy C1-C6 alkyl group; R 15 and R 16 These may also be joined together to form a ring; R 15 and R 16 It may also combine with RingB to form a ring; m is either 0 or 1; RingB is R 17 , R 18 and R 19 Aromatic hydrocarbon ring groups, C3~C may be substituted with 10 It is a cycloalkyl group, a 5-10 membered heteroaryl group, or a 3-10 membered heterocycloalkyl group; R 17 and R 18 Each of these is independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a cyano group, a carbamoyl group (-CONH2), a C1-C6 alkyl group, a halo-C1-C6 alkyl group, a hydroxy-C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylsulfanyl group, a halo-C1-C6 alkylsulfanyl group, a C1-C6 acyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylaminocarbonyl group, or a C1-C6 acylamino group; R 19 Ha-(CR 20 R 21 ) r -V-(CR 22 R 23 ) q -Q is; V is a bond, -O-, -NR 24 - or -S(O) t -and; t is an integer between 0 and 2; R 20 , R 21 , R 22 , R 23 and R 24 Each of these is independently a hydrogen atom or a C1-C6 alkyl group; q and r are each independent integers between 0 and 6; Q is a hydrogen atom, amino group, hydroxyl group, C1-C6 alkyl group, C1-C6 alkylamino group, C3-C 10 Cycloalkyl groups, 5-10 membered heteroaryl groups or 3-10 membered heterocycloalkyl groups (the C1-C6 alkylamino group, C3-C 10 The cycloalkyl group, the 5-10 membered heteroaryl group, and the 3-10 membered heterocycloalkyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylaminocarbonyl group, and a hydroxy C1-C6 alkyl group; R 17 , R 18 and R 19 They may also be joined to each other to form a ring; R 4 and R 5 These may also be joined together to form a ring; R 1 is a nitrogen atom, m is 0, and RingB is R 17 , R 18 and R 19 If it is a phenyl group that may be substituted with, 1 The phenyl group may bond to form a benzimidazole ring. A compound represented by , or a pharmacologically acceptable salt thereof. [2] In formula (I), R 1 The compound described in [1], or a pharmacoposly acceptable salt thereof, wherein is an oxygen atom. [3] In formula (I), R 2 The following is A1) or A2):

[0017] [Chemical formula] The compound according to [2], or a pharmacologically acceptable salt thereof. [4] In formula (I), R 2 is as follows in A2);

[0018] [Chemical formula] R 2a is a C1-C6 alkyl group, a C3-C 10 cycloalkyl group or a hydroxy C1-C6 alkyl group, The compound according to [3], or a pharmacologically acceptable salt thereof. [5] In formula (I), R 2 is as follows in A2b),

[0019] [Chemical formula] The compound according to [4], or a pharmacologically acceptable salt thereof. [6] In formula (I), R 2 is as follows in A2b);

[0020] [Chemical formula] R 2a is a C1-C6 alkyl group or a C3-C 10 cycloalkyl group; R 2d , R 2e are each independently a C1-C6 alkyl group; R 2d and R 2e may be bonded to each other to form a ring, The compound according to [5], or a pharmacologically acceptable salt thereof. [7] In formula (I), R 3 is *-(CH2) x -T-(CR 13 R 14 ) y-U, where * indicates the bond position with -CH- in formula (I); T represents a bond or -S(O). p -and; U is a hydrogen atom, C3~C 10 It is a cycloalkyl group or an aromatic hydrocarbon ring group (the aromatic hydrocarbon ring group may be substituted with one or more halogen atoms); R 13 and R 14 Each of these is independently a hydrogen atom or a C1-C6 alkyl group; x and y are independent integers between 0 and 2; p is 0; (However, R 3 (Except when it is a hydrogen atom or a methyl group) R 5 The following B1) or C1-C6 alkyl groups, where * indicates the bond position with -N- in formula (I);

[0021] [ka] RingB is R 17 , R 18 and R 19 Aromatic hydrocarbon ring groups, C3~C may be substituted with 10 It is a cycloalkyl group, a 5-10 membered heteroaryl group, or a 3-10 membered heterocycloalkyl group; R 17 and R 18 Each of these is independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a cyano group, a C1-C6 alkyl group, a halo-C1-C6 alkyl group, a hydroxy-C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylsulfanyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylaminocarbonyl group, or a C1-C6 acylamino group. The compounds described in [6], or their pharmacoposly acceptable salts. [8] In formula (I), R 3 is *-(CH2) x -T-(CR 13R 14 ) y -U is the group represented by -U, and * indicates the bond position with -CH- in formula (I); T is a bond; U is a hydrogen atom or C3~C 10 It is a cycloalkyl group; R 13 and R 14 is a hydrogen atom; x and y are each independent integers between 1 and 2; R 5 The following B1) or C1-C6 alkyl groups, where * indicates the bond position with -N- in formula (I);

[0022] [ka] RingB is R 17 , R 18 and R 19 Aromatic hydrocarbon ring groups, C3~C may be substituted with 10 It is a cycloalkyl group, a 5-10 membered heteroaryl group, or a 3-10 membered heterocycloalkyl group; R 17 and R 18 Each of these is independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a cyano group, a C1-C6 alkyl group, a halo-C1-C6 alkyl group, a hydroxy-C1-C6 alkyl group, or a C1-C6 alkoxy group. The compounds described in [7], or their pharmaceutically acceptable salts. [9] In formula (I), R 2a , R 2d and R 2e Each of these is independently a C1-C3 alkyl group; R 3 is an n-butyl group or a 2-cyclopropylethane-1-yl group. [8] The compounds described therein, or pharmacologically acceptable salts thereof.

[10] In formula (I), R 2 The following is A1);

[0023] [ka] R 2a , R 2b and R 2c Each of these is independently a C1-C6 alkyl group, a C1-C6 alkoxycarbonyl group, or a C3-C6 alkyl group. 10 It is a cycloalkyl group; R 3 is *-(CH2) x -T-(CR 13 R 14 ) y -U, where * indicates the bond position with -CH- in formula (I); T is a bond; U is a hydrogen atom or C3~C 10 It is a cycloalkyl group; R 13 and R 14 is a hydrogen atom; x and y are independent integers between 1 and 2. [3] The compounds described therein, or pharmacologically acceptable salts thereof.

[11] In formula (I), R 2 The following is A1a);

[0024] [ka] R 2a is a hydrogen atom or a C1-C6 alkyl group; R 2f It is a C1-C6 alkoxy group; R 2g is a hydrogen atom or a C1-C6 alkoxy group; R 3 is *-(CH2) x -T-(CR 13 R 14 ) y -U, where * indicates the bond position with -CH- in formula (I); T is a bond; U is a hydrogen atom or C3~C 10 It is a cycloalkyl group; R 13 and R14 is a hydrogen atom; x and y are independent integers between 1 and 2. [3] The compounds described therein, or pharmacologically acceptable salts thereof.

[12] In formula (I), R 5 This is B1a) below, where * indicates the bond position with -N- in formula (I);

[0025] [ka] G is either CH or N; J stands for join, -O- or -NR 25 -and; R 25 is a hydrogen atom or a C1-C6 alkyl group; K is a hydrogen atom, a cyano group, a C1-C6 alkyl group, a halo-C1-C6 alkyl group, or a 3-10 member heterocycloalkyl group (the 3-10 member heterocycloalkyl group may be substituted with one or more C1-C6 alkyl groups). [2] The compounds described therein, or pharmacologically acceptable salts thereof.

[13] In formula (I), R 3 is *-(CH2) x -T-(CR 13 R 14 ) y -U, where * indicates the bond position with -CH- in formula (I); T is a bond; U is a hydrogen atom or C3~C 10 It is a cycloalkyl group; R 13 and R 14 is a hydrogen atom; x and y are each independent integers between 1 and 2. R 5 This is B1b) below, where * indicates the bond position with -N- in formula (I);

[0026] [ka] J stands for join, -O- or -NR 25 -and; R 25 is a hydrogen atom or a C1-C6 alkyl group; K is a hydrogen atom, a cyano group, a C1-C6 alkyl group, a halo-C1-C6 alkyl group, or a 3-10 member heterocycloalkyl group (the 3-10 member heterocycloalkyl group may be substituted with one or more C1-C6 alkyl groups). The compounds described in

[12] , or their pharmaceutically acceptable salts.

[14] In formula (I), R 5 The following is B1c), where * indicates the bond position with -N- in formula (I);

[0027] [ka] J stands for join, -O- or -NR 25 -and; R 25 is a hydrogen atom or a C1-C6 alkyl group; K is a hydrogen atom, a cyano group, a C1-C6 alkyl group, a halo-C1-C6 alkyl group, or a 3-10 member heterocycloalkyl group (the 3-10 member heterocycloalkyl group may be substituted with one or more C1-C6 alkyl groups). The compounds described in

[12] , or their pharmaceutically acceptable salts.

[15] In formula (I), R 2 This is A3) below.

[0028] [ka] The compounds described in

[14] , or pharmacologically acceptable salts thereof.

[16] In formula (I), R 2 This is A3) below;

[0029] [ka] n is 0; R 3 is *-(CH2)x -T-(CR 13 R 14 ) y -U, where * indicates the bond position with -CH- in formula (I); T is a bond; U is a hydrogen atom or C3~C 10 It is a cycloalkyl group; R 13 and R 14 is a hydrogen atom; x and y are independent integers between 1 and 2. The compounds described in

[15] , or their pharmaceutically acceptable salts.

[17] In formula (I), R 2 This is A3) below;

[0030] [ka] n is 0; RingA is R 8 and R 9 It is an aromatic hydrocarbon ring group that may be substituted with The compounds described in

[16] , or their pharmacoposly acceptable salts.

[18] In formula (I); R 2 The following is A3a);

[0031] [ka] R 26 is a hydrogen atom or a C1-C6 alkyl group; R 27 and R 28 Each of these is independently a hydrogen atom, a C1-C6 alkyl group, or a halo-C1-C6 alkyl group. The compounds described in

[17] , or their pharmaceutically acceptable salts.

[19] In formula (I), R 5 The following is B1c), where * indicates the bond position with -N- in formula (I);

[0032] [ka] J is a bond or -O-; K is a hydrogen atom or a C1-C6 alkyl group.

[18] The compounds described therein, or pharmacologically acceptable salts thereof.

[20] In formula (I), R 2 This is A3) below;

[0033] [ka] n is 1; R 3 is *-(CH2) x -T-(CR 13 R 14 ) y -U, where * indicates the bond position with -CH- in formula (I); T is a bond; U is a hydrogen atom or C3~C 10 It is a cycloalkyl group; R 13 and R 14 is a hydrogen atom; x and y are independent integers between 1 and 2. The compounds described in

[15] , or their pharmaceutically acceptable salts.

[21] In formula (I), R 2 This is A3) below;

[0034] [ka] n is 1; RingA is R 8 and R 9 It is an aromatic hydrocarbon ring group which may be substituted with; R 9 is -YZ; Y is a bond, -O-, -NR 10 - or - (CR 11 R 12 ) s -and; R 10 , R 11and R 12 Each of these is independently a hydrogen atom or a C1-C6 alkyl group; s is an integer between 0 and 6; Z is a hydrogen atom, a C1-C6 alkyl group, a halo-C1-C6 alkyl group, a C1-C6 alkoxy group, or a C1-C6 alkylamino group. The compounds described in

[20] , or their pharmaceutically acceptable salts.

[22] A compound represented by general formula (I) is given by the following formula (II):

[0035] [ka] [1] The compounds described therein, or pharmacologically acceptable salts thereof.

[23] A compound represented by general formula (I) is given by the following formula (II);

[0036] [ka] In formula (II), R 2 The following is A2b);

[0037] [ka] R 2a C1-C6 alkyl groups, C3-C 10 It is a cycloalkyl group or a hydroxy C1-C6 alkyl group; R 2d and R 2e Each of these is independently a C1-C6 alkyl group or a hydroxy C1-C6 alkyl group; R 2d and R 2e These may also be joined together to form a ring; R 3 is *-(CH2) x -T-(CR 13 R 14 ) y -U, where * indicates the bond position with -CH- in equation (II); T is a bond; U is a hydrogen atom or C3~C 10 It is a cycloalkyl group; R 13 and R 14 is a hydrogen atom; x and y are independent integers between 1 and 2. The compounds described in

[22] , or their pharmaceutically acceptable salts.

[24] A compound represented by general formula (I) is given by the following formula (III);

[0038] [ka] In formula (III), R 2 The following is A2b);

[0039] [ka] R 2a , R 2d , and R 2e Each of these is independently a C1-C3 alkyl group; R 3 is *-(CH2) x -T-(CR 13 R 14 ) y -U, where * indicates the bond position with -CH- in formula (III); T is a bond; U is a hydrogen atom or C3~C 10 It is a cycloalkyl group; R 13 and R 14 is a hydrogen atom; x and y are each independent integers between 1 and 2. R 5 This is B1) below, where * indicates the bond position with -N- in formula (I);

[0040] [ka] R 15 and R 16Each of these is independently a hydrogen atom or a C1-C6 alkyl group; m is either 0 or 1; RingB is R 17 , R 18 and R 19 A ring group of aromatic hydrocarbons or a 5-10 membered heteroaryl group, which may be substituted with; R 17 and R 18 Each of these is independently a hydrogen atom, a cyano group, a C1-C6 alkyl group, or a C1-C6 alkoxy group; R 19 Ha-(CR 20 R 21 ) r -V-(CR 22 R 23 ) q -Q is; V indicates a bond, -O- or -NR 24 -and; R 20 , R 21 , R 22 , R 23 and R 24 is a hydrogen atom; q and r are each independent integers between 0 and 2; Q is a hydrogen atom, a C1-C6 alkylamino group, or a 3-10 member heterocycloalkyl group (the 3-10 member heterocycloalkyl group may be substituted with one or more C1-C6 alkyl groups); R 4 and R 5 These may be joined together to form a ring. [1] The compounds described therein, or pharmacologically acceptable salts thereof.

[25] Below,

[0041] [Table 1]

[0042] [Table 2]

[0043] [Table 3]

[0044] [Table 4]

[0045] [Table 5]

[0046] [Table 6]

[0047] [Table 7]

[0048] [Table 8]

[0049] [Table 9]

[0050] [Table 10] A compound selected from, or a pharmacologically acceptable salt thereof. A G9a enzyme inhibitory composition containing one of the compounds described in any one of items

[26] [1] to

[25] or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition containing any one of the compounds described in

[27] [1] to

[25] or a pharmaceutically acceptable salt thereof as an active ingredient. A method for preventing or treating at least one disease selected from the group of diseases consisting of proliferative disorders such as cancer, β-globin disorders, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy, and autism, comprising administering a compound or a pharmacologically acceptable salt thereof as described in any one of paragraphs [1] to

[25] .

[29] Use of any one of the compounds described in [1] to

[25] or a pharmaceutically acceptable salt thereof for the manufacture of a medicine for the prevention or treatment of at least one disease selected from the group of diseases consisting of proliferative disorders such as cancer, β-globin disorders, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy, and autism.

[30] A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable carrier, used for the prevention or treatment of at least one disease selected from the group of diseases consisting of proliferative disorders such as cancer, β-globin disorders, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy, and autism, as described in any one of items [1] to

[25] . [Effects of the Invention]

[0051] Compound (I), or a pharmacologically acceptable salt thereof, showed, for example, potent G9a enzyme inhibitory activity. Therefore, compound (I) or a pharmaceutically acceptable salt thereof according to the present invention is useful as a therapeutic agent or prophylactic agent for proliferative disorders such as cancer, β-globin disorders, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy, autism, etc. Furthermore, compound (I) or its pharmacologically acceptable salts according to the present invention have high utility in the treatment, prevention, or suppression of various pathological conditions (for example, β-globin disorders such as sickle cell anemia, gastric cancer, hepatocellular carcinoma, leukemias such as acute myeloid leukemia and chronic myeloid leukemia, cervical cancer, neuroblastoma, glioma, pancreatic cancer, colorectal cancer, head and neck squamous cell carcinoma, breast cancer, lung cancer, ovarian cancer, melanoma, fibrosis such as pulmonary fibrosis and renal fibrosis, pain, neurodegenerative diseases such as Alzheimer's disease, Prader-Willi syndrome, malaria, foot-and-mouth disease, viral infections such as vesicular stomatitis, cardiomyopathy, myopathy, autism, etc.). In addition, compound (I) or its pharmacologically acceptable salts according to the present invention have high utility in suppressing cancer metastasis and sex reversal. [Modes for carrying out the invention]

[0052] This document explains the terminology used herein.

[0053] As used herein, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0054] As used herein, "C1-C6 alkyl group" refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Examples of C1-C6 alkyl groups include methyl group, ethyl group, 1-propyl group, isopropyl group, 1-butyl group, isobutyl group, sec-butyl group, tert-butyl group, 1-pentyl group, isopentyl group, neopentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, 1-hexyl group, isohexyl group, and the like. Furthermore, "C1-C3 alkyl group" refers to a linear or branched saturated hydrocarbon group having 1 to 3 carbon atoms.

[0055] As used herein, "C2-C6 alkenyl group" means a straight-chain or branched-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms and having at least one double bond. Examples of C2-C6 alkenyl groups include vinyl group, 2-propenyl group, 1-propenyl group, 1-buten-1-yl group, 1-buten-2-yl group, 1-buten-3-yl group, 2-buten-1-yl group, 2-buten-2-yl group, 1-penten-1-yl group, 1-penten-2-yl group, 1-penten-3-yl group, 2-penten-1-yl group, 2-penten-2-yl group, 2-penten-3-yl group, 1-hexen-1-yl group, 1-hexen-2-yl group, 1-hexen-3-yl group, and 2-methyl-1-propen-1-yl group.

[0056] In this specification, "C1-C6 acyl group" means an acyl group derived from a linear or branched aliphatic carboxylic acid having 1 to 6 carbon atoms. Examples include the formyl group, acetyl group, propanoyl group, 1-butanoyl group, 1-pentanoyl group, and 1-hexanoyl group.

[0057] As used herein, "halo-C1-C6 alkyl group" means a C1-C6 alkyl group in which at least one hydrogen atom is substituted with an identical or heterogeneous halogen atom. Examples of halo-C1-C6 alkyl groups include fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2,2-difluoroethyl group, 1,1-difluoroethyl group, 1,2-difluoroethyl group, 1-chloro-2-fluoroethyl group, 2,2,2-trifluoroethyl group, 1,1,2,2,2-pentafluoroethyl group, 2,2,2-trichloroethyl group, 3-fluoropropyl group, 2-fluoropropyl group, 1-fluoropropyl group, 3,3-difluoropropyl group, 2,2-difluoropropyl group, 1,1-difluoropropyl group, 4-fluorobutyl group, 5-fluoropentyl group, and 6-fluorohexyl group.

[0058] As used herein, "hydroxy C1-C6 alkyl group" means a C1-C6 alkyl group in which at least one hydrogen atom is substituted with a hydroxyl group. Examples of hydroxy C1-C6 alkyl groups include hydroxymethyl group, 1-hydroxyethyl group, 1-hydroxy-1,1-dimethylmethyl group, 2-hydroxyethyl group, 2-hydroxy-2-methylpropyl group, and 3-hydroxypropyl group. Furthermore, "hydroxy C1-C3 alkyl group" means a hydroxyalkyl group having 1 to 3 carbon atoms.

[0059] In this specification, "C1-C6 alkoxy group" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms. Examples of C1-C6 alkoxy groups include methoxy, ethoxy, 1-propoxy, isopropoxy, isobutoxy, 1-butoxy, sec-butoxy, tert-butoxy, 1-pentyloxy, and 1-hexyloxy groups.

[0060] As used herein, "halo-C1-C6 alkoxy group" means a C1-C6 alkoxy group in which at least one hydrogen atom is substituted with a halogen atom of the same or different type. Examples of halo-C1~C6 alkoxy groups include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-chloroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,1-difluoroethoxy, 1,2-difluoroethoxy, 1-chloro-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2,2-pentafluoroethoxy, 2,2,2-trichloroethoxy, 3-fluoropropoxy, 2-fluoropropoxy, 1-fluoropropoxy, 3,3-difluoropropoxy, 2,2-difluoropropoxy, 1,1-difluoropropoxy, 4-fluorobutoxy, 5-fluoropentyloxy, and 6-fluorohexyloxy.

[0061] In this specification, "C1-C6 alkoxycarbonyl group" means a carbonyl group to which a linear or branched alkoxy group having 1 to 6 carbon atoms is attached. Examples of C1-C6 alkoxycarbonyl groups include methoxycarbonyl group, ethoxycarbonyl group, 1-propoxycarbonyl group, isopropoxycarbonyl group, isobutoxycarbonyl group, 1-butoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, 1-pentyloxycarbonyl group, and 1-hexyloxycarbonyl group.

[0062] In this specification, "C1-C6 alkylamino group" means an amino group in which one or two hydrogen atoms of the amino group are replaced by a linear or branched alkyl group with a total of 1 to 6 carbon atoms. Examples of C1-C6 alkylamino groups include methylamino group, ethylamino group, 1-propylamino group, isopropylamino group, 1-butylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group, 1-pentylamino group, isopentylamino group, neopentylamino group, 1-methylbutylamino group, 2-methylbutylamino group, 1,2-dimethylpropylamino group, 1-hexylamino group, isohexylamino group, dimethylamino group, diethylamino group, N-ethyl-N-methylamino group, N-ethyl-N-propylamino group, and the like.

[0063] In this specification, "C1-C6 alkylaminocarbonyl group" means a carbonyl group to which a linear or branched alkylamino group with a total of 1 to 6 carbon atoms is attached. Examples of C1-C6 alkylaminocarbonyl groups include methylaminocarbonyl group, ethylaminocarbonyl group, 1-propylaminocarbonyl group, isopropylaminocarbonyl group, 1-butylaminocarbonyl group, isobutylaminocarbonyl group, sec-butylaminocarbonyl group, tert-butylaminocarbonyl group, 1-pentylaminocarbonyl group, isopentylaminocarbonyl group, neopentylaminocarbonyl group, 1-methylbutylaminocarbonyl group, 2-methylbutylaminocarbonyl group, 1,2-dimethylpropylaminocarbonyl group, 1-hexylaminocarbonyl group, isohexylaminocarbonyl group, dimethylaminocarbonyl group, diethylaminocarbonyl group, N-ethyl-N-methylaminocarbonyl group, and N-ethyl-N-propylaminocarbonyl group.

[0064] As used herein, "C1-C6 acylamino group" means an amino group in which one or two hydrogen atoms of the amino group are replaced by a linear or branched acyl group having 1 to 6 carbon atoms. Examples of C1-C6 acylamino groups include formylamino group, acetylamino group, 1-propanoylamino group, 1-butanoylamino group, 1-pentanoylamino group, and hexanoylamino group.

[0065] As used herein, "C1-C6 alkylsulfanyl group" refers to a group in which a linear or branched alkyl group having 1 to 6 carbon atoms is bonded to a sulfur atom. Examples of C1-C6 alkylsulfanyl groups include methylsulfanyl group, ethylsulfanyl group, 1-propylsulfanyl group, isopropylsulfanyl group, 1-butylsulfanyl group, isobutylsulfanyl group, sec-butylsulfanyl group, tert-butylsulfanyl group, and the like.

[0066] As used herein, "halo-C1-C6 alkylsulfanyl group" means a C1-C6 alkylsulfanyl group in which at least one hydrogen atom is substituted with an identical or heterogeneous halogen atom. Examples of halo-C1-C6 alkylsulfanyl groups include fluoromethylsulfanyl group, difluoromethylsulfanyl group, trifluoromethylsulfanyl group, 2-fluoroethylsulfanyl group, 2-chloroethylsulfanyl group, 2,2-difluoroethylsulfanyl group, 1,1-difluoroethylsulfanyl group, 1,2-difluoroethylsulfanyl group, 1-chloro-2-fluoroethylsulfanyl group, 2,2,2-trifluoroethylsulfanyl group, and 1,1,2,2 Examples include 2-pentafluoroethylsulfanyl group, 2,2,2-trichloroethylsulfanyl group, 3-fluoropropylsulfanyl group, 2-fluoropropylsulfanyl group, 1-fluoropropylsulfanyl group, 3,3-difluoropropylsulfanyl group, 2,2-difluoropropylsulfanyl group, 1,1-difluoropropylsulfanyl group, 4-fluorobutylsulfanyl group, 5-fluoropentylsulfanyl group, and 6-fluorohexylsulfanyl group.

[0067] Examples of "aromatic hydrocarbon ring groups" as shown herein include phenyl group, indenyl group, 1-naphthyl group, 2-naphthyl group, azlenyl group, heptarenyl group, biphenyl group, indacenyl group, acenaphthyl group, fluorenyl group, phenalenyl group, phenantrenyl group, anthracenyl group, and benzocyclooctenyl group.

[0068] As used herein, “5-10 membered heteroaryl group” means a 5-10 membered monocyclic aromatic heterocyclic or fused aromatic heterocyclic group containing 1-4 intracyclic heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the nitrogen and sulfur atoms may be oxidized as desired (i.e., N → O, SO, or SO2). Examples of 5-10 membered heteroaryl groups include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzoisoxazolyl, benzoisothiazolyl, benzimidazolinyl, furanyl, imidazolidinyl, imidazolyl, 1H-indazolyl, imidazolopylidinyl, and indolenyl. Group, indolidinyl group, 3H-indolyl group, isobenzofuranyl group, isoindazolyl group, isoindolyl group, isoquinolinyl group, isothiazolyl group, isothiazolopyridinyl group, isoxazolyl group, isoxazolopyridinyl group, naphthilidinyl group, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl group, oxazolidinyl group, oxazolyl group, oxazolopyridinyl Group, oxazolidinylperimidinyl group, oxyindolyl group, pyrimidinyl group, pyrazinyl group, pyrazolidinyl group, pyrazolinyl group, pyrazolopyridinyl group, pyrazolyl group, pyridadinyl group, pyridooxazolyl group, pyridoimidazolyl group, pyridothiazolyl group, pyridinyl group, pyrrolopyridinyl group, quinazolinyl group, quinolinyl group, 4H-quinolidinyl group, quinoxalinyl group, quinuclidinyl group, tetrazolyl group, 6H-1,2,5-thiadiadinyl group, Examples include 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, 1,3,4-thiadiazolyl group, thianthrenyl group, thiazolyl group, thienyl group, thiazolopyridinyl group, thienohiazolyl group, thienoxazolyl group, thienoimidazolyl group, thiophenyl group, triazinyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, 1,2,5-triazolyl group, and 1,3,4-triazolyl group.Furthermore, fused ring and spiro ring compounds containing the above-mentioned heterocycles are also included.

[0069] "C3~C" as shown in this specification 10 A "cycloalkyl group" refers to a monocyclic or bicyclic saturated alicyclic hydrocarbon group having 3 to 10 carbon atoms, and can be of the bridging or spirotype type. 10 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, spiroheptyl, spirooctyl, and octahydropentarenyl groups. Also, C3-C 10 The cycloalkyl group may be condensed with a further aromatic hydrocarbon ring group or a 5-10 membered heteroaryl group, and the condensed aromatic hydrocarbon ring group or 5-10 membered heteroaryl group is C3-C 10 Examples of cycloalkyl groups include dihydroindenyl groups and tetrahydronaphthyl groups. Furthermore, "C3-C4 cycloalkyl group" refers to a cycloalkyl group with 3 to 4 carbon atoms.

[0070] As used herein, "3-10 membered heterocycloalkyl group" means a heterocycloalkyl group having a monocyclic, bicyclic, or tricyclic 3-10 membered ring containing 1-4 intraring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the nitrogen and sulfur heteroatoms may be oxidized as desired (i.e., N → O, SO, or SO2), the nitrogen atom may be substituted or unsubstituted, and the group may have 1-3 carbonyl groups and 1 intraring double bond. The 3-10 membered heterocycloalkyl group may also be bridging or spiro-type. The 3-10 membered heterocycloalkyl group may be condensed with a further aromatic hydrocarbon ring group or a 5-10 membered heteroaryl group.Examples of 3- to 10-membered heterocycloalkyl groups include azilidinyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, azepanyl group, azokanyl group, dihydropyrrolyl group, tetrahydropyridinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, 1-oxidethiomorpholinyl group, 1,1-dioxidethiomorpholinyl group, oxazepinyl group, thiazepanyl group, 1-oxide-1,4-thiazepanyl group, 1,1-dioxide-1,4-thiazepanyl group, 1,4-diazepanyl group, and 1,4-oxy Sazokanyl group, 1,5-oxazokanyl group, oxetanyl group, tetrahydrofuranyl group, tetrahydropyranyl group, octahydrocyclopenta[c]pyrrolyl group, 3-azabicyclo[3.2.0]heptanyl group, 3-azabicyclo[3.1.0]hexanyl group, 5-azabicyclo[2.1.1]hexanyl group, 2-azabicyclo[2.1.1]hexanyl group, 2-azabicyclo[4.1.0]heptanyl group, 3-azabicyclo[4.1.0]heptanyl group, 2-azabicyclo[4.2.0]octanyl group, 3-azabicyclo[4.2.0]octanyl group Bicyclo[4.2.0]octanyl group, 3-azabicyclo[3.1.1]heptanyl group, 2-azabicyclo[2,2,1]heptanyl group, 6-azabicyclo[3.1.1]heptanyl group, 8-azabicyclo[3.2.1]octanyl group, 3-azabicyclo[3.2.1]octanyl group, 6-azabicyclo[3.2.1]octanyl group, 4-azaspiro[2.4]heptanyl group, 5-azaspiro[2.4]heptanyl group, 1-oxo-5-azaspiro[2.4]heptanyl group, 5-azaspiro[3.4]octanyl group Examples include the 6-azaspiro[3.4]octanyl group, the 2-oxo-6-azaspiro[3.4]octanyl group, the 1-oxo-6-azaspiro[3.4]octanyl group, the 4-azaspiro[2.5]octanyl group, the 5-azaspiro[2.5]octanyl group, the 6-azaspiro[2.5]octanyl group, the 1-oxa-5-azaspiro[2.5]octanyl group, the 4-oxa-7-azaspiro[2.5]octanyl group, the 1-oxa-6-azaspiro[2.5]octanyl group, and the 2,6-diazaspiro[3.4]octanyl group.

[0071] In this specification, "bonding to each other to form a ring" means removing one arbitrary hydrogen atom from each of the two substituents that form the ring, and then bonding the hydrogen-free sites together. For example, if a methylene group has two substituents, and the two substituents that form the ring are a methyl group and a 1-hydroxyethyl group,

[0072] [ka] These are some examples.

[0073] In this specification, the notations "3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxylic acid" or "3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid" both refer to the same compound A, and related compounds follow the same naming convention.

[0074] [ka]

[0075] The present embodiment will be described in more detail below.

[0076] In the following, the definitions of functional groups in the general formula may be omitted by referencing definitions already provided. The definitions referred to are those described in the following descriptions of embodiments.

[0077] Furthermore, regarding the definitions of functional groups in a general formula, unless otherwise specified, definitions represented by the same sign are common among all general formulas containing that sign.

[0078] This embodiment relates to a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. General formula (I):

[0079] [ka] [In formula (I), R 1 is an oxygen atom, a nitrogen atom, or a hydrogen atom; R 1 If R is an oxygen atom or a nitrogen atom, 1 The bond between the carbon atom and the carbon atom is a double bond; R 1 If R is a hydrogen atom, 1 The bond between the carbon atom and the carbon atom is a single bond; R 2 The following are A1), A2), or A3), where * indicates the bond position with -CO- in formula (I);

[0080] [ka] E is either an oxygen atom or a hydrogen atom; If E is an oxygen atom, the bond between E and the carbon atom is a double bond; If E is a hydrogen atom, the bond between E and the carbon atom is a single bond; R 2a , R 2b and R 2c Each of these is independently a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a halo C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a C1-C6 acyl group, a C1-C6 alkoxycarbonyl group, and a C3-C 10 Cycloalkyl groups or hydroxy C1-C6 alkyl groups (the C1-C6 alkyl groups, C2-C6 alkenyl groups, halo-C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylamino groups, C1-C6 acyl groups, C1-C6 alkoxycarbonyl groups, C3-C 10 The cycloalkyl group and the hydroxyC1-C6 alkyl group may be substituted with one or more substituents selected from the group consisting of C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylamino groups, and hydroxyC1-C6 alkyl groups, and the substituents may be bonded to each other to form a ring; R 2b and R 2c These may also be joined together to form a ring; R 2d and R 2e Each of these is independently a C1-C6 alkyl group or a hydroxy C1-C6 alkyl group; R 2d and R 2e These may be joined together to form a ring; R 6 and R 7 Each of these is independently a hydrogen atom, a C1-C6 alkyl group, an aromatic hydrocarbon ring group, and a C3-C6 alkyl group. 10 It is a cycloalkyl group, a 5-10 member heteroaryl group, or a 3-10 member heterocycloalkyl group; R 6 and R 7 These may also be joined together to form a ring; n is either 0 or 1; RingA is R 8 and R 9 Aromatic hydrocarbon ring groups, C3~C may be substituted with 10 It is a cycloalkyl group, a 5-10 member heteroaryl group, or a 3-10 member heterocycloalkyl group; R 8 These are hydrogen atoms, halogen atoms, cyano groups, amino groups, aminosulfonyl groups (-SO2NH2), C1-C6 alkyl groups, halo-C1-C6 alkyl groups, or C1-C6 alkoxy groups; R 9 is -YZ; Y is a bond, -O-, -NR 10 - or - (CR 11 R 12 ) s -and; R 10 , R 11 and R 12 Each of these is independently a hydrogen atom or a C1-C6 alkyl group; s is an integer between 0 and 6; Z represents a hydrogen atom, a C1-C6 alkyl group, a halo-C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, an aromatic hydrocarbon ring group, or a C3-C 10Cycloalkyl groups, 5-10 member heteroaryl groups or 3-10 member heterocycloalkyl groups (the C1-C6 alkyl groups, aromatic hydrocarbon ring groups, C3-C 10 The cycloalkyl groups, 5-10 membered heteroaryl groups, and 3-10 membered heterocycloalkyl groups may be substituted with one or more substituents selected from the group consisting of C1-C6 alkyl groups, halo-C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylamino groups, C1-C6 acyl groups, and C1-C6 alkoxycarbonyl groups; R 3 is *-(CH2) x -T-(CR 13 R 14 ) y -U, where * indicates the bond position with -CH- in formula (I); T represents a bond, -NH-, -O-, or -S(O). p -and; U is a hydrogen atom, C3~C 10 It is a cycloalkyl group or an aromatic hydrocarbon ring group (the aromatic hydrocarbon ring group may be substituted with one or more halogen atoms); R 13 and R 14 Each of these is independently a hydrogen atom or a C1-C6 alkyl group; x and y are independent integers between 0 and 4; p is an integer between 0 and 2; R 4 is a hydrogen atom or a C1-C6 alkyl group; R 5 The following B1) or C1-C6 alkyl groups, where * indicates the bond position with -N- in formula (I);

[0081] [ka] R 15 and R 16 Each of these is independently a hydrogen atom, a C1-C6 alkyl group, or a hydroxy C1-C6 alkyl group; R 15 and R 16 These may also be joined together to form a ring; R 15 and R 16 It may also combine with RingB to form a ring; m is either 0 or 1; RingB is R 17 , R 18 and R 19 Aromatic hydrocarbon ring groups, C3~C may be substituted with 10 It is a cycloalkyl group, a 5-10 membered heteroaryl group, or a 3-10 membered heterocycloalkyl group; R 17 and R 18 Each of these is independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a cyano group, a carbamoyl group (-CONH2), a C1-C6 alkyl group, a halo-C1-C6 alkyl group, a hydroxy-C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylsulfanyl group, a halo-C1-C6 alkylsulfanyl group, a C1-C6 acyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylaminocarbonyl group, or a C1-C6 acylamino group; R 19 Ha-(CR 20 R 21 ) r -V-(CR 22 R 23 ) q -Q is; V is a bond, -O-, -NR 24 - or -S(O) t -and; t is an integer between 0 and 2; R 20 , R 21 , R 22 , R 23 and R 24 Each of these is independently a hydrogen atom or a C1-C6 alkyl group; q and r are each independent integers between 0 and 6; Q is a hydrogen atom, amino group, hydroxyl group, C1-C6 alkyl group, C1-C6 alkylamino group, C3-C 10Cycloalkyl groups, 5-10 membered heteroaryl groups or 3-10 membered heterocycloalkyl groups (the C1-C6 alkylamino group, C3-C 10 The cycloalkyl group, the 5-10 membered heteroaryl group, and the 3-10 membered heterocycloalkyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylaminocarbonyl group, and a hydroxyC1-C6 alkyl group; R 17 , R 18 and R 19 They may also be joined to each other to form a ring; R 4 and R 5 These may also be joined together to form a ring; R 1 is a nitrogen atom, m is 0, and RingB is R 17 , R 18 and R 19 If it is a phenyl group that may be substituted with, 1 The phenyl group may bond to form a benzimidazole ring. A compound represented by , or a pharmacologically acceptable salt thereof.

[0082] Preferred compounds in this embodiment include, for example, the following compounds.

[0083] [Table 11]

[0084] [Table 12]

[0085] [Table 13]

[0086] [Table 14]

[0087] [Table 15]

[0088] [Table 16]

[0089] [Table 17]

[0090] [Table 18]

[0091] [Table 19]

[0092] [Table 20]

[0093] Furthermore, compound (I) of this embodiment, or a pharmaceutically acceptable salt thereof, may also exist as a hydrate or solvate. Any hydrates and solvates formed by the derivatives or salts of the general formula (I), including the preferred compounds specifically described above, are all included within the scope of the present invention. Solvents that can form solvates include methanol, ethanol, isopropyl alcohol, acetone, ethyl acetate, dichloromethane, and diisopropyl ether.

[0094] Compound (I) of this embodiment may, if necessary, be a pharmaceutically acceptable salt thereof. A pharmaceutically acceptable salt means a salt with a pharmaceutically acceptable non-toxic base or acid (e.g., an inorganic or organic base and an inorganic or organic acid). A pharmaceutically acceptable salt of compound (I) of this embodiment can be prepared by the methods described in the 5th edition of Experimental Chemistry (edited by the Chemical Society of Japan, published by Maruzen Co., Ltd.), J. Pharm. Sci. 1977, 66, 1-19, and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) and similar methods.

[0095] Examples of salts derived from pharmaceutically acceptable non-toxic bases include salts with inorganic bases such as sodium, potassium, calcium, and magnesium salts, and salts with organic bases such as piperidine, morpholine, pyrrolidine, arginine, and lysine.

[0096] Examples of salts derived from pharmaceutically acceptable non-toxic acids include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and nitric acid, and acid addition salts with organic acids such as formic acid, acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, and palmitic acid.

[0097] Compound (I) of this embodiment, or its pharmaceutically acceptable salts, also include stereoisomers such as racemates and optically active compounds.

[0098] If compound (I) of this embodiment is an optical isomer having one or more chiral carbon atoms or sulfur atoms, the stereoconfiguration of each chiral carbon atom or sulfur atom in compound (I) may be either the R configuration or the S configuration. Furthermore, the present invention encompasses any single enantiomer, a single diastereomer, a mixture of enantiomers, or a mixture of diastereomers. In addition, in a mixture of optically active compounds, a racemic mixture consisting of equal amounts of each optical isomer is also included in the scope of the present invention. If compound (I) of this embodiment is a racemic solid or crystalline compound, racemic compounds, racemic mixtures, and racemic solid solutions are also included in the scope of the present invention.

[0099] In compound (I) of this embodiment, the diastereomer mixture can be separated into individual diastereomers by conventional methods such as chromatography or crystallization. Alternatively, each diastereomer can be synthesized by using stereochemically monolithic starting materials or by synthetic methods employing stereoselective reactions.

[0100] In the compound (I) of this embodiment, if geometric isomers such as cis isomers and trans isomers exist, the present invention encompasses all of those geometric isomers.

[0101] In the case of compound (I) of this embodiment, if tautomers exist, the present invention encompasses all of those tautomers.

[0102] Compound (I) of this embodiment, or a pharmaceutically acceptable salt thereof, is an isotope (e.g., 3 H, 14 C, 35 Compounds labeled with s(S, etc.) are also included in the present invention.

[0103] Furthermore, compound (I) of this embodiment, or a pharmaceutically acceptable salt thereof, 1 H 2 The deuterium converter may be converted to H(D). Such compounds are also included in the present invention.

[0104] Method for producing compound (I) of this embodiment Compound (I) of this embodiment can be produced, for example, by the methods detailed in the following synthesis routes 1 to 46 or similar methods, or by other methods described in the literature or similar methods. Compounds (2) to (122) in the formula may form salts, such as those similar to the salt of compound (I). Furthermore, the compounds obtained in each step can be used in subsequent reactions either as reaction solutions or as crude products, but they can also be easily isolated and purified from the reaction mixture by conventional methods such as recrystallization, distillation, and chromatography.

[0105] [Synthesis Route 1] Of the compounds (I), R 1 If the compound is an oxygen atom, i.e., represented by compound (2), it can be manufactured, for example, by the method shown in synthesis route 1, or a similar method, or by other methods described in the literature or similar methods.

[0106] [ka]

[0107] (In the formula, R 29 represents a C1-C6 alkyl group, X represents a halogen atom such as a chlorine atom or a bromine atom, and R 2 , R 3 , R 4 and R 5 This is synonymous with what was mentioned above.

[0108] Process 1-1 Compound (5) can be produced by amidating compound (3) with compound (4a) or compound (4b). The reaction can be carried out at 0°C to room temperature, or under reflux, by adding compound (4a) or compound (4b) to a solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, ethyl acetate, dichloromethane, acetonitrile, toluene, benzene, 1,4-dioxane, tetrahydrofuran, or a mixture thereof. If necessary, a base such as triethylamine or N,N-diisopropylethylamine can also be added. Additionally, if necessary, condensing agents such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), or 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (DMT-MM), or reaction accelerators such as N,N-dimethyl-4-aminopyridine, pyridine, 1-hydroxybenzotriazole (HOBT), or 1-hydroxy-7-azabenzotriazole (HOAt) may be added.

[0109] Process 1-2 Compound (6) can be produced by hydrolyzing compound (5). The reaction can be carried out under basic conditions at 0°C under reflux by adding alkali metal salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, or cesium carbonate to water, methanol, ethanol, 1-propanol, isopropyl alcohol, tetrahydrofuran, 1,4-dioxane, or aqueous mixed solvents thereof. Alternatively, the reaction can be carried out under acidic conditions at 0°C under reflux by adding hydrogen chloride, etc., to water, tetrahydrofuran, 1,4-dioxane, or aqueous mixed solvents thereof.

[0110] Process 1-3 Compound (2) can be produced by amidating compound (6) with compound (7). The reaction can be carried out in the same manner as in step 1-1 by adding compound (7) or salts thereof, such as aniline or benzylamine, as the reaction conditions.

[0111] [Synthesis Route 2] The compound (2) described above can also be produced, for example, by the method shown in synthesis route 2, or a similar method, or by other methods described in the literature or similar methods.

[0112] [ka]

[0113] (In the formula, R 2 , R 3 , R 4 and R 5 This is synonymous with what was mentioned above.

[0114] Process 2-1 Compound (8) can be produced by esterifying compound (6) with pentafluorophenol. The reaction can be carried out in the same manner as in steps 1-3, with the addition of pentafluorophenol.

[0115] Process 2-2 Compound (2) can be produced by amidating compound (8) with compound (7). The reaction can be carried out at -78°C under reflux by adding compound (7) or its salts, such as aniline or benzylamine, to a solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, ethyl acetate, dichloromethane, acetonitrile, toluene, benzene, 1,4-dioxane, tetrahydrofuran, or a mixture thereof. Triethylamine, N,N-diisopropylethylamine, pyridine, etc., can also be added as needed.

[0116] [Synthesis Path 3] The compound (2) described above can also be produced, for example, by the method detailed in synthesis route 3 or a similar method, or by other methods described in the literature or a similar method.

[0117] [ka]

[0118] (In the formula, PG represents a protecting group such as a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, a benzyl group, an acetyl group, a benzoyl group, or a tert-butyldimethylsilyl group, and X, R 2 , R 3 , R 4 and R 5 This is synonymous with what was mentioned above.

[0119] Process 3-1 Compound (10) can be produced by amidating compound (9) with compound (7). The reaction can be carried out using the same method as in steps 1-3.

[0120] Process 3-2 Compound (11) can be produced by removing the protecting group from compound (10). As for the reaction conditions, if the PG is a tert-butoxycarbonyl group, the reaction can be carried out at -78°C to room temperature, or under reflux if necessary. This can be done by adding an acid such as trifluoroacetic acid, p-toluenesulfonic acid, hydrogen chloride, hydrobromic acid, sulfuric acid, boron trifluoride diethyl ether complex, boron tribromide, or aluminum chloride to a solvent such as dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, methanol, ethanol, ethyl acetate, or water, or a mixture thereof. When PG is a benzyloxycarbonyl group, the reaction can be carried out at 0°C under reflux with the addition of a catalyst such as palladium carbon, rhodium carbon, platinum carbon, or platinum oxide in a hydrogen atmosphere in methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, water, tetrahydrofuran, tert-butyl methyl ether, N,N-dimethylformamide, toluene, etc., or a mixture thereof. If necessary, an acid such as acetic acid, trifluoroacetic acid, or 2,2,2-trifluoroethanol can be added as a reaction accelerator. Alternatively, the reaction can be carried out at 0°C under reflux with the addition of an acid such as trifluoroacetic acid in methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, water, tetrahydrofuran, tert-butyl methyl ether, N,N-dimethylformamide, toluene, etc., or a mixture thereof.

[0121] Process 3-3 Compound (2) can be produced by amidating compound (11) with compound (4a) or compound (4b). The reaction can be carried out in the same manner as in step 1-1 by adding compound (4a) or compound (4b), etc., as the reaction conditions.

[0122] [Synthesis Route 4] If the above-mentioned compound (2) is represented by compound (2a) or compound (2b), it can be manufactured, for example, by the method detailed in synthesis route 4 below or a similar method, or by other methods described in the literature or a similar method.

[0123] [ka]

[0124] (In the formula, LG represents a halogen atom such as a chlorine atom or a bromine atom, or a leaving group such as a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a p-toluenesulfonyloxy group, R30 and R 31 Each of these independently represents a hydrogen atom, a C1-C6 alkyl group, or a halo-C1-C6 alkyl group, and R 30 and R 31 They may bond to each other to form a ring, such as PG, R 2 , R 3 , R 4 , R 15 , R 16 , R 17 , R 18 , R 20 , R 21 , R 22 , R 23 (RingB, V, m, r, and q are synonymous with those mentioned above.)

[0125] Process 4-1 Compound (13) can be produced by converting the hydroxyl group of compound (12) to a suitable leaving group (LG) such as a halogen atom, a methanesulfonyloxy group, or a p-toluenesulfonyloxy group. For example, if LG is a chlorine atom, the process can be carried out by adding a chlorinating agent such as thionyl chloride or phosphorus oxychloride to a solvent such as dichloromethane, chloroform, benzene, toluene, N,N-dimethylformamide, tetrahydrofuran, pyridine, diethyl ether, or a mixture thereof, and heating under reflux from -78°C. Furthermore, for example, if LG is a bromine atom, the process can be carried out by adding a brominating agent such as carbon tetrabromide or N-bromosuccinimide, and a phosphorus reagent such as triphenylphosphine, to a solvent such as dichloromethane, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, toluene, or a mixture thereof, and heating under reflux from -78°C. Furthermore, for example, if LG is a methanesulfonyloxy group, a methanesulfonylation agent such as methanesulfonyl chloride can be added to a solvent such as dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, water, or a mixture thereof, and the process can be carried out at -78°C to room temperature, or under reflux if necessary. In addition, a base such as triethylamine, N,N-diisopropylethylamine, or pyridine can be added as needed. Furthermore, for example, if LG is a p-toluenesulfonyloxy group, a p-toluenesulfonylation agent such as p-toluenesulfonyl chloride can be added to dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, water, or a mixture thereof, and the process can be carried out at -78°C to room temperature, or under reflux if necessary. In addition, a base such as triethylamine, N,N-diisopropylethylamine, or pyridine can be added as needed.

[0126] Process 4-2 Compound (2a) can be produced by reacting compound (13) and compound (14). The reaction can be carried out at -78°C under reflux by adding compound (14) or its salts, such as methylamine, dimethylamine, or a tetrahydrofuran solution containing them, to a solvent such as dichloromethane, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, acetonitrile, or a mixture thereof. If necessary, a base such as sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N,N-diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), or 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN) can be added.

[0127] Process 4-3 Compound (16) can be produced by reacting compound (13) and compound (15). The reaction can be carried out at -78°C under reflux by adding compound (15) or a salt thereof, such as di-tert-butyl iminodicarboxylic acid, to a solvent such as dichloromethane, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, acetonitrile, or a mixture thereof. If necessary, a base such as sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N,N-diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), or 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN) can be added.

[0128] Process 4-4 Compound (2b) can be produced by removing the protecting group from compound (16). If the PG is a tert-butoxycarbonyl group, the reaction can be carried out in the same manner as in step 3-2.

[0129] [Synthesis Path 5] When compound (2) described above is represented by compound (2c), it can be produced, for example, by the method detailed in synthesis route 5 below or a similar method, or by other methods described in the literature or a similar method.

[0130] [ka]

[0131] (In the formula, R 32 R represents a C1-C6 alkyl group, 33 and R 34 Each of these independently represents a hydrogen atom or a C1-C6 alkyl group, and R 33 and R 34 They may bond to each other to form a ring, R 2 , R 3 , R 4 , R 15 , R 16 , R 17 , R18 (RingB and m are synonymous with those mentioned above.)

[0132] Process 5-1 Compound (18) can be produced by hydrolyzing compound (17). The reaction can be carried out using the same method as in step 1-2.

[0133] Process 5-2 Compound (2c) can be produced by amidating compound (18) with compound (19). The reaction can be carried out in the same manner as in steps 1-3 by adding compound (19), for example, a solution of methanol, ethanol, 1,4-dioxane, or water containing ammonia, ammonium chloride, ammonium acetate, ammonium formate, or primary amines, secondary amines, or their salts, for example, methylamine, dimethylamine, or a tetrahydrofuran solution containing them, as the reaction conditions.

[0134] [Synthesis Path 6] When compound (2) described above is represented by compound (2d), it can be produced, for example, by the method detailed in synthesis route 6 below or a similar method, or by other methods described in the literature or a similar method.

[0135] [ka]

[0136] (In the formula, R 2 , R 3 , R 4 , R 15 , R 16 , R 17 , R 18 (RingB and m are synonymous with those mentioned above.)

[0137] Process 6-1 Compound (2d) can be produced by reducing the nitro group of compound (20). The reaction conditions can be those of a general nitro group reduction. For example, methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, water, tetrahydrofuran, diethyl ether, tert-butylmethyl ether, N,N-dimethylformamide, toluene, n-hexane, etc., or a mixture thereof, can be used with iron powder, zinc powder, tin(II) chloride, metallic tin, metallic indium, metallic samarium, Raney nickel, formic acid, sodium borohydride, nickel borohydride, cobalt borohydride, lithium aluminum hydride, sodium dithionite, sodium sulfide, sodium hydrogen sulfide, or hydrazine, and the reaction can be carried out at 0°C to room temperature, or under reflux if necessary. If necessary, acids such as ammonium chloride, hydrogen chloride, acetic acid, trifluoroacetic acid, and sulfuric acid, or bases such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, sodium bicarbonate, potassium bicarbonate, pyridine, triethylamine, or N,N-diisopropylethylamine can be added. Alternatively, reduction can be performed by adding catalysts such as palladium carbon, rhodium carbon, platinum carbon, or platinum oxide in a hydrogen atmosphere in a solvent such as methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, acetic acid, ethyl acetate, water, tetrahydrofuran, tert-butyl methyl ether, N,N-dimethylformamide, toluene, or a mixture thereof.

[0138] [Synthesis Path 7] If the above-mentioned compound (2) is represented by compound (2e) or compound (2f), it can be manufactured, for example, by the method detailed in synthesis route 7 below or a similar method, or by other methods described in the literature or a similar method.

[0139] [ka]

[0140] (In the formula, A represents a carbon atom or a nitrogen atom, and R 35 , R 36 and R 37 Each of the following independently represents a hydrogen atom or a C1-C6 alkyl group, and a and b each independently represent an integer from 0 to 3, PG, R 2 , R 3 , R 4 , R 15 , R 16 , R 17 , R 18 , R 20 , R 21 , R 22 , R 23 (RingB, V, m, r, and q are synonymous with those mentioned above.)

[0141] Process 7-1 Compound (2e) can be produced by reductive alkylation using compounds (21) and (22). The reaction can be carried out at -78°C to room temperature, or under reflux if necessary, by adding compound (22), such as paraformaldehyde, aqueous formalin solution, or glycolaldehyde dimer, to a solvent such as dichloromethane, 1,2-dichloroethane, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, methanol, ethanol, or a mixture thereof, and then adding a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, borane-dimethyl sulfide complex, lithium aluminum hydride, or 2-picolylborane. Alternatively, the reaction can be carried out under a hydrogen atmosphere by adding a catalyst such as palladium carbon, rhodium carbon, platinum carbon, or platinum oxide to a solvent such as methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, water, tetrahydrofuran, tert-butylmethyl ether, N,N-dimethylformamide, toluene, or a mixture thereof. If necessary, reaction accelerators such as acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride diethyl ether complex, boron tribromide, aluminum chloride, chlorotrimethylsilane, 2,2,2-trifluoroethanol, and tetraisopropyl orthotitanate can be added.

[0142] Process 7-2 Compound (24) can be produced by reductive alkylation using compounds (21) and (23). The reaction can be carried out using the same method as in step 7-1.

[0143] Process 7-3 Compound (2f) can be produced by removing the protecting group from compound (24). For the reaction conditions, when PG is a benzyl group, the reaction can be carried out at 0°C to room temperature, or under reflux, using a solvent such as methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, acetic acid, ethyl acetate, water, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, N,N-dimethylformamide, toluene, n-hexane, or a mixture thereof, along with Raney nickel, hydrogen, ammonium formate, etc. Catalysts such as palladium carbon, rhodium carbon, platinum carbon, palladium hydroxide, and platinum oxide can be added as needed. Additionally, acids such as trifluoroacetic acid can be added as reaction accelerators as needed. Alternatively, the reaction can be carried out at -78°C under reflux by adding an acid such as trifluoroacetic acid, p-toluenesulfonic acid, sulfuric acid, hydrogen chloride, hydrobromic acid, boron trifluoride diethyl ether complex, boron tribromide, or aluminum chloride to a solvent such as dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, water, or a mixture thereof. If necessary, anisole, pentamethylbenzene, dimethyl sulfide, etc., can be added as reaction accelerators.

[0144] [Synthesis Path 8] When compound (2) described above is represented as compound (2g), it can be produced, for example, by the method detailed in synthesis route 8 below or a similar method, or by other methods described in the literature or a similar method.

[0145] [ka]

[0146] (In the formula, R 38 represents a hydrogen atom or a C1-C6 alkyl group, and PG, R 2 , R 3 , R 4 , R 15 , R 16 , R 17 , R 18 , R 22 , R23 (RingB, V, m, and q are synonymous with those mentioned above.)

[0147] Process 8-1 Compound (2g) can be prepared by removing the protecting group from compound (25). If the PG is a tert-butoxycarbonyl group, the reaction can be carried out in the same manner as in step 3-2.

[0148] [Synthesis Path 9] When the above-mentioned compound (2) is represented as compound (2h), it can be produced, for example, by the method detailed in the following synthesis route 9 or a similar method, or by other methods described in the literature or a similar method.

[0149] [ka]

[0150] (In the formula, c represents an integer from 0 to 3 independently, and PG and R 2 , R 3 , R 4 , R 15 , R 16 (And m are synonymous with those mentioned above.)

[0151] Process 9-1 Compound (2h) can be produced by removing the protecting group from compound (26). If the PG is a tert-butoxycarbonyl group, the reaction can be carried out in the same manner as in step 3-2.

[0152] [Synthesis Route 10] When compound (2) described above is represented by compound (2i), it can be produced, for example, by the method detailed in the following synthesis route 10 or a similar method, or by other methods described in the literature or a similar method.

[0153] [ka]

[0154] (In the formula, d is an independent integer between 0 and 3, and A, PG, R 2 , R 3 , R 4 , R 15 , R 16 , R 17 , R 18 , R 22 , R 23 (RingB, V, m, and q are synonymous with those mentioned above.)

[0155] Process 10-1 Compound (2i) can be produced by removing the protecting group from compound (27). If the PG is a tert-butoxycarbonyl group, the reaction can be carried out in the same manner as in step 3-2.

[0156] [Synthesis Route 11] When the above-mentioned compound (2) is represented as compound (2j), it can be produced, for example, by the method detailed in the following synthesis route 11 or a similar method, or by other methods described in the literature or a similar method.

[0157] [ka]

[0158] (In the formula, e is an independent integer between 0 and 3, and A, PG, R 2 , R 3 , R 4 , R 15 , R 16 , R 17 , R 18 , R 22 , R 23 (RingB, V, m, and q are synonymous with those mentioned above.)

[0159] Process 11-1 Compound (2j) can be produced by removing the protecting group from compound (28). If the PG is a tert-butoxycarbonyl group, the reaction can be carried out in the same manner as in step 3-2.

[0160] [Synthesis Route 12] When compound (2) described above is represented as compound (2k), it can be produced, for example, by the method detailed in synthesis route 12 below or a similar method, or by other methods described in the literature or a similar method.

[0161] [ka]

[0162] (In the formula, f is an independent integer between 0 and 3, and PG, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 (RingA, Y, and n are synonymous with those mentioned above.)

[0163] Process 12-1 Compound (2k) can be produced by removing the protecting group from compound (29). If the PG is a tert-butoxycarbonyl group, the reaction can be carried out in the same manner as in step 3-2.

[0164] [Synthesis Route 13] When the above-mentioned compound (2) is represented as compound (2l), it can be produced, for example, by the method detailed in the following synthesis route 13 or a similar method, or by other methods described in the literature or a similar method.

[0165] [ka]

[0166] (In the formula, R 3 , R 4 , R 5 , R 6 , R 7 (RingA, Y, Z, and n are synonymous with those mentioned above.)

[0167] Process 13-1 Compound (2l) can be produced by reducing the nitro group of compound (30). The reaction can be carried out using the same method as in step 6-1.

[0168] [Synthesis Route 14] When the above-mentioned compound (7) is represented by compound (7a), it can be produced, for example, by the method detailed in the following synthesis route 14 or a similar method, or by other methods described in the literature or a similar method.

[0169] [ka]

[0170] (In the formula, R 17 , R 18 , R 20 , R 21 , R 22 , R 23 (RingB, V, Q, r, and q are synonymous with those mentioned above.)

[0171] Process 14-1 Compound (7a) can be produced by reducing the nitro group of compound (31). The reaction can be carried out using the same method as in step 6-1.

[0172] [Synthesis Route 15] If the compound (31) described above is represented by compound (31a) or compound (31b), it can be produced, for example, by the method detailed in the following synthesis route 15 or a similar method, or by other methods described in the literature or a similar method.

[0173] [ka]

[0174] (In the formula, g is an independent integer between 0 and 3, R 39 and R 40 Each of these independently represents a hydrogen atom or a C1-C6 alkyl group, and A, PG, R 17 , R 18 , R 22 , R 23 (RingB, V, Q, and q are synonymous with those mentioned above.)

[0175] Process 15-1 Compound (31a) can be produced by reacting compound (32) and compound (33). The reaction can be carried out under the following conditions: compound (33) is added to acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, or a mixture thereof, and the reaction is carried out at 0°C under reflux. If necessary, bases such as sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, triethylamine, N,N-diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene, sodium hydride, and n-butyllithium can be added.

[0176] Process 15-2 Compound (35) can be produced by reacting compound (32) and compound (34). The reaction can be carried out using the same method as in step 15-1.

[0177] Process 15-3 Compound (36) can be produced by removing the protecting group from compound (35). If the PG is a tert-butoxycarbonyl group, the reaction can be carried out in the same manner as in step 3-2.

[0178] Process 15-4 Compound (31b) can be produced by reacting compound (36) and compound (37). The reaction can be carried out using the same method as in step 7-1.

[0179] [Synthesis Route 16] When the above-mentioned compound (31) is represented as compound (31c), it can be produced, for example, by the method detailed in the following synthesis route 16 or a similar method, or by other methods described in the literature or a similar method.

[0180] [ka]

[0181] (In the formula, R 41 and R 42 Each of these independently represents a hydrogen atom, a C1-C6 alkyl group, or a halo-C1-C6 alkyl group, and R 41 and R 42 They may be bonded to each other to form a ring, LG, R 17 , R 18 , R 20 , R 21 , R 22 , R 23 (RingB, V, r, and q are synonymous with those mentioned above.)

[0182] Process 16-1 Compound (39) can be produced by converting the hydroxyl group of compound (38) to a suitable leaving group (LG). The reaction can be carried out using the same method as in step 4-1.

[0183] Process 16-2 Compound (31c) can be produced by reacting compound (39) and compound (40). The reaction can be carried out using the same method as in step 4-2.

[0184] [Synthesis Route 17] When compound (7) described above is represented by compound (7b), it can be produced, for example, by the method detailed in the following synthesis route 17 or a similar method, or by other methods described in the literature or a similar method.

[0185] [ka]

[0186] (In the formula, LG, R 15 , R 16 , R 17 , R 18 , R 20 , R 21 , R 22 , R 23 (RingB, V, Q, m, r, and q are synonymous with those mentioned above.)

[0187] Process 17-1 Compound (42) can be produced by converting the hydroxyl group of compound (41) to a suitable leaving group (LG). The reaction can be carried out using the same method as in step 4-1.

[0188] Process 17-2 Compound (43) can be produced by azidating compound (42). The reaction conditions can be those of a general azide reaction. For example, an azidating agent, such as sodium azide or trimethylsilyl azide, can be added to water, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, ethanol, methanol, or a mixture thereof, and the reaction can be carried out at -78°C or under reflux. Additionally, if necessary, tetra-n-butylammonium fluoride (TBAF), boron trifluoride diethyl ether complex, aluminum chloride, etc., can be added as reaction accelerators.

[0189] Process 17-3 Compound (7b) can be produced by reducing the azide group of compound (43). The reaction conditions can be those of a general azide group reduction reaction. For example, the reaction can be carried out at -78°C under reflux by adding a reducing agent such as lithium aluminum hydride, triphenylphosphine, or hydrogen to water, tetrahydrofuran, 1,4-dioxane, diethyl ether, ethanol, methanol, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, acetonitrile, acetone, ethyl acetate, or a mixture thereof. Additionally, catalysts such as palladium carbon, rhodium carbon, platinum carbon, palladium hydroxide, or platinum oxide can be added as needed.

[0190] [Synthesis Route 18] When compound (7) described above is represented by compound (7c), it can be produced, for example, by the method detailed in the following synthesis route 18 or a similar method, or by other methods described in the literature or a similar method.

[0191] [ka]

[0192] (In the formula, R 43 and R 44 Each of these independently represents a hydrogen atom or a C1-C6 alkyl group (the C1-C6 alkyl group may be substituted with one or more C1-C6 alkylamino groups), R 43 and R 44 They may be bonded to each other to form a ring, such as LG, PG, R 15 , R 16 , R 17 , R 18 , R 20 , R 21 , R 22 , R 23(RingB, V, m, r, and q are synonymous with those mentioned above.)

[0193] Process 18-1 Compound (45) can be produced by converting the hydroxyl group of compound (44) to a suitable leaving group (LG). The reaction can be carried out using the same method as in step 4-1.

[0194] Process 18-2 Compound (47) can be produced by reacting compound (45) and compound (46). The reaction can be carried out using the same method as in step 4-2.

[0195] Process 18-3 Compound (7c) can be produced by removing the protecting group from compound (47). If the PG is a tert-butoxycarbonyl group, the reaction can be carried out in the same manner as in step 3-2.

[0196] [Synthesis Route 19] When compound (7) described above is represented by compound (7d), it can be produced, for example, by the method detailed in the following synthesis route 19 or a similar method, or by other methods described in the literature or a similar method.

[0197] [ka]

[0198] (In the formula, R 17 , R 18 , R 20 , R 21 , R 22 , R 23 (RingB, V, Q, r, and q are synonymous with those mentioned above.)

[0199] Process 19-1 Compound (7d) can be produced by subjecting compound (48) to a Curtius rearrangement reaction. General Curtius rearrangement reaction conditions can be applied as reaction conditions. For example, an azidating agent, such as diphenyl phosphate azide or sodium azide, and a base such as triethylamine or pyridine can be added to a solvent such as toluene, benzene, diphenyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, or a mixture thereof, and the reaction can be carried out at 0°C under reflux, followed by the addition of water, and the reaction can be carried out at 0°C under reflux. If necessary, an acid such as hydrogen chloride can be added as a reaction accelerator.

[0200] [Synthesis Route 20] When compound (7) described above is represented by compound (7e), it can be produced, for example, by the method detailed in the following synthesis route 20 or a similar method, or by other methods described in the literature or a similar method.

[0201] [ka]

[0202] (In the formula, h is an integer from 0 to 3, R 45 and R 46 Each of these independently represents a hydrogen atom or a C1-C6 alkyl group, and R 45 and R 46 They may bond to each other to form a ring, R 17 and R 18 This is synonymous with what was mentioned above.

[0203] Process 20-1 Compound (51) can be produced by reacting compound (49) and compound (50). The reaction can be carried out using the same method as in step 7-1.

[0204] Process 20-2 Compound (7e) can be produced by reducing compound (51). The reaction can be carried out under solvent-free conditions, or in a solvent such as water, tetrahydrofuran, 1,4-dioxane, diethyl ether, ethanol, methanol, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, acetonitrile, acetone, ethyl acetate, dichloromethane, or a mixture thereof, with the addition of reducing agents such as triethylsilane, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, borane-dimethyl sulfide complex, lithium aluminum hydride, or hydrogen, and heated under reflux from -78°C. If necessary, acids such as trifluoroacetic acid, acetic acid, or boron trifluoride diethyl ether complex, or catalysts such as palladium carbon, rhodium carbon, platinum carbon, palladium hydroxide, or platinum oxide can be added.

[0205] [Synthesis Route 21] When compound (7) described above is represented as compound (7f), it can be produced, for example, by the method detailed in the following synthesis route 21 or a similar method, or by other methods described in the literature or a similar method.

[0206] [ka]

[0207] (In the formula, PG, RingB, R 17 and R 18 This is synonymous with what was mentioned above.

[0208] Process 21-1 Compound (53) can be produced by protecting the amino group of compound (52). For the reaction conditions, if the PG is a tert-butoxycarbonyl group, the reaction can be carried out at -78°C to room temperature, or under reflux if necessary, by adding di-tert-butyl dicarbonate, etc., to a solvent such as dichloromethane, 1,4-dioxane, tetrahydrofuran, toluene, ethyl acetate, water, or a mixture thereof. If necessary, a base such as triethylamine, N,N-diisopropylethylamine, potassium carbonate, or sodium carbonate can be added. In addition, reaction accelerators such as pyridine or N,N-dimethyl-4-aminopyridine can be added if necessary.

[0209] Process 21-2 Compound (7f) can be produced by reducing the nitro group of compound (53). The reaction can be carried out using the same method as in step 6-1.

[0210] [Synthesis Pathway 22] When the above-mentioned compound (7) is represented as compound (7g), it can be produced, for example, by the method detailed in the following synthesis route 22 or a similar method, or by other methods described in the literature or a similar method.

[0211] [ka]

[0212] (In the formula, i represents an integer from 0 to 3 independently, and PG, LG, R 22 , R 23 q and Q are synonymous with those mentioned above.

[0213] Process 22-1 Compound (57) can be produced by reacting compound (55) and compound (56). The reaction can be carried out using the same method as in step 4-2.

[0214] Process 22-2 Compound (7g) can be prepared by removing the protecting group from compound (57). If the PG is a tert-butoxycarbonyl group, the reaction can be carried out in the same manner as in step 3-2.

[0215] [Synthesis Path 23] When the above-mentioned compound (7) is represented as compound (7h), it can be produced, for example, by the method detailed in the following synthesis route 23 or a similar method, or by other methods described in the literature or a similar method.

[0216] [ka]

[0217] (In the formula, LG, R 17 , R 18 , R 20 , R 21 , R 22 , R 23 RingB, r, q, and Q are synonymous with those mentioned above.

[0218] Process 23-1 Compound (59) can be produced by reacting compound (58) and compound (56). The reaction can be carried out at -78°C under reflux by adding compound (56) or salts thereof to a solvent such as dichloromethane, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, acetonitrile, or a mixture thereof. If necessary, a base such as sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N,N-diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), or 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN) can be added.

[0219] Process 23-2 Compound (7h) can be produced by amination of compound (59). The reaction conditions involve adding an amination agent such as benzophenone imine to a solvent such as 1,2-dimethoxyethane, 1,4-dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, or a mixture thereof, and then adding a base such as potassium carbonate, tripotassium phosphate, sodium carbonate, cesium carbonate, potassium acetate, or triethylamine, followed by tris(dibenzylideneacetone)dipalladium(0)(Pd2(dba)3), vinegar, etc. Palladium acid (Pd(OAc)2), bis(triphenylphosphine)palladium(II) dichloride (PdCl2(Ph3P)2), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (PdCl2(dppf)), tetrakis(triphenylphosphine)palladium (Pd(Ph3P)4), or (2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl)aminobiphenylpalladium chloride (XPhos A palladium catalyst such as Pd G3) can be added, and if necessary, ligands such as 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (tert-BuXPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos) can be added and the reaction carried out at room temperature under reflux, after which an acidic aqueous solution such as hydrochloric acid can be added and the reaction can be carried out at -78°C under reflux.

[0220] [Synthesis Path 24] When compound (7) described above is represented by compound (7i), it can be produced, for example, by the method detailed in the following synthesis route 24 or a similar method, or by other methods described in the literature or a similar method.

[0221] [ka]

[0222] (In the formula, R 47 represents a hydrogen atom or a C1-C6 alkyl group, and PG, R 4 , R 15 , R 16 , R 17 , R 18 (RingB and m are synonymous with those mentioned above.)

[0223] Process 24-1 Compound (62) can be produced by reducing the cyano group of compound (61). The reaction can be carried out at 0°C to room temperature, or under reflux if necessary, by adding a reducing agent such as Raney nickel, formic acid, sodium borohydride, nickel borohydride, cobalt borohydride, or lithium aluminum hydride to methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, acetic acid, water, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, N,N-dimethylformamide, toluene, n-hexane, or a mixture thereof, under a hydrogen atmosphere. Alternatively, the reaction can be carried out at 0°C to room temperature, or under reflux if necessary.

[0224] Process 24-2 Compound (64) can be produced by reductive alkylation of compound (62) using compound (63). The reaction conditions involve adding an aldehyde represented by compound (63) or a similar compound, such as paraformaldehyde, aqueous formalin solution, or glycolaldehyde dimer, to a solvent such as dichloromethane, 1,2-dichloroethane, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, methanol, ethanol, or a mixture thereof. A reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, borane-dimethyl sulfide complex, lithium aluminum hydride, or 2-picolylborane is then added, and the reaction can be carried out at -78°C to room temperature, or under reflux if necessary. Alternatively, the reaction can be reduced by adding a catalyst such as palladium carbon, rhodium carbon, platinum carbon, or platinum oxide in a hydrogen atmosphere in methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, water, tetrahydrofuran, tert-butyl methyl ether, N,N-dimethylformamide, toluene, or a mixture thereof. If necessary, reaction accelerators such as acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride diethyl ether complex, boron tribromide, aluminum chloride, chlorotrimethylsilane, 2,2,2-trifluoroethanol, or tetraisopropyl orthotitanate may be added.

[0225] Process 24-3 Compound (7i) can be prepared by removing the protecting group from compound (64). If the PG is a tert-butoxycarbonyl group, the reaction can be carried out in the same manner as in step 3-2.

[0226] [Synthesis Route 25] The compound (4a) described above can be produced, for example, by the method detailed in the following synthesis route 25 or a similar method, or by other methods described in the literature or a similar method.

[0227] [ka]

[0228] (In the formula, R 48 R represents a C1-C6 alkyl group, 2 This is synonymous with what was mentioned above.

[0229] Process 25-1 Compound (4a) can be produced by hydrolyzing compound (65). The reaction can be carried out using the same method as in step 1-2.

[0230] [Synthesis Route 26] If the above-mentioned compound (65) is represented by compound (65a) or compound (65b), it can be produced, for example, by the method detailed in the following synthesis route 26 or a similar method, or by other methods described in the literature or a similar method.

[0231] [ka]

[0232] (In the formula, R 50 R represents a C1-C6 alkyl group, 2a , R 2d and R 2e This is synonymous with what was mentioned above.

[0233] Process 26-1 Compound (67) can be produced by oximating compound (66). The reaction can be carried out at -78°C to room temperature, or under reflux, by adding sodium nitrite, isoamyl nitrite, etc., to water, tetrahydrofuran, diethyl ether, dichloromethane, ethyl acetate, etc., or a mixture thereof. Acids such as acetic acid and hydrogen chloride can be added as needed.

[0234] Process 26-2 Compound (65a) can be produced by reacting compound (67) and compound (68). The reaction can be carried out under the following conditions: zinc powder is added to a solvent such as acetic acid, and the reaction is carried out at 0°C under reflux. Sodium acetate or other substances can be added as needed.

[0235] Process 26-3 Compound (65b) can be produced by reducing the carbonyl group of compound (65a). The reaction can be carried out at -78°C to room temperature, or under reflux, using a reducing agent such as sodium borohydride in a solvent such as 1,4-dioxane, tetrahydrofuran, diethyl ether, or a mixture thereof. A reaction accelerator such as boron trifluoride diethyl ether complex may be added as needed.

[0236] [Synthesis Route 27] When the above-mentioned compound (65) is represented as compound (65c), it can be produced, for example, by the method detailed in the following synthesis route 27 or a similar method, or by other methods described in the literature or a similar method.

[0237] [ka]

[0238] (In the formula, R 52 R represents a C1-C6 alkyl group, 53 R represents a hydrogen atom, a C1-C6 alkyl group, or a C2-C6 alkenyl group. 53 Z and X, R may be joined to each other to form a ring. 6 , R 7 , R 8 RingA, n, and Z are synonymous with those mentioned above.

[0239] Process 27-1 Compound (65c) can be produced by reacting compound (69) and compound (70). The reaction can be carried out at room temperature under reflux conditions by adding compound (70) to a solvent such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, ethanol, or a mixture thereof. If necessary, a base such as potassium carbonate, tripotassium phosphate, sodium carbonate, cesium carbonate, potassium acetate, or triethylamine, tris(dibenzylideneacetone)dipalladium(0)(Pd2(dba)3), palladium acetate (Pd(OAc)2), bis(triphenylphosphine)palladium(II) dichloride (PdCl2(Ph3P)2), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (PdCl2(dppf)), tetrakis(triphenylphosphine)palladium (Pd(Ph3P)4), or (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl)aminobiphenylpalladium chloride (XPhosPd Palladium catalysts such as G3) and ligands such as 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (tert-BuXPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos) can be added.

[0240] [Synthesis Route 28] When the above-mentioned compound (65) is represented as compound (65d), it can be produced, for example, by the method detailed in the following synthesis route 28 or a similar method, or by other methods described in the literature or a similar method.

[0241] [ka]

[0242] (In the formula, R 54represents a C1-C6 alkyl group, and LG, R 6 , R 7 , R 8 RingA, n, and Z are synonymous with those mentioned above.

[0243] Process 28-1 Compound (65d) can be produced by reacting compound (71) and compound (72). The reaction can be carried out using the same method as in step 23-1.

[0244] [Synthesis Route 29] When the above-mentioned compound (65) is represented as compound (65e), it can be produced, for example, by the method detailed in the following synthesis route 29 or a similar method, or by other methods described in the literature or a similar method.

[0245] [ka]

[0246] (In the formula, R 55 R represents a C1-C6 alkyl group, 56 and R 57 Each of these independently represents a hydrogen atom or a C1-C6 alkyl group (the C1-C6 alkyl group may be substituted with one or more C1-C6 alkylamino groups), R 56 and R 57 They may bond to each other to form a ring, R 6 , R 7 , R 8 (RingA and n are synonymous with those mentioned above.)

[0247] Process 29-1 Compound (65e) can be produced by reductive alkylation of compound (73) with compound (74). The reaction can be carried out using the same method as in step 7-1.

[0248] [Synthesis Route 30] When the above-mentioned compound (65) is represented as compound (65f), it can be produced, for example, by the method detailed in the following synthesis route 30 or a similar method, or by other methods described in the literature or a similar method.

[0249] [ka]

[0250] (In the formula, R 58 R represents a hydrogen atom or a C1-C6 alkyl group. 58 They may be bonded to each other to form a ring, X, R 6 , R 7 , R 8 , R 52 RingA, n, and Z are synonymous with those mentioned above.

[0251] Process 30-1 Compound (65f) can be produced by coupling compound (69) and compound (75). The general conditions for the Suzuki-Miyaura coupling reaction can be applied as reaction conditions. For example, compound (75) is added to a solvent such as dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, toluene, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, water, or a mixture thereof, and a base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, cesium fluoride, triethylamine, or N,N-diisopropylethylamine is added to produce bis(triphenylphosphine)palladium(II) dichloride (PdCl2(PPh3)2), [1,1'-bis(diphenyl This process can be carried out at 0°C under reflux using palladium catalysts such as [phosphino)ferrocene]palladium(II) dichloride dichloromethane complex (PdCl2(dppf)·CH2Cl2), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (PdCl2(dppf)), tetrakis(triphenylphosphine)palladium (Pd(Ph3P)4), palladium acetate (Pd(OAc)2), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl)aminobiphenylpalladium chloride (XPhos Pd G3). Additionally, ligands such as 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (tert-BuXPhos) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos) can be added as needed.

[0252] [Synthesis Route 31] When the above-mentioned compound (65) is represented as compound (65g) or compound (65h), it can be produced, for example, by the method detailed in the following synthesis route 31 or a similar method, or by other methods described in the literature or a similar method.

[0253] [ka]

[0254] (In the formula, each j represents an integer from 0 to 3 independently, R 59 R represents a protecting group such as a tert-butoxycarbonyl group, benzyloxycarbonyl group, benzyl group, acetyl group, benzoyl group, or 9-fluorenylmethyloxycarbonyl group, or a C1-C6 alkyl group. 60 R represents a hydrogen atom or a C1-C6 alkyl group. 60 They may each combine to form a ring, X, R 6 , R 7 , R 8 , R 52 (RingA and n are synonymous with those mentioned above.)

[0255] Process 31-1 Compound (65g) can be produced by coupling compound (69) and compound (76). The reaction can be carried out using the same method as in step 30-1.

[0256] Process 31-2 Compound (65h) can be produced by reducing the unsaturated bonds of compound (65g). The reaction can be carried out under a hydrogen atmosphere in methanol, ethanol, isopropyl alcohol, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, water, tetrahydrofuran, tert-butyl methyl ether, N,N-dimethylformamide, toluene, or a mixture thereof, with the addition of a catalyst such as palladium carbon, rhodium carbon, platinum carbon, or platinum oxide, and heated under reflux from 0°C. If necessary, acetic acid, trifluoroacetic acid, 2,2,2-trifluoroethanol, etc., can be added as reaction accelerators.

[0257] [Synthesis Path 32] When the above-mentioned compound (65) is represented as compound (65i), it can be produced, for example, by the method detailed in the following synthesis route 32 or a similar method, or by other methods described in the literature or a similar method.

[0258] [ka]

[0259] (In the formula, X, R 6 , R 7 , R 8 , R 52 (RingA and n are synonymous with those mentioned above.)

[0260] Process 32-1 Compound (78) can be produced by coupling compound (69) and compound (77). The reaction can be carried out using the same method as in step 30-1.

[0261] Process 32-2 Compound (65i) can be produced by reducing the unsaturated bond of compound (78). The reaction can be carried out using the same method as in step 31-2.

[0262] [Synthesis Path 33] When the above-mentioned compound (65) is represented as compound (65j), it can be produced, for example, by the method detailed in the following synthesis route 33 or a similar method, or by other methods described in the literature or a similar method.

[0263] [ka]

[0264] (In the formula, R 61 R represents a C1-C6 alkyl group, 8 Y and Z are synonymous with those mentioned above.

[0265] Process 33-1 Compound (81) can be produced by reacting compound (79) and compound (80). The reaction can be carried out at room temperature under reflux by adding compound (80) to methanol, ethanol, 1-propanol, isopropyl alcohol, tetrahydrofuran, 1,4-dioxane, toluene, N,N-dimethylformamide, or a mixture thereof.

[0266] Process 33-2 Compound (65j) can be produced by dehydrating compound (81). The reaction can be carried out at room temperature or under reflux conditions by adding an acid such as p-toluenesulfonic acid or camphor sulfonic acid to a solvent such as benzene, toluene, xylene, or a mixture thereof.

[0267] [Synthesis Path 34] When compound (3) above is represented by compound (3a), or when compound (9) above is represented by compound (9a), it can be produced, for example, by the method detailed in the following synthesis route 34 or a similar method, or by other methods described in the literature or a similar method.

[0268] [ka]

[0269] (In the formula, R 62 represents a C1-C6 alkyl group, and LG, PG, and R 3 This is synonymous with what was mentioned above.

[0270] Process 34-1 Compound (83) can be produced by converting the hydroxyl group of compound (82) to a suitable leaving group (LG). The reaction can be carried out using the same method as in step 4-1.

[0271] Process 34-2 Compound (85) can be produced by reacting compound (84) and compound (83). The reaction can be carried out under the following conditions: compound (83) is added to N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, or a mixture thereof, and the reaction is carried out at 0°C under reflux. If necessary, bases such as sodium hydride, tert-butoxypotassium, 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), or 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN) can be added.

[0272] Process 34-3 Compound (86) can be produced by hydrolyzing compound (85). The reaction can be carried out using the same method as in step 1-2.

[0273] Process 34-4 Compound (87) can be produced by decarboxylating compound (86). The reaction can be carried out at room temperature or under reflux in a solvent such as benzene, toluene, xylene, 1,2-dichlorobenzene, dimethyl sulfoxide, or a mixture thereof. Hydrogen chloride, p-toluenesulfonic acid, etc., can be added as reaction accelerators as needed.

[0274] Process 34-5 Compound (9a) can be produced by hydrolyzing compound (87). The reaction can be carried out using the same method as in step 1-2.

[0275] Process 34-6 Compound (87) can be produced by esterifying compound (9a). The reaction can be carried out at 0°C to room temperature by adding trimethylsilyldiazomethane, etc., to methanol, diethyl ether, tetrahydrofuran, n-hexane, benzene, toluene, etc., or a mixture thereof, as the reaction conditions.

[0276] Process 34-7 Compound (3a) can be produced by removing the protecting group from compound (87). If the PG is a tert-butoxycarbonyl group, the reaction can be carried out in the same manner as in step 3-2.

[0277] [Synthesis Route 35] When compound (3) described above is represented by compound (3b), and when compound (9) described above is represented by compound (9b), the compounds can also be produced, for example, by the method detailed in the following synthesis route 35 or a similar method, or by other methods described in the literature or a similar method.

[0278] [ka]

[0279] (In the formula, LG, PG and R 3 This is synonymous with what was mentioned above.

[0280] Process 35-1 Compound (89) can be produced by reacting compound (88) and compound (83). The reaction can be carried out at -78°C to room temperature by adding compound (83) to a solvent such as tetrahydrofuran, n-hexane, or a mixture thereof, and then adding a base such as n-butyllithium.

[0281] Process 35-2 Compound (3b) can be produced by hydrolyzing compound (89). The reaction can be carried out at 0°C under reflux by adding hydrogen chloride or the like to water, tetrahydrofuran, 1,4-dioxane, or a aqueous mixture thereof.

[0282] Process 35-3 Compound (90) can be produced by protecting the amino group of compound (3b). If the PG is a tert-butoxycarbonyl group, the reaction can be carried out in the same manner as in step 21-1.

[0283] Process 35-4 Compound (9b) can be produced by hydrolyzing compound (90). The reaction can be carried out using the same method as in step 1-2.

[0284] [Synthesis Route 36] When the above-mentioned compound (10) is represented as compound (10a), it can be produced, for example, by the method detailed in the following synthesis route 36 or a similar method, or by other methods described in the literature or a similar method.

[0285] [ka]

[0286] (In the formula, X, PG, R 3 , R 4 , R 15 , R 16 , R 17 , R 18 (RingB and m are synonymous with those mentioned above.)

[0287] Process 36-1 Compound (93) can be produced by coupling compound (91) and compound (92). The reaction can be carried out using the same method as in step 30-1.

[0288] Process 36-2 Compound (10a) can be produced by reducing the unsaturated bond of compound (93). The reaction can be carried out using the same method as in step 31-2.

[0289] [Synthesis Route 37] When the above-mentioned compound (10) is represented by compound (10b), it can be produced, for example, by the method detailed in the following synthesis route 37 or a similar method, or by other methods described in the literature or a similar method.

[0290] [ka]

[0291] (In the formula, X, PG, R 3 , R 4 , R 15 , R 16 , R 17 , R 18 (RingB and m are synonymous with those mentioned above.)

[0292] Process 37-1 Compound (10b) can be produced by subjecting compound (91) to a cyanation reaction. As reaction conditions, a cyanating agent such as zinc cyanide is added to dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, toluene, tetrahydrofuran, 1,2-dimethoxyethane, water, etc., or a mixture thereof, to produce bis(triphenylphosphine)palladium(II) dichloride (PdCl2(PPh3)2) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (PdCl2(dppf)·C The process can be carried out at 0°C under reflux using a palladium catalyst such as H2Cl2, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (PdCl2(dppf)), tetrakis(triphenylphosphine)palladium (Pd(Ph3P)4), palladium acetate (Pd(OAc)2), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), or 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl)aminobiphenylpalladium chloride (XPhos Pd G3). Ligands such as 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (tert-BuXPhos) or 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos) can also be used as needed.

[0293] [Synthesis Route 38] When the above-mentioned compound (10) is represented as compound (10c), it can be produced, for example, by the method detailed in the following synthesis route 38 or a similar method, or by other methods described in the literature or a similar method.

[0294] [ka]

[0295] (In the formula, R 63 represents a C1-C6 alkyl group, PG, R 3 , R 4 , R 15 , R 16 , R 17 , R20 , R 21 , R 22 , R 23 (RingB, m, r, q, V, and Q are synonymous with those mentioned above.)

[0296] Process 38-1 Compound (10c) can be produced by reducing compound (94). The reaction can be carried out at -78°C under reflux conditions using a hydride reducing agent such as diisobutylaluminum hydride, lithium aluminum hydride, lithium borohydride, sodium borohydride, sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), or lithium tri(sec-butyl)borohydride in methanol, ethanol, tetrahydrofuran, diethyl ether, dichloromethane, toluene, benzene, n-hexane, or a mixture thereof.

[0297] [Synthesis Route 39] Of the compounds (I) mentioned above, R 1 is a nitrogen atom, and R 5 R 17 , R 18 and R 19 A phenyl group which may be substituted with R 1 and R 5 If the compound is formed by the bonding of to form a benzimidazole ring, i.e., represented by compound (98), it can be produced, for example, by the method detailed in the following synthesis route 39 or a similar method, or by other methods described in the literature or a similar method.

[0298] [ka]

[0299] (In the formula, PG, X, R 2 , R 3 , R 4 , R 17 , R 18 and R 19 This is synonymous with what was mentioned above.

[0300] Process 39-1 Compound (96) can be produced by reacting compound (9) and compound (95). The reaction conditions involve adding compound (95) and carrying out a dehydration condensation reaction in the same manner as in steps 1-3. Then, acetic acid, hydrogen chloride, p-toluenesulfonic acid, etc., are added to a solvent-free solution, water, 1,4-dioxane, toluene, xylene, ethanol, acetonitrile, etc., or a mixture thereof, and the reaction can be carried out at 0°C under reflux.

[0301] Process 39-2 Compound (97) can be produced by removing the protecting group from compound (96). If the PG is a tert-butoxycarbonyl group, the reaction can be carried out in the same manner as in step 3-2.

[0302] Process 39-3 Compound (98) can be produced by amidating compound (97) with compound (4a) or compound (4b). The reaction can be carried out in the same manner as in step 1-1 by adding compound (4a) or compound (4b), etc., as the reaction conditions.

[0303] [Synthesis Route 40] When the above-mentioned compound (96) is represented by compound (96a), it can be produced, for example, by the method detailed in the following synthesis route 40 or a similar method, or by other methods described in the literature or a similar method.

[0304] [ka]

[0305] (In the formula, R 64 and R 65Each of these independently represents a hydrogen atom, a C1-C6 alkyl group, or a 3-10 membered heterocycloalkyl group (the C1-C6 alkyl group and the 3-10 membered heterocycloalkyl group may be substituted with one or more C1-C6 alkyl groups or C1-C6 alkylamino groups), R 64 and R 65 They may bond to each other to form a ring, X, PG, R 2 , R 3 , R 4 , R 17 , R 18 , R 20 , R 21 (and r are synonymous with those mentioned above.)

[0306] Process 40-1 Compound (100) can be produced by halogenating compound (99). The reaction can be carried out at room temperature under reflux conditions, using a solvent-free solution, carbon tetrachloride, acetonitrile, or a mixture thereof, with the addition of halogenating agents such as N-bromosuccinimide and bromine, and radical initiators such as 2,2'-azobis(isobutyronitrile) and benzoyl peroxide. Light irradiation can also be used if necessary.

[0307] Process 40-2 Compound (96a) can be produced by reacting compound (100) and compound (101). The reaction can be carried out using the same method as in step 4-2.

[0308] [Synthesis Pathway 41] When the above-mentioned compound (96) is represented by compound (96b), it can be produced, for example, by the method detailed in the following synthesis route 41 or a similar method, or by other methods described in the literature or a similar method.

[0309] [ka]

[0310] (In the formula, R 66 R represents a C1-C6 alkyl group, 67 and R 68 Each of these independently represents a hydrogen atom or a C1-C6 alkyl group, and R 67 and R 68 They may be bonded to each other to form a ring, such as LG, PG, R 3 and R 4 This is synonymous with what was mentioned above.

[0311] Process 41-1 Compound (103) can be produced by reducing compound (102). The reaction can be carried out using the same method as in step 38-1.

[0312] Process 41-2 Compound (104) can be produced by converting the hydroxyl group of compound (103) to a suitable leaving group (LG). The reaction can be carried out using the same method as in step 4-1.

[0313] Process 41-3 Compound (96b) can be produced by reacting compound (104) and compound (105). The reaction can be carried out using the same method as in step 4-2.

[0314] [Synthesis Path 42] When the above-mentioned compound (98) is represented as compound (98a), it can be produced, for example, by the method detailed in the following synthesis route 42 or a similar method, or by other methods described in the literature or a similar method.

[0315] [ka]

[0316] (In the formula, PG 1 represents a protecting group such as a tert-butoxycarbonyl group or a benzyloxycarbonyl group, PG2 R represents a protecting group such as a benzyl group or a tert-butyldimethylsilyl group. 2a , R 2d , R 2e , R 3 , R 17 , R 18 , R 22 , R 23 (Q and q are synonymous with those mentioned above.)

[0317] Process 42-1 Compound (107) has a protecting group (PG) on the pyrrole ring of compound (106) and on the nitrogen atom of the benzimidazole ring. 1 It can be manufactured by adding ). As reaction conditions, PG 1 If the group is a tert-butoxycarbonyl group, the process can be carried out in the same manner as in step 21-1.

[0318] Process 42-2 Compound (108) is a protecting group (PG) on the hydroxyl group of compound (107). 2 It can be manufactured by removing ). As reaction conditions, PG 2 If the group is a benzyl group, the process can be carried out in the same manner as in step 7-3.

[0319] Process 42-3 Compound (110) can be produced by the Mitsunobu reaction between compound (108) and compound (109). The reaction conditions can be those of the general Mitsunobu reaction. For example, compound (109) can be added to a solvent-free solution, tetrahydrofuran, 1,4-dioxane, toluene, benzene, or a mixture thereof, followed by the addition of phosphorus reagents such as triphenylphosphine, tributylphosphine, or trimethylphosphine, and azo compounds such as diisopropyl azodicarboxylate (DIAD), diethyl azodicarboxylate (DEAD), or 1,1'-azobis(N,N-dimethylformamide) (TMAD), and the reaction can be carried out at room temperature under reflux.

[0320] Process 42-4 Compound (98a) has a protecting group (PG) on the nitrogen atom of the pyrrole ring and benzimidazole ring of compound (110). 1 It can be manufactured by removing ). As reaction conditions, PG 1 If the group is a tert-butoxycarbonyl group, the process can be carried out in the same manner as in step 3-2.

[0321] [Synthesis Path 43] When the above-mentioned compound (98) is represented by compound (98b), it can be produced, for example, by the method detailed in the following synthesis route 43 or a similar method, or by other methods described in the literature or a similar method.

[0322] [ka]

[0323] (In the formula, PG 3 represents a protecting group such as a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and k independently represents an integer from 0 to 3, A, PG 1 , R 2a , R 2d , R 2e , R 3 , R 17 , R 18 , R 22 , R 23 , and q are synonymous with those mentioned above.

[0324] Process 43-1 Compound (112) can be produced by the Mitsunobu reaction between compound (108) and compound (111). The reaction can be carried out using the same method as in step 42-3.

[0325] Process 43-2 Compound (113) has a protecting group (PG) on the nitrogen atom of the pyrrole ring and benzimidazole ring of compound (112). 1It can be manufactured by removing ). As reaction conditions, PG 1 If the group is a tert-butoxycarbonyl group, the process can be carried out in the same manner as in step 3-2.

[0326] Process 43-3 Compound (98b) is a protecting group (PG) on the amino group of compound (113). 3 It can be manufactured by removing ). As reaction conditions, PG 3 If the group is a benzyloxycarbonyl group, the process can be carried out in the same manner as in step 3-2.

[0327] [Synthesis Path 44] When the above-mentioned compound (98) is represented by compound (98c), it can be produced, for example, by the method detailed in the following synthesis route 44 or a similar method, or by other methods described in the literature or a similar method.

[0328] [ka]

[0329] (In the formula, PG 1 PG 2 , R 2a , R 2d , R 2e , R 3 , R 17 , R 18 , R 22 , R 23 (And q are synonymous with those mentioned above.)

[0330] Process 44-1 Compound (115) can be produced by the Mitsunobu reaction between compound (108) and compound (114). The reaction can be carried out using the same method as in step 42-3.

[0331] Process 44-2 Compound (116) is a protecting group (PG) on the hydroxyl group of compound (115). 2 It can be manufactured by removing ). As reaction conditions, PG 2 If the group is a tert-butyldimethylsilyl group, the process can be carried out by adding an acid such as tetra-n-butylammonium fluoride (TBAF), cesium fluoride, tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), trifluoroacetic acid, p-toluenesulfonic acid, sulfuric acid, hydrogen chloride, hydrobromic acid, boron trifluoride diethyl ether complex, boron tribromide, or aluminum chloride to water, acetone, dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, benzene, methanol, ethanol, or a mixture thereof, and heating under reflux from -78°C.

[0332] Process 44-3 Compound (98c) has a protecting group (PG) on the nitrogen atom of the pyrrole ring and benzimidazole ring of compound (116). 1 It can be manufactured by removing ). As reaction conditions, PG 1 If the group is a tert-butoxycarbonyl group, the process can be carried out in the same manner as in step 3-2.

[0333] [Synthesis Route 45] When the above-mentioned compound (98) is represented as compound (98d), it can be produced, for example, by the method detailed in the following synthesis route 45 or a similar method, or by other methods described in the literature or a similar method.

[0334] [ka]

[0335] (In the formula, R 69 and R 70 Each of these independently represents a hydrogen atom, a C1-C6 alkyl group, or a hydroxy C1-C6 alkyl group, and R 69 and R 70They may bond to each other to form a ring, PG 1 LG, R 2a , R 2d , R 2e , R 3 , R 17 , R 18 , R 22 , R 23 (And q are synonymous with those mentioned above.)

[0336] Process 45-1 Compound (118) can be produced by the Mitsunobu reaction between compound (108) and compound (117). The reaction can be carried out using the same method as in step 42-3.

[0337] Process 45-2 Compound (119) has a protecting group (PG) on the nitrogen atom of the pyrrole ring and benzimidazole ring of compound (118). 1 It can be manufactured by removing ). As reaction conditions, PG 1 If the group is a tert-butoxycarbonyl group, the process can be carried out in the same manner as in step 3-2.

[0338] Process 45-3 Compound (98d) can be produced by reacting compound (119) and compound (120). The reaction can be carried out using compound (120) in the same manner as in step 4-2.

[0339] [Synthesis Route 46] R in compound (I) described above 1 If the compound is represented as a hydrogen atom, i.e., compound (122), it can be produced, for example, by the method detailed in the following synthesis route 46 or a similar method, or by other methods described in the literature or a similar method.

[0340] [ka]

[0341] (In the formula, R 2 , R 3 , R 4 , R 5 (And X is synonymous with what was mentioned above.)

[0342] Process 46-1 Compound (121) can be produced by reducing the carbonyl group of compound (11). The reaction can be carried out at 0°C under reflux using a hydride reducing agent such as a borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, or lithium aluminum hydride in a solvent such as tetrahydrofuran, diethyl ether, methanol, ethanol, dichloromethane, toluene, benzene, n-hexane, or a mixture thereof.

[0343] Process 46-2 Compound (122) can be produced by amidating compound (121) with compound (4a) or compound (4b). The reaction can be carried out in the same manner as in step 1-1 by adding compound (4a) or compound (4b), etc., as the reaction conditions.

[0344] The synthesis routes described above are illustrative of methods for producing compound (I) of this embodiment, and compound (I) of this embodiment can be produced according to the methods described above or similar methods, or other methods described in the literature or similar methods. These production methods can be modified in various ways to schemes that are easily understood by those skilled in the art.

[0345] Furthermore, if a protecting group is required depending on the type of functional group, it can be carried out by combining introduction and elimination operations as appropriate according to conventional methods. For information on the types of protecting groups, introduction, and elimination, see, for example, the methods described in Theodra W. Green & Peter GM Wuts, eds., "Greene's Protective Groups in Organic Synthesis," fourth edition, Wiley-Interscience, 2006.

[0346] The intermediate used to produce compound (I) of this embodiment can be isolated and purified, if necessary, by isolation and purification methods well known to those skilled in the art, such as solvent extraction, crystallization, recrystallization, chromatography, and preparative high-performance liquid chromatography. Furthermore, if necessary, the intermediate may be used in the next reaction as a crude product without isolation or purification.

[0347] In this embodiment, "G9a inhibitory action" refers to the action of inhibiting G9a, the major enzyme involved in the mono- and dimethylation (H3K9me1 and H3K9me2) of the 9th lysine residue of histone H3. Compound (I) of this embodiment, or a pharmaceutically acceptable salt thereof, exhibits potent inhibitory activity, for example, in a G9a inhibitory activity test. As a result, it can be understood that compound (I) of this embodiment or its pharmacologically acceptable salts are useful as therapeutic agents or preventive agents for proliferative disorders such as cancer, β-globin disorders, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy, autism, and the like.

[0348] A pharmaceutical product containing compound (I) of this embodiment as an active ingredient can be in various dosage forms depending on the method of use. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, liquids, ointments, suppositories, patches, sublingual preparations, and the like.

[0349] These pharmaceuticals can be prepared as pharmaceutical compositions containing compound (I) of this embodiment as an active ingredient and pharmaceutically acceptable additives, according to known methods depending on the dosage form. Examples of additives contained in the pharmaceutical composition include excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizers. The pharmaceutical composition can be prepared by appropriately mixing compound (I) of this embodiment with the additives, or by diluting and dissolving compound (I) with the additives.

[0350] The pharmaceutical product according to this embodiment can be administered systemically or locally, orally or parenterally (e.g., nasally, through the lungs, intravenously, rectally, subcutaneously, intramuscularly, percutaneously, etc.).

[0351] (Examples) The present invention will be described in more detail below based on test examples, examples, and reference examples. Furthermore, since the raw material compounds used in the production of compound (I) include novel compounds, examples of the production of these raw material compounds will also be described as reference examples. The present invention is not limited to the compounds described in the following examples, and may be modified without departing from the scope of the present invention.

[0352] Of the symbols used in each reference example, each embodiment, and each table, 1 H-NMR refers to the spectrum measured by proton nuclear magnetic resonance spectroscopy. CDCl3 means chloroform-d, DMSO-D6 means dimethyl sulfoxide-d6, and CD3OD means methanol-d4. MS(ESI + ) and MS (ESI - ) is electrospray ionization, MS (FI + ) is the field ionization method, MS (FD + ) is the field desorption ionization method, MS (EI + ) is an electron ionization method, MS (CI + ) refers to mass spectrometry spectral data measured by chemical ionization. Room temperature means 1 to 30°C.

[0353] <Reference example 1-1>

[0354] [ka]

[0355] Under an argon atmosphere, 55% sodium hydride (550 mg) was gradually added at 0°C to a solution of 2-chloro-5-nitropyridine (1.00 g) and tert-butyl 3-hydroxyazetidine-1-carboxylate (2.18 g) in tetrahydrofuran (15.0 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to water and extracted once with ethyl acetate. The extract layer was washed with water and then saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1 to 2:1) to obtain tert-butyl 3-(5-nitropyridine-2-yl)oxyazetidine-1-carboxylate (1.82 g). 1 H-NMR (CDCl3, 400MHz) δ: 1.45 (9H, s), 3.97-4.04 (2H, m), 4.32-4.40 (2H, m), 5.38-5.47 (1H, m), 6.90 (1H, d, J = 9.2 Hz), 8.40 (1H, dd, J = 9.2, 2.4 Hz), 9.03 (1H, d, J = 2.4 Hz). MS (FI + ): 296.1 [M+H] +

[0356] Using the corresponding starting materials and reagents, Reference Examples 1-2 to 1-6 were obtained using the same method as in Reference Example 1-1, the method described in Step 15-1 or Step 15-2, or a similar method.

[0357] [Table 21]

[0358] [Table 22]

[0359] <Reference example 2-1>

[0360] [ka]

[0361] Under an argon atmosphere, 5% palladium carbon (66.6 mg) was added to a tetrahydrofuran-ethanol mixed solution (7.04 mL, 1:1) of N-(1-methylpiperidine-4-yl)-5-nitropyridine-2-amine (333 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 8 hours. After replacing the reaction system with an argon atmosphere, the reaction mixture was filtered through Celite, and the solvent was removed. The residue was purified by amination silica gel column chromatography (ethyl acetate : methanol = 9:1) to obtain 2-N-(1-methylpiperidine-4-yl)pyridine-2,5-diamine (232 mg). 1 H-NMR (CDCl3, 400 MHz) δ: 1.47-1.58 (2H, m), 2.01-2.08 (2H, m), 2.13-2.21 (2H, m), 2.31 (3H, s), 2.78-2.86 (2H, m), 3.19 (2H, brs), 3.49-3.57 (1H, m), 3.96 (1H, d, J = 7.3 Hz), 6.30 (1H, d, J = 8.5 Hz), 6.94 (1H, dd, J = 8.5, 3.0 Hz), 7.68 (1H, d, J = 3.0 Hz). HRMS (ESI + ):207.16063 [M+H] +

[0362] Using the corresponding starting materials and reagents, Reference Examples 2-2 to 2-7 were obtained using the same method as in Reference Example 2-1, the method described in Step 14-1, or a similar method.

[0363] [Table 23]

[0364] [Table 24]

[0365] <Reference example 3>

[0366] [ka]

[0367] To a solution of tert-butyl 3-(5-nitropyridine-2-yl)oxyazetidine-1-carboxylate (500 mg) in dichloromethane (3.00 mL), trifluoroacetic acid (3.00 mL) was added at room temperature and the mixture was stirred for 1 hour. After removing the solvent and other components from the reaction mixture under reduced pressure, the residue was used as is in Reference Example 4 as the trifluoroacetate salt of 2-(azetidine-3-yloxy)-5-nitropyridine.

[0368] <Reference example 4>

[0369] [ka]

[0370] To a solution of the crude product of Reference Example 3, 2-(azetidine-3-yloxy)-5-nitropyridine trifluoroacetate, in dichloromethane (10.0 mL), 37% formaldehyde aqueous solution (0.672 mL) and sodium triacetoxyborohydride (897 mg) were added at room temperature and the mixture was stirred for 2 hours. After removing the solvent and other components from the reaction mixture under reduced pressure, the residue was purified by amination silica gel column chromatography (hexane:ethyl acetate = 3:1 to 0:1) to obtain 2-(1-methylazetidine-3-yl)oxy-5-nitropyridine (142 mg). 1H-NMR (CDCl3, 400MHz) δ: 2.63 (3H, s), 3.47-3.55 (2H, m), 4.23-4.31 (2H, m), 5.39-5.48 (1H, m), 6.88 (1H, d, J = 9.1 Hz), 8.40 (1H, dd, J = 9.1, 3.0 Hz), 9.02 (1H, d, J = 3.0 Hz). MS (ESI + ): 210.1 [M+H] +

[0371] <Reference example 5>

[0372] [ka]

[0373] Under an argon atmosphere, 140 mg of 2-(1-methylazetidine-3-yl)oxy-5-nitropyridine was added to a solution of 2-(1-methylazetidine-3-yl)oxypyridine-3-amine (140 mg) in ethanol (6.50 mL) at room temperature. The mixture was stirred under a hydrogen atmosphere for 1.5 hours, after which the hydrogen in the reaction vessel was replaced with argon. The reaction mixture was filtered using Celite, and the solvent and other components of the filtrate were removed under reduced pressure. The residue was purified by amination silica gel column chromatography (ethyl acetate : methanol = 1 : 0 ~ 9 : 1) to obtain 6-(1-methylazetidine-3-yl)oxypyridine-3-amine (46.0 mg). 1 H-NMR (CDCl3, 400MHz) δ: 2.39 (3H, s), 3.04-3.11 (2H, m), 3.35 (2H, br s), 3.75-3.82 (2H, m), 5.06-5.15 (1H, m), 6.58 (1H, d, J = 8.5 Hz), 7.02 (1H, dd, J = 8.5, 3.0 Hz), 7.60 (1H, d, J = 3.0 Hz). MS (EI + ): 179.1 [M] +

[0374] <Reference example 6>

[0375] [ka]

[0376] It was synthesized using 2-(4-nitrophenyl)ethanol in the same manner as in Reference Example 80.

[0377] <Reference example 7>

[0378] [ka]

[0379] Under an argon atmosphere, 200 mg of 2-(4-nitrophenyl)ethyl methanesulfonate was dissolved in 1.00 mL of acetonitrile, to which piperidine (0.404 mL) was added at room temperature and the mixture was stirred for 69 hours. The reaction mixture was added to water and extracted twice with ethyl acetate. The combined extract layers were then washed with water and saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was purified by amination silica gel column chromatography (hexane:ethyl acetate = 9:1 to 0:1) to obtain 1-[2-(4-nitrophenyl)ethyl]piperidine (191 mg). 1 H-NMR (CDCl3, 400MHz) δ: 1.41-1.51 (2H, m), 1.56-1.65 (4H, m), 2.38-2.52 (4H, m), 2.55-2.61 (2H, m), 2.86-2.96 (2H, m), 7.36 (2H, d, J = 8.5 Hz), 8.14 (2H, d, J = 8.5 Hz). MS (FI + ): 234.1 [M] +

[0380] <Reference example 8>

[0381] [ka]

[0382] It was synthesized using 1-[2-(4-nitrophenyl)ethyl]piperidine in the same manner as in Reference Example 5. 1 H-NMR (DMSO-D6, 400MHz) δ: 1.31-1.39 (2H, m), 1.42-1.51 (4H, m), 2.28-2.41 (6H, m), 2.47-2.54 (2H, m), 4.78 (2H, s), 6.45 (2H, d, J = 8.5 Hz), 6.82 (2H, d, J = 7.9 Hz). MS (ESI + ): 205.2 [M+H] +

[0383] <Reference example 9>

[0384] [ka]

[0385] Under an argon atmosphere, potassium carbonate (384 mg) and 1-(bromomethyl)-4-nitrobenzene (200 mg) were added to a solution of 4,4-difluoropiperidine hydrochloride (219 mg) in acetonitrile (2.00 mL) at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was added to water and extracted twice with ethyl acetate. The combined extract layers were washed with water and then saturated saline solution, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1 to 1:1) to obtain 4,4-difluoro-1-[(4-nitrophenyl)methyl]piperidine (220 mg). 1 H-NMR (CDCl3, 400MHz) δ: 1.94-2.08 (4H, m), 2.51-2.61 (4H, m), 3.64 (2H, s), 7.51 (2H, d, J = 8.5 Hz), 8.19 (2H, d, J = 8.5 Hz). MS (EI + ): 256.1 [M] +

[0386] <Reference example 10>

[0387] [ka]

[0388] The synthesis was carried out using 4,4-difluoro-1-[(4-nitrophenyl)methyl]piperidine, in the same manner as in Reference Example 5. 1 H-NMR (CDCl3, 400MHz) δ: 1.90-2.03 (4H, m), 2.45-2.58 (4H, m), 3.43 (2H, s), 3.62 (2H, br s), 6.64 (2H, d, J = 8.5 Hz), 7.08 (2H, d, J = 8.5 Hz). MS (EI + ): 226.1 [M] +

[0389] <Reference example 11>

[0390] [ka]

[0391] Under an argon atmosphere, triphenylphosphine (2.35 g) and carbon tetrabromide (2.97 g) were added to a tetrahydrofuran solution (40.7 mL) of tert-butyl N-[2-[4-(hydroxymethyl)phenyl]ethyl]carbamate (2.05 g) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Diethyl ether (50.0 mL) and hexane (50.0 mL) were added to the reaction mixture, and the resulting solid was filtered off with Celite and washed with diethyl ether. The obtained filtrate was concentrated under reduced pressure to obtain tert-butyl N-[2-[4-(bromomethyl)phenyl]ethyl]carbamate. The obtained crude product was used directly in the next step without further purification.

[0392] <Reference example 12>

[0393] [ka]

[0394] Under an argon atmosphere, sodium azide (636 mg) was added to a 40.8 mL solution of the crude product, tert-butyl N-[2-[4-(bromomethyl)phenyl]ethyl]carbamate, in N,N-dimethylformamide, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to obtain tert-butyl N-[2-[4-(azidomethyl)phenyl]ethyl]carbamate (1.85 g). 1 H-NMR (CDCl3, 400 MHz) δ: 1.43 (9H, s), 2.80 (2H, t, J = 7.3 Hz), 3.33-3.41 (2H, m), 4.31 (2H, s), 4.56 (1H, brs), 7.21 (2H, d, J = 7.9 Hz), 7.26 (2H, d, J = 7.9 Hz). HRMS (FI + ):276.15809 [M] +

[0395] <Reference example 13>

[0396] [ka]

[0397] Under an argon atmosphere, 10.3 mL of tetrahydrofuran solution of lithium aluminum hydride (626 mg) was added to 10.3 mL of tetrahydrofuran solution of tert-butyl N-[2-[4-(azidomethyl)phenyl]ethyl]carbamate (1.14 g) under ice cooling, and the mixture was stirred under ice cooling for 4 hours. Water (0.626 mL), 15% aqueous sodium hydroxide solution (0.626 mL), and water (1.88 mL) were added to the reaction mixture, and the mixture was stirred for 2 hours. The resulting suspension was filtered using Celite, and the filtrate was concentrated to obtain tert-butyl N-[2-[4-(aminomethyl)phenyl]ethyl]carbamate (915 mg). 1 H-NMR (CDCl3, 400 MHz) δ: 1.43 (9H, s), 2.78 (2H, t, J = 6.7 Hz), 3.36 (2H, q, J = 6.7 Hz), 3.84 (2H, s), 4.50-4.70 (1H, m), 7.16 (2H, d, J = 7.9 Hz), 7.25 (2H, d, J = 7.9 Hz). HRMS (ESI + ):251.17652 [M+H] +

[0398] <Reference example 14>

[0399] [ka]

[0400] Under an argon atmosphere, triphenylphosphine (186 mg) and carbon tetrabromide (274 mg) were added to a 2.96 mL dichloromethane solution of tert-butyl N-[[6-(hydroxymethyl)pyridine-2-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (200 mg) under ice cooling, and the mixture was stirred for 1 hour under ice cooling. After concentrating the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate : hexane = 1:4) to obtain tert-butyl N-[[6-(bromomethyl)pyridine-2-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (222 mg). 1 H-NMR (CDCl3, 400 MHz) δ: 1.45 (18H, s), 4.51 (2H, s), 4.91 (2H, s), 7.09 (1H, d, J = 7.9 Hz), 7.31 (1H, d, J = 7.9 Hz), 7.65 (1H, t, J = 7.9 Hz). HRMS (ESI + ):401.10834 [M+H] +

[0401] <Reference example 15-1>

[0402] [ka]

[0403] Under an argon atmosphere, 220 mg of tert-butyl N-[[6-(bromomethyl)pyridine-2-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (220 mg) was added to a 2.74 mL solution of N,N-dimethylformamide, to which dimethylamine (0.820 mL, 2 mol / L tetrahydrofuran solution) and potassium carbonate (227 mg) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by amination silica gel column chromatography (ethyl acetate / hexane = 33%) to obtain 177 mg of tert-butyl N-[[6-[(dimethylamino)methyl]pyridine-2-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (177 mg). 1 H-NMR (CDCl3, 400 MHz) δ: 1.43 (18H, s), 2.28 (6H, s), 3.56 (2H, s), 4.92 (2H, s), 7.03 (1H, d, J = 7.9 Hz), 7.25 (1H, d, J = 7.9 Hz), 7.61 (1H, t, J = 7.9 Hz). HRMS (ESI + ):366.23889 [M+H] +

[0404] Using the corresponding starting materials and reagents, Reference Example 15-2 was obtained by the same method as in Reference Example 15-1, the method described in step 18-2, or a similar method.

[0405] [Table 25]

[0406] <Reference example 16>

[0407] [ka]

[0408] Under an argon atmosphere, triethylamine (0.379 mL) and diphenyl phosphate azide (0.585 mL) were added to a solution of 4-ethyl-6-methylpyridine-3-carboxylic acid (224 mg) in 1,4-dioxane (13.0 mL) at room temperature, and the mixture was stirred at 60°C for 1 hour and then at 80°C for 30 minutes. 1 mol / L hydrochloric acid (5.00 mL) was added to the reaction mixture, and the mixture was stirred at the same temperature for 15 minutes. Diisopropylamine (1 mL) was added to the reaction mixture, and the mixture was purified by amination silica gel column chromatography (hexane:ethyl acetate = 5:1 to 0:1) to obtain 4-ethyl-6-methylpyridine-3-amine (100 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: 1.25 (3H, t, J = 7.3 Hz), 2.43 (3H, s), 2.48 (2H, q, J = 7.3 Hz), 3.48 (2H, brs), 6.85 (1H, s), 7.16 (1H, s). MS (EI + ): 136.1 [M] +

[0409] <Reference example 17>

[0410] [ka]

[0411] Under an argon atmosphere, dimethylamine (1.55 mL, 2 mol / L tetrahydrofuran solution) and acetic acid (0.589 mL) were added to a tetrahydrofuran solution (10.3 mL) of 1H-indole-4-carbaldehyde (300 mg) and stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (875 mg) was added and stirred at room temperature for 4 hours. Saturated sodium bicarbonate was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by amination silica gel column chromatography (hexane:ethyl acetate = 2:1) to obtain 1-(1H-indole-4-yl)-N,N-dimethylmethaneamine (334 mg). 1 H-NMR (CDCl3, 400 MHz) δ: 2.30 (6H, s), 3.71 (2H, s), 6.69 (1H, t, J = 2.4 Hz), 7.07 (1H, d, J = 7.3 Hz), 7.16 (1H, t, J = 7.3 Hz), 7.21 (1H, t, J = 2.4 Hz), 7.31 (1H, d, J = 7.3 Hz), 8.22 (1H, brs). HRMS (ESI + ):175.12376 [M+H] +

[0412] <Reference example 18>

[0413] [ka]

[0414] Under an argon atmosphere, 0.752 mL of trifluoroacetic acid solution of 1-(1H-indole-4-yl)-N,N-dimethylmethaneamine (131 mg) was mixed with triethylsilane (0.240 mL) under ice cooling and stirred for 2 hours under ice cooling. Saturated sodium bicarbonate was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by amination silica gel column chromatography (hexane:ethyl acetate = 2:1) to obtain 1-(2,3-dihydro-1H-indole-4-yl)-N,N-dimethylmethaneamine (103 mg). 1 H-NMR (CDCl3, 400 MHz) δ: 2.29 (6H, s), 3.04 (2H, t, J = 8.3 Hz), 3.40 (2H, s), 3.56 (2H, t, J = 8.3 Hz), 6.57 (1H, d, J = 7.9 Hz), 6.68 (1H, d, J = 7.9 Hz), 7.00 (1H, t, J = 7.9 Hz). HRMS (EI + ): 176.13135 [M] +

[0415] <Reference example 19>

[0416] [ka]

[0417] Under an argon atmosphere, 1.00 g of 4-methyl-6-nitro-1,3-benzothiazole-2-amine was mixed with 25.0 mL of dichloromethane and 25.0 mL of tetrahydrofuran. At room temperature, 1.15 g of di-tert-butyl dicarbonate and N,N-dimethyl-4-aminopyridine were added, and the mixture was stirred for 20 hours. After filtering off insoluble matter from the reaction mixture, the solvent and other components were removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1 to 1:1) to obtain tert-butyl N-(4-methyl-6-nitro-1,3-benzothiazole-2-yl)carbamate (1.30 g). 1 H-NMR (DMSO-D6, 400MHz) δ: 1.51 (9H, s), 2.60 (3H, s), 8.10 (1H, dd, J = 2.4, 1.2 Hz), 8.81 (1H, d, J = 2.4 Hz), 12.27 (1H, s). MS (ESI-): 308.1 [MH] -

[0418] <Reference example 20>

[0419] [ka]

[0420] It was synthesized using tert-butyl N-(4-methyl-6-nitro-1,3-benzothiazole-2-yl)carbamate in the same manner as in Reference Example 5. 1 H-NMR (DMSO-D6, 400MHz) δ: 1.47 (9H, s), 2.38 (3H, s), 4.97 (2H, s), 6.48 (1H, d, J = 2.4 Hz), 6.78 (1H, d, J = 2.4 Hz), 11.37 (1H, s). MS (ESI + ): 280.1 [M+H] +

[0421] <Reference example 21>

[0422] [ka]

[0423] Under an argon atmosphere, tert-butyl N-piperidine-4-ylcarbamate (200 mg) was dissolved in tetrahydrofuran (5.00 mL), to which N,N-diisopropylethylamine (0.340 mL) and 1-(3-bromopropyl)pyrrolidine hydrobromide (300 mg) were added at room temperature and the mixture was stirred at 40°C for 24 hours. The reaction mixture was added to water and extracted three times with ethyl acetate. The combined extract layers were dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was crudely purified by amination silica gel column chromatography (ethyl acetate : methanol = 1 : 0 ~ 9 : 1) to obtain tert-butyl N-[1-(3-pyrrolidine-1-ylpropyl)piperidine-4-yl]carbamate (169 mg) containing impurities. The obtained crude product was used directly in Reference Example 22 without further purification.

[0424] <Reference example 22>

[0425] [ka]

[0426] To a solution of tert-butyl N-[1-(3-pyrrolidine-1-ylpropyl)piperidine-4-yl]carbamate (163 mg) containing impurities obtained in Reference Example 21 in dichloromethane (1.00 mL), trifluoroacetic acid (1.00 mL) was added at room temperature and the mixture was stirred for 10 minutes. After removing the solvent and other components from the reaction solution under reduced pressure, the residue was used as is in Examples 1-56 as the trifluoroacetate salt of 1-(3-pyrrolidine-1-ylpropyl)piperidine-4-amine.

[0427] <Reference example 23>

[0428] [ka]

[0429] Under an argon atmosphere, a solution of (5-bromopyridine-2-yl)methanol (200 mg) in N,N-dimethylformamide (1.00 mL) was added dropwise to a solution of 55% sodium hydride (55.4 mg) in N,N-dimethylformamide (2.00 mL) at 0°C and stirred for 15 minutes. Then, a solution of methyl iodide (72.8 μL) in N,N-dimethylformamide (1.00 mL) was added dropwise and stirred at room temperature for 1 hour. The reaction mixture was added to saturated saline and extracted twice with ethyl acetate. The combined extract layers were washed with water and then saturated saline, dried with anhydrous sodium sulfate, filtered off insoluble matter, and removed by vacuum distillation to obtain a mixture of 5-bromo-2-(methoxymethyl)pyridine : N,N-dimethylformamide = 1 : 0.45 (227 mg). 1 H-NMR (CDCl3, 400MHz) δ: 3.48 (3H, s), 4.54 (2H, s), 7.34 (1H, d, J = 8.5 Hz), 7.82 (1H, dd, J = 8.5, 2.4 Hz), 8.62 (1H, d, J = 2.4 Hz).

[0430] <Reference example 24>

[0431] [ka]

[0432] Under an argon atmosphere, a solution of 5-bromo-2-(methoxymethyl)pyridine (210 mg), benzophenone imine (0.210 mL), tripotassium phosphate (552 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform complex (26.9 mg), and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (26.5 mg) in 1,2-dimethoxyethane (2.00 mL) was stirred at 40°C for 4 hours. After filtering off insoluble matter using Celite, 1 mol / L hydrochloric acid was added to the reaction mixture to adjust the pH to 1, and the mixture was stirred at room temperature for 10 minutes. After washing the reaction mixture with ethyl acetate, saturated sodium bicarbonate aqueous solution was added to the aqueous layer to adjust the pH to 8. The reaction mixture was purified by amination silica gel column chromatography (hexane:ethyl acetate = 3:1 to 0:1) to obtain 6-(methoxymethyl)pyridine-3-amine (66.0 mg). 1 H-NMR (CDCl3, 400MHz) δ: 3.43 (3H, s), 3.69 (2H, brs), 4.46 (2H, s), 6.99 (1H, dd, J = 8.5, 2.4 Hz), 7.18 (1H, d, J = 8.5 Hz), 8.06 (1H, d, J = 2.4 Hz). MS (EI + ): 138.1 [M] +

[0433] <Reference example 25>

[0434] [ka]

[0435] 626 mg of tert-butyl-(4-cyanobenzyl)(methyl)carbamate, 130 mg of 10% palladium carbon, and 20 mL of methanol were stirred under a hydrogen atmosphere for 5 days. The reaction product was filtered, and the filtrate was concentrated under reduced pressure to obtain 597 mg of tert-butyl (4-(aminomethyl)benzyl)(methyl)carbamate. The crude product was used in the next reaction without purification. 1 H-NMR (270 MHz, CDCl3) δ: 1.48 (9H, s), 1.68 (2H, s), 2.81 (3H, s), 4.41 (2H, s), 7.09-7.34 (4H, m). MS (ESI + ): 251.28 [M+H] +

[0436] <Reference example 26>

[0437] [ka]

[0438] A mixture of tert-butyl (4-(aminomethyl)benzyl)(methyl)carbamate (597 mg), paraformaldehyde (573 mg), and trifluoroethanol (20 mL) was stirred at room temperature for 15 minutes, and sodium borohydride (361 mg) was added and the mixture was stirred overnight at room temperature. The solvent was concentrated under reduced pressure, water was added, and the mixture was extracted twice with ethyl acetate. The mixture was concentrated under reduced pressure and purified by aminopropyl silica gel chromatography to obtain tert-butyl (4-((dimethylamino)methyl)benzyl)(methyl)carbamate (424 mg). 1 H-NMR (270 MHz, CDCl3) δ: 1.48 (9H, s), 2.23 (6H, s), 2.81 (3H, br s), 3.40 (2H, s), 4.40 (2H, s), 7.17 (2H, d, J = 8.1 Hz), 7.26 (2H, d, J = 8.1 Hz). MS (ESI + ): 278.20 [M+H] +

[0439] <Reference example 27>

[0440] [ka]

[0441] 424 mg of tert-butyl(4-((dimethylamino)methyl)benzyl)(methyl)carbamate was dissolved in 5 mL of dichloromethane, and trifluoroacetic acid (1 mL) was added and stirred overnight. 2N sodium hydroxide aqueous solution was added to adjust the pH from 13 to 14, and the mixture was extracted twice with dichloromethane. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain N,N-dimethyl-1-(4-((methylamino)methyl)phenyl)methaneamine (244 mg). 1 H-NMR (270 MHz, CDCl3) δ: 2.23 (s, 6H), 2.45 (s, 3H), 3.40 (s, 2H), 3.73 (s, 2H), 7.26 (s, 4H). MS (ESI + ): 179.18 [M+H] +

[0442] <Reference example 28>

[0443] [ka]

[0444] To a solution of ethyl 4-methyl-3-oxopentanate (1.5 g) cooled to 10°C in acetic acid (1.2 mL), aqueous solution of sodium nitrite (654 mg) (1.2 mL) was added dropwise until the solution temperature was below 20°C. After the addition was complete, the reaction solution was allowed to return to room temperature and stirred for 1 hour. The reaction solution was then extracted three times with diethyl ether. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain ethyl 2-(hydroxyimino)-4-methyl-3-oxopentanate (1.85 g). The crude product was used in the next reaction without purification. MS (ESI + ): 188.10 [M+H] +

[0445] <Reference example 29>

[0446] [ka]

[0447] A solution of sodium acetate trihydrate (811 mg) and 5,5-dimethyl-1,3-cyclohexadione (1.39 g) in acetic acid (40 mL) was heated and stirred at 70°C. While controlling the reaction temperature to 70-80°C, a solution of 2-(hydroxyimino)-4-methyl-3-oxopentanoate ethyl (1.85 g) in acetic acid (20 mL) was added dropwise, while simultaneously adding zinc powder (1.03 g) over 30 minutes. The reaction solution was heated to 100°C and stirred for 1 hour, then cooled to 70°C, water was added, and the mixture was heated again to 100°C and stirred for 6 hours. The reaction solution was returned to room temperature and extracted with dichloromethane in an ice-water mixture. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by silica gel column chromatography (chloroform / methanol) to obtain ethyl 3-isopropyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (986 mg). 1 H-NMR(270 MHz, CDCl3)δ:1.10 (6H, s), 1.32 (6H, d, J = 6.9 Hz), 1.38 (3H, t, J = 7.3 Hz), 2.37 (2H, s), 2.66 (2H, s), 4.07 (1H, m), 4.35 (2H, q, J = 7.3 Hz), 8.95 (1H, brs). MS (ESI + ): 278.23 [M+H] +

[0448] <Reference example 30-1>

[0449] [ka]

[0450] A mixed solution of ethyl 3-isopropyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid (980 mg) and potassium hydroxide (496 mg) in ethanol (10 mL) and water (3 mL) was heated and stirred under reflux conditions for 6 hours. The reaction mixture was cooled to 60°C, neutralized with acetic acid, and water was added. The precipitated solid was filtered, washed with water, and dried to obtain 570 mg of 3-isopropyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid. 1 H-NMR(500 MHz, CDCl3+CD3OD)δ:1.10 (6H, s), 1.31 (6H, d, J = 7.0 Hz), 2.36 (2H, s), 2.66 (2H, s), 3.42 (1H, m), 4.06 (1H, m, J = 7.0 Hz). MS (ESI + ): 250.19 [M+H] +

[0451] Using the corresponding starting materials and reagents, Reference Examples 30-2 to 30-6 were obtained using the same method as in Reference Example 30-1, the methods described in steps 26-1 to 26-2 and step 25-1 or similar methods, or methods described in the literature or similar methods.

[0452] [Table 26]

[0453] <Reference example 31>

[0454] [ka]

[0455] To a solution of sodium borohydride (115 mg) in tetrahydrofuran (10 mL), ethyl 3-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (200 mg) was added and the mixture was cooled to -5°C. Under a nitrogen atmosphere, diethyl boron trifluoride ether complex (0.54 mL) was slowly added dropwise, and after the addition, the cooling bath was removed and the mixture was allowed to return to room temperature and stirred for 2 hours. The reaction mixture was added to ice water, and the precipitated solid was filtered off. It was washed with water and dried under reduced pressure to obtain ethyl 3-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (193 mg). 1 H-NMR (270 MHz, CDCl3) δ: 0.95 (6H, s), 1.10 (3H, t, J = 7.5 Hz), 1.31 (3H, t, J = 7.0 Hz), 1.52 (2H, t, J = 6.5 Hz), 2.34 (2H, s), 2.43 (2H, t, J = 6.5 Hz), 2.72 (2H, q, J = 7.5 Hz), 4.29 (2H, q, J = 7.0 Hz), 8.45 (1H, brs). MS (ESI + ): 250.33 [M+H] +

[0456] <Reference example 32>

[0457] [ka]

[0458] 182 mg of ethyl 3-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid (ethyl) was dissolved in ethanol (4 mL), to which 1 N potassium hydroxide (5 mL) was added and the mixture was stirred at 70°C for 12 hours. The reaction mixture was neutralized with 1 N hydrochloric acid aqueous solution and extracted twice with chloroform. After drying over magnesium sulfate, the mixture was filtered and concentrated under reduced pressure to obtain 115 mg of ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid. MS (ESI + ): 222.26 [M+H] +

[0459] <Reference example 33-1>

[0460] [ka]

[0461] Under an argon atmosphere, methyl 4-bromo-2-methylbenzoate (500 mg), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (22.7 mg), palladium(II) acetate (8.2 mg), and cesium carbonate (2.96 g) were added to a toluene solution (18.2 mL) of pyridine-4-amine (171 mg) and stirred at 120°C for 8 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1 - ethyl acetate:methanol = 5:1) to obtain methyl 2-methyl-4-(pyridine-4-ylamino)benzoate (79.0 mg). 1 H-NMR (CDCl3, 400 MHz) δ: 2.61 (3H, s), 3.88 (3H, d, J = 1.2 Hz), 6.26 (1H, brs), 6.94 (2H, dd, J = 6.1, 1.2 Hz), 7.01 (1H, s), 7.02-7.05 (1H, m), 7.95 (1H, d, J = 8.5 Hz), 8.38 (2H, d, J = 6.1 Hz). HRMS (FI + ):242.10567 [M] +

[0462] Using the corresponding starting materials and reagents, Reference Examples 33-2 to 33-14 were obtained by the same method as in Reference Example 33-1, the method described in Step 27-1, or a similar method.

[0463] [Table 27]

[0464] [Table 28]

[0465] <Reference example 34-1>

[0466] [ka]

[0467] Under an argon atmosphere, lithium hydroxide monohydrate (20.5 mg) was added to a methanol-tetrahydrofuran-water mixture (1.63 mL, 1:1:1) of methyl 2-methyl-4-(pyridine-4-ylamino)benzoate (79.0 mg), and the mixture was stirred at room temperature for 18 hours. After concentrating the reaction mixture under reduced pressure, 1 mol / L hydrochloric acid was added to adjust the pH to 5, and the resulting solid was filtered to obtain 2-methyl-4-(pyridine-4-ylamino)benzoic acid (60.6 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: 2.52 (3H, s), 7.03 (2H, d, J = 6.1 Hz), 7.05 (1H, d, J = 1.8 Hz), 7.08 (1H, dd, J = 8.5, 1.8 Hz), 7.84 (1H, d, J = 8.5 Hz), 8.27 (2H, d, J = 6.1 Hz), 9.10 (1H, s), 12.44 (1H, brs). HRMS (ESI + ):229.09846 [M+H] +

[0468] Using the corresponding starting materials and reagents, Reference Examples 34-2 to 34-14 were obtained by the same method as in Reference Example 34-1, the method described in Step 25-1, or a similar method.

[0469] [Table 29]

[0470] [Table 30]

[0471] [Table 31]

[0472] <Reference example 35>

[0473] [ka]

[0474] Under an argon atmosphere, potassium carbonate (1.66 g) was added at room temperature to a solution of N,N-dimethylethane-1,2-diamine (1.31 mL) and ethyl 4-fluorobenzoate (0.877 mL) in dimethyl sulfoxide (10.0 mL), and the mixture was stirred at 80°C for 25.5 hours. The reaction mixture was added to water and extracted three times with ethyl acetate. The combined extract layers were washed with water and then saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was purified by amination silica gel column chromatography (hexane:ethyl acetate = 9:1 to 0:1) to obtain ethyl 4-[2-(dimethylamino)ethylamino]benzoate (510 mg). 1 H-NMR (CDCl3, 400MHz) δ: 1.36 (3H, t, J = 7.3 Hz), 2.25 (6H, s), 2.53-2.59 (2H, m), 3.15-3.21 (2H, m), 4.31 (2H, q, J = 7.3 Hz), 4.71-4.83 (1H, br s), 6.56 (2H, d, J = 8.6 Hz), 7.87 (2H, d, J = 8.6 Hz).

[0475] <Reference example 36>

[0476] [ka]

[0477] To a mixed solution of ethyl 4-[2-(dimethylamino)ethylamino]benzoate (35.4 mg), ethanol (0.250 mL), and water (0.250 mL), lithium hydroxide (4.30 mg) was added at room temperature and stirred for 15 hours, then at 50°C for 2.5 hours, and at 70°C for 5 hours. After stirring, 1 mol / L hydrochloric acid was added to the reaction mixture to adjust the pH to 1. After removing the solvent and other components from the reaction mixture under reduced pressure, the residue was used as is in Examples 6-66 as the hydrochloride salt of 4-[2-(dimethylamino)ethylamino]benzoic acid.

[0478] <Reference example 37>

[0479] [ka]

[0480] Under an argon atmosphere, 2-chloro-N,N-dimethylethaneamine hydrochloride (317 mg) was added at room temperature to a solution of ethyl 4-hydroxybenzoate (332 mg) and potassium carbonate (967 mg) in N,N-dimethylformamide (4.00 mL), and the mixture was stirred at 110°C for 29 hours. The reaction mixture was added to water and extracted twice with ethyl acetate. The combined extract layers were washed with water and then saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was purified by amination silica gel column chromatography (hexane:ethyl acetate = 9:1 to 1:2) to obtain ethyl 4-[2-(dimethylamino)ethoxy]benzoate (398 mg). 1H-NMR (CDCl3, 400MHz) δ: 1.38 (3H, t, J = 7.3 Hz), 2.34 (6H, s), 2.75 (2H, t, J = 5.5 Hz), 4.11 (2H, t, J = 5.5 Hz), 4.34 (2H, q, J = 7.3 Hz), 6.93 (2H, d, J = 8.6 Hz), 7.99 (2H, d, J = 8.6 Hz).

[0481] <Reference example 38>

[0482] [ka]

[0483] Using ethyl 4-[2-(dimethylamino)ethoxy]benzoate, the compound was synthesized in the same manner as in Reference Example 36, and the crude product was used in the next step without purification.

[0484] <Reference example 39>

[0485] [ka]

[0486] Under an argon atmosphere, 1.00 g of 1-methylpiperidine-4-one and 0.917 mL of methyl 4-aminobenzoate were mixed in 30.0 mL of dichloromethane. Acetic acid (0.755 mL) was added at room temperature, and the mixture was stirred for 15 minutes. Then, sodium triacetoxyborohydride (4.22 g) was added to the reaction mixture, and the mixture was stirred for 25 hours. The reaction mixture was added to saturated sodium bicarbonate aqueous solution and extracted twice with ethyl acetate. The combined extract layers were washed with water and then saturated saline solution, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was purified by amination silica gel column chromatography (ethyl acetate) to obtain methyl 4-[(1-methylpiperidine-4-yl)amino]benzoate (705 mg). 1H-NMR (DMSO-D6, 400MHz) δ: 1.32-1.46 (2H, m), 1.79-1.89 (2H, m), 1.93-2.04 (2H, m), 2.15 (3H, s), 2.65-2.76 (2H, m), 3.15-3.29 (1H, m), 3.72 (3H, s), 6.38 (1H, d, J = 7.3 Hz), 6.57 (2H, d, J = 9.1 Hz), 7.65 (2H, d, J = 9.1 Hz). MS (FI + ): 248.2 [M] +

[0487] <Reference example 40>

[0488] [ka]

[0489] A mixed solution of methyl 4-[(1-methylpiperidine-4-yl)amino]benzoate (705 mg) in methanol (7.50 mL) and water (7.50 mL) was mixed with lithium hydroxide (68.0 mg) at room temperature and stirred for 18 hours, 7 hours at 40°C, and 2.5 hours at 60°C. After washing the reaction mixture with ethyl acetate, 1 mol / L hydrochloric acid was added to the aqueous layer to adjust the pH to 1. After removing the solvent and other components from the reaction mixture under reduced pressure, the residue was used as is in Example 6-59 as the hydrochloride salt of 4-[(1-methylpiperidine-4-yl)amino]benzoic acid.

[0490] <Reference example 41>

[0491] [ka]

[0492] Under an argon atmosphere, pyridine-4-ylboronic acid (241 mg), bis(triphenylphosphine)palladium(II) dichloride (91.9 mg), and 2 mol / L aqueous sodium carbonate solution (1.97 mL) were added to a 1,2-dimethoxyethane solution (6.55 mL) of methyl 4-bromo-2-methylbenzoate (300 mg), and the mixture was stirred at 60°C for 8 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 3:2) to obtain methyl 2-methyl-4-pyridine-4-ylbenzoate (215 mg). 1 H-NMR (CDCl3, 400 MHz) δ: 2.69 (3H, s), 3.93 (3H, s), 7.49-7.53 (4H, m), 8.03 (1H, d, J = 8.5 Hz), 8.69 (2H, d, J = 6.1 Hz). HRMS (ESI + ):228.10273 [M+H] +

[0493] <Reference example 42>

[0494] [ka]

[0495] Under an argon atmosphere, lithium hydroxide monohydrate (59.6 mg) was added to a methanol-tetrahydrofuran-water mixture (4.74 mL, 1:1:1) of methyl 2-methyl-4-pyridine-4-ylbenzoate (215 mg), and the mixture was stirred at room temperature for 7 hours. After concentrating the reaction mixture under reduced pressure, 1 mol / L hydrochloric acid was added to adjust the pH to 5, and the resulting solid was filtered to obtain 2-methyl-4-pyridine-4-ylbenzoic acid (164 mg). 1H-NMR (DMSO-D6, 400MHz) δ: 2.62 (3H, s), 7.72 (1H, dd, J = 7.9, 1.8 Hz), 7.75-7.78 (3H, m), 7.95 (1H, d, J = 7.9 Hz), 8.67 (2H, d, J = 6.1 Hz), 12.98 (1H, brs). HRMS (ESI + ):214.08724 [M+H] +

[0496] <Reference example 43-1>

[0497] [ka]

[0498] Under an argon atmosphere, potassium carbonate (929 mg), tetrakis(triphenylphosphine)palladium (0) (518 mg), and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (1.00 g) were added at room temperature to a solution of ethyl 4-bromobenzoate (0.718 mL) and 1,4-dioxane (15.00 mL), and the mixture was stirred at 110°C for 22 hours. The reaction mixture was added to water and extracted twice with ethyl acetate. The combined extract layers were washed with water and then saturated saline solution, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was purified by amination silica gel column chromatography (hexane:ethyl acetate = 9:1 to 1:2) to obtain ethyl 4-(1-methyl-3,6-dihydro-2H-pyridine-4-yl)benzoate (1.16 g). 1H-NMR (CDCl3, 400MHz) δ: 1.39 (3H, t, J = 6.7 Hz), 2.42 (3H, s), 2.56-2.64 (2H, m), 2.65-2.71 (2H, m), 3.12-3.16 (2H, m), 4.37 (2H, q, J = 6.7 Hz), 6.17-6.22 (1H, m), 7.44 (2H, d, J = 8.6 Hz), 7.99 (2H, d, J = 8.6 Hz).

[0499] Using the corresponding starting materials and reagents, Reference Example 43-2 was obtained by the same method as in Reference Example 43-1, the method described in step 31-1, or a similar method.

[0500] [Table 32]

[0501] <Reference example 44-1>

[0502] [ka]

[0503] Under an argon atmosphere, 60.0 mg of 10% palladium carbon was added to a solution of ethyl 4-(1-methyl-3,6-dihydro-2H-pyridine-4-yl)benzoate (300 mg) in ethanol (6.00 mL) at room temperature. The mixture was stirred under a hydrogen atmosphere for 4 hours, after which the hydrogen in the reaction vessel was replaced with argon. The reaction mixture was filtered using Celite, and the solvent and other components of the filtrate were removed under reduced pressure. The residue was purified by amination silica gel column chromatography (hexane:ethyl acetate = 5:1 to 0:1) to obtain ethyl 4-(1-methylpiperidine-4-yl)benzoate (295 mg). 1H-NMR (CDCl3, 400MHz) δ: 1.38 (3H, t, J = 7.3 Hz), 1.75-1.88 (4H, m), 2.00-2.10 (2H, m), 2.33 (3H, s), 2.47-2.59 (1H, m), 2.94-3.02 (2H, m), 4.36 (2H, q, J = 7.3 Hz), 7.29 (2H, d, J = 8.6 Hz), 7.98 (2H, d, J = 8.6 Hz).

[0504] Using the corresponding starting materials and reagents, Reference Example 44-2 was obtained by the same method as in Reference Example 44-1, the method described in step 31-2, or a similar method.

[0505] [Table 33]

[0506] <Reference example 45>

[0507] [ka]

[0508] To a mixed solution of tert-butyl 4-(4-ethoxycarbonylphenyl)piperidine-1-carboxylate (140 mg) in ethanol (1.00 mL) and water (1.00 mL), lithium hydroxide (15.1 mg) was added at room temperature and the mixture was stirred for 22 hours. 1 mol / L hydrochloric acid was added to the reaction mixture to adjust the pH to 3, and the mixture was extracted twice with ethyl acetate. The combined extract layers were washed with water and then saturated saline solution, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was washed with diisopropyl ether to obtain 4-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-4-yl]benzoic acid (97.0 mg). 1H-NMR (DMSO-D6, 400MHz) δ: 1.40 (9H, s), 1.42-1.57 (2H, m), 1.69-1.81 (2H, m), 2.69-2.93 (3H, m), 3.96-4.17 (2H, m), 7.36 (2H, d, J = 8.6 Hz), 7.86 (2H, d, J = 8.6 Hz), 12.80 (1H, br s).

[0509] <Reference example 46>

[0510] [ka]

[0511] A mixture of ethyl 4-(1-methylpiperidine-4-yl)benzoate (37.1 mg), ethanol (0.250 mL), and water (0.250 mL) was mixed with lithium hydroxide (4.31 mg) at room temperature and stirred for 18 hours. Then, 1 mol / L hydrochloric acid was added to the reaction mixture to adjust the pH to 1. After removing the solvent and other components from the reaction mixture under reduced pressure, the residue was used as is in Examples 6-69 as the hydrochloride salt of 4-(1-methylpiperidine-4-yl)benzoic acid.

[0512] <Reference example 47>

[0513] [ka]

[0514] A mixture of ethyl 4-(1-methyl-3,6-dihydro-2H-pyridine-4-yl)benzoate (36.8 mg), ethanol (0.250 mL), and water (0.250 mL) was mixed with lithium hydroxide (4.31 mg) at room temperature and stirred for 44 hours, then at 70°C for 20 hours. After stirring, 1 mol / L hydrochloric acid was added to the reaction mixture to adjust the pH to 1. After removing the solvent and other components from the reaction mixture under reduced pressure, the residue was used as is in Examples 6-68 as the hydrochloride salt of 4-(1-methyl-3,6-dihydro-2H-pyridine-4-yl)benzoic acid.

[0515] <Reference example 48>

[0516] [ka]

[0517] Under an argon atmosphere, a tetrahydrofuran (15.0 mL)-water (3.00 mL) mixed solution of methyl 4-chloro-6-methylpyridine-3-carboxylate (700 mg), potassium vinyl trifluoroborate (556 mg), and cesium carbonate (3.68 g) was mixed with [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (154 mg) at room temperature, and the mixture was stirred under reflux for 14.5 hours. After filtering off insoluble matter from the reaction mixture using Celite, water was added, and the mixture was extracted twice with ethyl acetate. The combined extract layers were washed with water and then saturated brine, dried over anhydrous sodium sulfate, and then filtered off insoluble matter. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:0 to 3:1) to obtain methyl 4-ethenyl-6-methylpyridine-3-carboxylate (345 mg). 1 H-NMR (CDCl3, 400MHz) δ: 2.61 (3H, s), 3.92 (3H, s), 5.53 (1H, dd, J = 10.9, 1.2 Hz), 5.83 (1H, dd, J = 17.6, 1.2 Hz), 7.32 (1H, s), 7.51 (1H, dd, J = 17.6, 10.9), 8.99 (1H, s). MS (ESI + ): 178.1 [M+H] +

[0518] <Reference example 49>

[0519] [ka]

[0520] Under an argon atmosphere, 345 mg of methyl 4-ethenyl-6-methylpyridine-3-carboxylate (345 mg) was dissolved in methanol (10.0 mL) at room temperature, to which 34.5 mg of palladium carbon was added. The mixture was stirred under a hydrogen atmosphere for 1.5 hours, after which the hydrogen in the reaction vessel was replaced with argon. The reaction mixture was filtered using Celite, and the solvent and other components of the filtrate were removed under reduced pressure to obtain methyl 4-ethyl-6-methylpyridine-3-carboxylate (349 mg). 1 H-NMR (CDCl3, 400MHz) δ: 1.24 (3H, t, J = 7.3 Hz), 2.58 (3H, s), 2.99 (2H, q, J = 7.3 Hz), 3.92 (3H, s), 7.07 (1H, s), 8.95 (1H, s). MS (EI + ): 179.1 [M] +

[0521] <Reference example 50>

[0522] [ka]

[0523] A mixture of methyl 4-ethyl-6-methylpyridine-3-carboxylate (349 mg) in methanol (5.00 mL) and water (5.00 mL) was mixed with lithium hydroxide monohydrate (123 mg) at room temperature and stirred for 18 hours. 1 mol / L hydrochloric acid was added to the reaction mixture to adjust the pH to 5-6, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate : methanol = 4:1) to obtain 4-ethyl-6-methylpyridine-3-carboxylic acid (322 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: 1.17 (3H, t, J = 7.9 Hz), 2.49 (3H, s), 2.94 (2H, q, J = 7.9 Hz), 7.22 (1H, s), 8.79 (1H, s). MS (ESI + ): 166.1 [M+H] +

[0524] <Reference example 51>

[0525] [ka]

[0526] A solution of ethyl 2-chloro-4,4,4-trifluoro-3-oxobutanoate (1.14 mL) and pyridine-3-carbothioamide (1.00 g) in ethanol (10.0 mL) was heated under reflux and stirred for 26 hours. The reaction mixture was added to water and extracted twice with ethyl acetate. The combined extract layers were washed with water and then saturated saline solution, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1 to 0:1) and washed with diisopropyl ether to obtain ethyl 4-hydroxy-2-pyridine-3-yl-4-(trifluoromethyl)-5H-1,3-thiazole-5-carboxylate (677 mg). 1 H-NMR (CDCl3, 400MHz) δ: 1.33 (3H, t, J = 7.3 Hz), 4.31 (2H, q, J = 7.1 Hz), 4.90 (1H, s), 7.40-7.43 (1H, m), 8.00 (1H, dt, J = 8.1, 2.0 Hz), 8.67 (1H, dd, J = 4.8, 1.8 Hz), 8.86 (1H, s), 9.54 (1H, d, J = 3.0 Hz). MS (FI + ): 320.1 [M] +

[0527] <Reference example 52>

[0528] [ka]

[0529] To a solution of ethyl 4-hydroxy-2-pyridine-3-yl-4-(trifluoromethyl)-5H-1,3-thiazole-5-carboxylate (632 mg) in toluene (10.0 mL), p-toluenesulfonic acid monohydrate (1.12 g) was added at room temperature and stirred under reflux for 1 hour. The reaction mixture was added to saturated sodium bicarbonate aqueous solution and extracted twice with ethyl acetate. The combined extract layers were washed with water and then saturated saline solution, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was purified by amination silica gel column chromatography (ethyl acetate) to obtain ethyl 2-pyridine-3-yl-4-(trifluoromethyl)-1,3-thiazole-5-carboxylate (155 mg). 1 H-NMR (CDCl3, 400MHz) δ: 1.42 (3H, t, J = 7.3 Hz), 4.44 (2H, q, J = 7.3 Hz), 7.45 (1H, dd, J = 7.3, 4.8 Hz), 8.32 (1H, td, J = 4.8, 2.8 Hz), 8.76 (1H, dd, J = 4.8, 1.8 Hz), 9.19 (1H, d, J = 1.8 Hz). MS (ESI + ): 303.0 [M+H] +

[0530] <Reference example 53>

[0531] [ka]

[0532] To a mixed solution of ethyl 2-pyridine-3-yl-4-(trifluoromethyl)-1,3-thiazole-5-carboxylate (150 mg) in ethanol (2.50 mL) and water (2.50 mL), lithium hydroxide (17.8 mg) was added at room temperature and stirred for 30 minutes. After washing the reaction mixture with ethyl acetate, 1 mol / L hydrochloric acid was added to the aqueous layer to adjust the pH to 3, and the mixture was extracted twice with ethyl acetate. The combined extract layers were washed with water and then saturated saline solution, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was washed with diisopropyl ether to obtain 2-pyridine-3-yl-4-(trifluoromethyl)-1,3-thiazole-5-carboxylic acid (95.0 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: 7.60 (1H, dt, J = 7.7, 3.2 Hz), 8.40 (1H, dt, J = 8.1, 2.0 Hz), 8.77 (1H, td, J = 5.3, 1.4 Hz), 9.19 (1H, d, J = 2.4 Hz). MS (ESI + ): 275.0 [M+H] +

[0533] <Reference example 54>

[0534] [ka]

[0535] Under an argon atmosphere, pyridine (1.12 mL) and p-toluenesulfonyl chloride (1.76 g) were added to a 9.25 mL solution of 2-cyclobutylethanol (926 mg) in dichloromethane, and the mixture was stirred at room temperature for 26 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with 1 mol / L hydrochloric acid and saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by amination silica gel column chromatography (hexane:ethyl acetate = 9:1) to obtain 2-cyclobutylethyl 4-methylbenzenesulfonate (1.94 g). 1 H-NMR (CDCl3, 400 MHz) δ: 1.54-1.62 (2H, m), 1.73 (2H, q, J = 6.7 Hz), 1.76-1.87 (2H, m), 1.94-2.02 (2H, m), 2.25-2.38 (1H, m), 2.45 (3H, s), 3.95 (2H, t, J = 6.7 Hz), 7.34 (2H, d, J = 8.5 Hz), 7.78 (2H, d, J = 8.5 Hz). HRMS (FI + ):254.09769 [M] +

[0536] <Reference example 55-1>

[0537] [ka]

[0538] Under an argon atmosphere, tert-butoxypotassium (1.20 g) was added to a solution of diethyl 2-[(2-methylpropan-2-yl)oxycarbonylamino]propanediote (3.14 g) in N,N-dimethylformamide (19.1 mL), and the mixture was stirred at 70°C for 30 minutes. After the resulting reaction mixture was allowed to cool to room temperature, a solution of 2-cyclobutylethyl 4-methylbenzenesulfonate (1.94 g) in N,N-dimethylformamide (19.0 mL) was added, and the mixture was stirred at 70°C for 6 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1) to obtain diethyl 2-(2-cyclobutylethyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanediote (1.76 g). 1H-NMR (CDCl3, 400 MHz) δ: 1.19-1.24 (2H, m), 1.25 (6H, t, J = 7.3 Hz), 1.43 (9H, s), 1.50-1.58 (2H, m), 1.74-1.87 (2H, m), 2.00-2.08 (2H, m), 2.12-2.20 (2H, m), 2.20-2.28 (1H, m), 4.18-4.28 (4H, m), 5.91 (1H, brs). HRMS (ESI + ):358.22297 [M+H] +

[0539] Using the corresponding starting materials and reagents, Reference Examples 55-2 to 55-3 were obtained by the same method as in Reference Example 55-1, the method described in step 34-2, or a similar method.

[0540] [Table 34]

[0541] <Reference example 56-1>

[0542] [ka]

[0543] Under an argon atmosphere, 24.6 mL of ethanol solution (2.71 mL) of diethyl 2-(2-cyclobutylethyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanediote (1.76 g) was added to 2 mol / L aqueous potassium hydroxide solution and stirred at room temperature for 4 hours. After concentrating the reaction mixture, 1 mol / L hydrochloric acid was added to adjust the pH to 2, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, 1.64 g of 4-cyclobutyl-2-ethoxycarbonyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid was obtained. 1H-NMR (DMSO-D6, 400MHz) δ: 1.14 (3H, t, J = 7.3 Hz), 1.19-1.24 (2H, m), 1.37 (9H, s), 1.43-1.52 (2H, m), 1.71-1.84 (2H, m), 1.90-2.01 (4H, m), 2.12-2.22 (1H, m), 4.06-4.18 (2H, m), 6.38 (1H, brs). HRMS (ESI + ):330.19229 [M+H] +

[0544] Using the corresponding starting materials and reagents, Reference Examples 56-2 to 56-3 were obtained using the same method as in Reference Example 56-1, the method described in step 34-3, or a similar method.

[0545] [Table 35]

[0546] <Reference example 57-1>

[0547] [ka]

[0548] Under an argon atmosphere, a 1,2-dichlorobenzene solution (9.84 mL) of 4-cyclobutyl-2-ethoxycarbonyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid (1.62 g) was stirred at 110°C for 1 hour. After the reaction mixture cooled to room temperature, it was purified by silica gel column chromatography (hexane - hexane : ethyl acetate = 4:1) to obtain ethyl 4-cyclobutyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate (1.27 g). 1H-NMR (CDCl3, 400 MHz) δ: 1.28 (3H, t, J = 7.3 Hz), 1.36-1.43 (2H, m), 1.45 (9H, s), 1.47-1.62 (4H, m), 1.65-1.74 (1H, m), 1.76-1.88 (2H, m), 1.99-2.07 (2H, m), 2.19-2.27 (1H, m), 4.14-4.26 (2H, m), 4.98 (1H, d, J = 7.9 Hz). HRMS (FI + ):286.20177 [M] +

[0549] Using the corresponding starting materials and reagents, Reference Examples 57-2 to 57-3 were obtained by the same method as in Reference Example 57-1, the method described in step 34-4, or a similar method.

[0550] [Table 36]

[0551] <Reference example 58-1>

[0552] [ka]

[0553] Under an argon atmosphere, 14.8 mL of ethanol solution (1.27 g) of ethyl 4-cyclobutyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate was mixed with 3.34 mL of 2 mol / L potassium hydroxide aqueous solution and stirred at room temperature for 16 hours. After concentrating the reaction mixture, 1 mol / L hydrochloric acid was added to adjust the pH to 2, and the resulting solid was filtered to obtain 4-cyclobutyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid (1.02 g). 1H-NMR (DMSO-D6, 400MHz) δ: 1.32-1.48 (2H, m), 1.38 (9H, s), 1.48-1.62 (4H, m), 1.72-1.84 (2H, m), 1.92-2.02 (2H, m), 2.14-2.23 (1H, m), 3.79 (1H, td, J = 7.9, 4.8 Hz), 7.00 (1H, d, J = 7.9 Hz). HRMS (FI + ):258.16971 [M] +

[0554] Using the corresponding starting materials and reagents, Reference Examples 58-2 to 58-3 were obtained by the same method as in Reference Example 58-1, the method described in step 34-5, or a similar method.

[0555] [Table 37]

[0556] <Reference example 59>

[0557] [ka]

[0558] To a mixed solution of 4-cyclopropyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid (200 mg) in methanol (4.00 mL) and toluene (4.00 mL), 0.615 mL of 2.0 mol / L trimethylsilyldiazomethane-diethyl ether solution was added dropwise at room temperature and the mixture was stirred for 20 minutes. Acetic acid was added to the reaction mixture until foaming and the yellow coloring disappeared. After removing the solvent and other components under reduced pressure, the residue was used as methyl 4-cyclopropyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate in Reference Examples 60 and 66.

[0559] <Reference example 60>

[0560] [ka]

[0561] Under an argon atmosphere, trifluoroacetic acid (4.00 mL) was added at room temperature to a solution of methyl 4-cyclopropyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate obtained as the residue of Reference Example 59 in dichloromethane (4.00 mL), and the mixture was stirred for 20 minutes. The residue obtained by distilling off the solvent and other components of the reaction solution under reduced pressure was used as the trifluoroacetate salt of methyl 2-amino-4-cyclopropylbutanoate in Reference Example 65-6.

[0562] <Reference example 61>

[0563] [ka]

[0564] Under an argon atmosphere, n-butyllithium (2.55 mL, 1.63 mol / L, n-hexane solution) was slowly added to a tetrahydrofuran solution (13.9 mL) of (2R)-3,6-dimethoxy-2-propan-2-yl-2,5-dihydropyrazine (766 mg) at -78°C, and the mixture was stirred at -78°C for 15 minutes. Then, a tetrahydrofuran solution (6.94 mL) of 2-cyclopropylethyl 4-methylbenzenesulfonate (1.00 g) was slowly added, and the mixture was stirred at -78°C for 1 hour, followed by stirring for 16 hours while gradually raising the temperature to room temperature. Saturated ammonium chloride aqueous solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 30:1) to obtain (2S,5R)-2-(2-cyclopropylethyl)-3,6-dimethoxy-5-propan-2-yl-2,5-dihydropyrazine (555 mg). 1H-NMR (CDCl3, 400 MHz) δ:0.00-0.04 (2H, m), 0.38 (1H, d, J = 1.8 Hz), 0.40 (1H, d, J = 1.8 Hz), 0.59-0.67 (1H, m), 0.69 (3H, d, J = 6.7 Hz), 1.05 (3H, d, J = 6.7 Hz), 1.08-1.26 (2H, m), 1.75-1.84 (1H, m), 1.88-1.97 (1H, m), 2.22-2.30 (1H, m), 3.67 (3H, s), 3.69 (3H, s), 3.92 (1H, dd, J = 3.6, 3.0 Hz), 4.04 (1H, td, J = 6.7, 3.0 Hz). HRMS (ESI + ):253.19083 [M+H] +

[0565] <Reference example 62>

[0566] [ka]

[0567] Under an argon atmosphere, 0.5 mol / L hydrochloric acid (11.0 mL) was added to tetrahydrofuran solution (11.0 mL) of (2S,5R)-2-(2-cyclopropylethyl)-3,6-dimethoxy-5-propan-2-yl-2,5-dihydropyrazine (555 mg), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was adjusted to pH 7 by adding 25% aqueous ammonium solution, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After concentrating the solvent under reduced pressure, methyl (2S)-2-amino-4-cyclopropylbutanoate was obtained. The crude product obtained was used directly in Reference Example 63 without further purification.

[0568] <Reference example 63>

[0569] [ka]

[0570] Under an argon atmosphere, a mixture of methyl (2S)-2-amino-4-cyclopropylbutanoate and impurities was prepared in an ethyl acetate-water mixture (11.0 mL, 1:1). Ditert-butyl dicarbonate (1.06 g) and sodium carbonate (700 mg) were added to the mixture under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1) to obtain methyl (2S)-4-cyclopropyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate (490 mg). 1 H-NMR (CDCl3, 400 MHz) δ:0.00-0.04 (2H, m), 0.40-0.45 (2H, m), 0.61-0.71 (1H, m), 1.21-1.29 (2H, m), 1.44 (9H, s), 1.67-1.77 (1H, m), 1.86-1.96 (1H, m), 3.74 (3H, s), 4.25-4.38 (1H, m), 4.90-5.10 (1H, m). HRMS (ESI + ):258.17006 [M+H] +

[0571] <Reference example 64>

[0572] [ka]

[0573] Under an argon atmosphere, lithium hydroxide monohydrate (120 mg) was added to a methanol-tetrahydrofuran-water mixture (9.52 mL, 3:3:1) of methyl (2S)-4-cyclopropyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate (490 mg) under ice cooling, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture under reduced pressure, the pH was adjusted to 2 by adding 1 mol / L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, (2S)-4-cyclopropyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid (418 mg) was obtained. 1 H-NMR (DMSO-D6, 400MHz) δ: 0.00-0.02 (2H, m), 0.32-0.41 (2H, m), 0.59-0.67 (1H, m), 1.18-1.26 (2H, m), 1.37 (9H, s), 1.58-1.68 (1H, m), 1.69-1.78 (1H, m), 3.85-3.92 (1H, m), 7.04 (1H, d, J = 7.9 Hz), 12.38 (1H, brs). HRMS (ESI + ):244.15499 [M+H] +

[0574] <Reference example 65-1>

[0575] [ka]

[0576] Under an argon atmosphere, 200 mg of 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxylic acid and 182 mg of methyl 2-amino-2-phenyl acetate hydrochloride were added to a 4.50 mL solution of N,N-dimethylformamide at room temperature. 165 mg of 1-hydroxybenzotriazole monohydrate, 191 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 0.616 mL of N,N-diisopropylethylamine were added and the mixture was stirred for 14 hours. After adding the reaction mixture to water and filtering off the resulting insoluble material, the mixture was washed with diisopropyl ether to obtain 296 mg of methyl 2-phenyl-2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]acetate. 1 H-NMR (DMSO-D6, 400MHz) δ: 1.03 (3H, s), 1.04 (3H, s), 2.24 (2H, s), 2.49 (3H, s), 2.65 (2H, s), 3.68 (3H, s), 5.57 (1H, d, J = 6.7 Hz), 7.37-7.51 (5H, m), 8.20 (1H, d, J = 6.7 Hz), 11.71 (1H, s). MS (ESI + ): 369.2 [M+H] +

[0577] Using the corresponding starting materials and reagents, Reference Examples 65-2 to 65-6 were obtained by the same method as in Reference Example 65-1, the method described in Step 1-1, or a similar method.

[0578] [Table 38]

[0579] [Table 39]

[0580] <Reference example 66>

[0581] [ka]

[0582] Under an argon atmosphere, a solution of methyl 4-cyclopropyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate obtained as the residue of Reference Example 59 was added to dichloromethane (4.00 mL) at room temperature and stirred for 20 minutes. To the solution of the residue obtained by distillation under reduced pressure from the reaction mixture, N,N-diisopropylethylamine (0.699 mL) and 2-phenylacetyl chloride (0.109 mL) were added at 0°C and stirred for 30 minutes at room temperature. The reaction mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1 to 0:1) to obtain methyl 4-cyclopropyl-2-[(2-phenylacetyl)amino]butanoate (189 mg). 1 H-NMR (CDCl3, 400MHz) δ: -0.13--0.03 (2H, m), 0.32-0.40 (2H, m), 0.51-0.63 (1H, m), 1.01-1.17 (2H, m), 1.63-1.73 (1H, m), 1.83-1.95 (1H, m), 3.60 (2H, s), 3.70 (3H, s), 4.58-4.67 (1H, m), 5.85 (1H, d, J = 7.3 Hz), 7.26-7.41 (5H, m). MS (ESI + ): 276.2 [M+H] +

[0583] <Reference example 67-1>

[0584] [ka]

[0585] 1.22 g of methyl 2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]hexanoate] was mixed with methanol (7.50 mL), tetrahydrofuran (7.50 mL), and water (15.0 mL). Lithium hydroxide monohydrate (220 mg) was added at room temperature and the mixture was stirred for 30 minutes. 1 mol / L hydrochloric acid was added to the reaction mixture, and the resulting insoluble matter was filtered to obtain 2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]hexanoic acid (1.09 g). HRMS (ESI + ): 335.19704 [M+H] +

[0586] Using the corresponding starting materials and reagents, Reference Examples 67-2 to 67-7 were obtained by the same method as in Reference Example 67-1, the method described in Step 1-2, or a similar method.

[0587] [Table 40]

[0588] [Table 41]

[0589] <Example 1-1>

[0590] [ka]

[0591] Under an argon atmosphere, 250 mg of 2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]hexanoic acid and 148 mg of 3-[4-(aminomethyl)phenyl]propan-1-ol] were added to a solution of N,N-dimethylformamide (4.00 mL) at room temperature, and 248 mg of 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride was added and the mixture was stirred for 1 hour. The reaction mixture was added to water and extracted twice with ethyl acetate. The combined extract layers were washed with water and then saturated saline solution, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1 to 0:1) to obtain N-[1-[[4-(3-hydroxypropyl)phenyl]methylamino]-1-oxohexane-2-yl]-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (241 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: 0.87 (3H, t, J = 7.0 Hz), 1.04 (6H, s), 1.23-1.37 (4H, m), 1.59-1.82 (4H, m), 2.24 (2H, s), 2.49 (3H, s), 2.55-2.62 (2H, m), 2.65 (2H, s), 3.38-3.44 (2H, m), 4.20-4.33 (2H, m), 4.41-4.50 (2H, m), 7.11-7.20 (4H, m), 7.47 (1H, d, J = 7.9 Hz), 8.53 (1H, t, J = 6.1 Hz), 11.72 (1H, s). HRMS (ESI + ): 482.30238 [M+H] +

[0592] Examples 1-2 to 1-149 were obtained using the corresponding starting materials and reagents by the same method as in Example 1-1, the method described in Step 1-3, or a similar method.

[0593] Table 42

[0594] Table 43

[0595] Table 44

[0596] Table 45

[0597] Table 46

[0598] Table 47

[0599] Table 48

[0600] Table 49

[0601] Table 50

[0602] Table 51

[0603] Table 52

[0604] Table 53

[0605] Table 54

[0606] Table 55

[0607] Table 56

[0608] Table 57

[0609] Table 58

[0610] Table 59

[0611] Table 60

[0612] Table 61

[0613] Table 62

[0614] Table 63

[0615] Table 64

[0616] Table 65

[0617] Table 66

[0618] Table 67

[0619] Table 68

[0620] Table 69

[0621] <Example 2-1>

[0622]

change

[0623] 50 mg of 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (50 mg) was added at room temperature to a solution of 2-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide)hexanoic acid (50 mg) and (S)-1-phenethylamine (20 mg) in N,N-dimethylformamide (2 mL). The mixture was stirred for 2 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated by liquid-liquid extraction. The aqueous layer was re-extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and two diastereomers were separated to isolate 3,6,6-trimethyl-4-oxo-N-((S)-1-oxo-1-(((S)-1-phenylethyl)amino)hexane-2-yl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamide and its isomers. 1 H-NMR (270 MHz, CDCl3) δ: 0.90 (3H, t, J = 7.0 Hz), 1.03-1.12 (6H, m), 1.30-1.41 (4H, m), 1.50 (3H, d, J = 7.1 Hz), 1.68-1.77 (1H, m), 1.88-2.02 (1H, m), 2.32 (2H, s), 2.58 (2H, s), 2.66 (3H, s), 4.56 (1H, dt, J = 7.2, 7.1 Hz), 5.11 (1H, dq, J = 7.6, 7.1 Hz), 6.48 (1H, d, J = 7.2Hz), 6.65 (1H, d, J = 7.6Hz), 7.18-7.35 (5H, m), 9.55 (1H, brs). MS (ESI + ): 438.42 [M+H] +

[0624] <Example 2-2>

[0625] [ka]

[0626] 3,6,6-trimethyl-4-oxo-N-((R)-1-oxo-1-(((S)-1-phenylethyl)amino)hexane-2-yl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamide 1 H-NMR (270 MHz, CDCl3) δ: 0.81 (3H, t, J = 6.8 Hz), 1.07 (6H, br, s), 1.18-1.31 (4H, m), 1.46 (3H, d, J = 6.9 Hz), 1.59-1.75 (1H, m), 1.77-1.93 (1H, m), 2.32 (2H, s), 2.58 (2H, s), 2.66 (3H, s), 4.59 (1H, dt, J = 7.9, 8.0 Hz), 5.11 (1H, dq, J = 7.7, 6.9 Hz), 6.69 (1H, d, J = 7.9 Hz), 6.83 (1H, d, J = 7.7 Hz), 7.21-7.38 (5H, m), 9.55 (1H, brs). MS (ESI + ): 438.41 [M+H] +

[0627] Examples 2-3 to 2-4 were obtained using the corresponding starting materials and reagents by the same method as in Example 2-1, the method described in Step 1-3, or a similar method.

[0628] [Table 70]

[0629] <Example 3-1>

[0630] [ka]

[0631] Using 2-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide)hexanoic acid and (R)-2-amino-2-phenylethane-1-ol, N-(1-(((R)-2-hydroxy-1-phenylethyl)amino)-1-oxohexanoyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide was obtained in the same manner as in Example 2-1. 1 H-NMR (270 MHz, CDCl3) δ: 0.80-0.90 (3H, m), 1.00-1.07 (6H, m), 1.21-1.42 (4H, m), 1.62-2.04 (2H, m), 2.29 (2 H, s), 2.50 and 2.53 (2H, s), 2.62 and 2.64 (3H, s), 3.85-4.05 (2H, m), 4.88-5.22 (2H, m), 6.70 and 6.86 (1H, d, J = 7.3 Hz), 7.19-7.38 (5H, m,), 8.13 and 8.21 (1H, d, J = 7.2 Hz), 9.95 and 10.26 (1H, s). MS (ESI + ): 454.36 [M+H] +

[0632] Using the corresponding starting materials and reagents, Example 3-2 was obtained by the same method as in Example 3-1, the method described in Step 1-3, or a similar method.

[0633] [Table 71]

[0634] <Reference example 68-1>

[0635] [ka]

[0636] It was synthesized using 2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]hexanoic acid and tert-butyl 3-(5-aminopyridine-2-yl)oxyazetidine-1-carboxylate, in the same manner as in Reference Example 1-1. 1 H-NMR (CDCl3, 400 MHz) δ: 0.89-0.93 (3H, m), 1.095 (3H, s), 1.101 (3H, s), 1.25-1.33 (4H, m), 1.38-1.43 (2H, m), 1.44 (9H, s), 2.35 (2H, s), 2.646 (2H, s), 2.654 (3H, s), 3.90-3.98 (2H, m), 4.29 (2H, dd, J = 9.7, 6.7 Hz), 4.61-4.70 (1H, m), 5.22-5.31 (1H, m), 6.40 (1H, d, J = 7.3 Hz), 6.74 (1H, d, J = 9.1 Hz), 7.92 (1H, dd, J = 9.1, 2.4 Hz), 8.15 (1H, d, J = 2.4 Hz), 8.45 (1H, s), 9.25 (1H, s).

[0637] Using the corresponding starting materials and reagents, Reference Examples 68-2 to 68-17 were obtained by the same method as in Reference Example 68-1, the method described in Step 1-3, or a similar method.

[0638] [Table 72]

[0639] [Table 73]

[0640] [Table 74]

[0641] [Table 75]

[0642] <Example 4>

[0643] [ka]

[0644] Under an argon atmosphere, trifluoroacetic acid (1.16 mL) was added to a dichloromethane solution (1.16 mL) of tert-butyl N-[[6-[(dimethylamino)methyl]pyridine-2-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (170 mg) under ice cooling, and the mixture was stirred at room temperature for 30 minutes before the reaction mixture was concentrated. To a 2.33 mL solution of the crude product obtained in N,N-dimethylformamide, 2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]hexanoic acid (156 mg) and 1-hydroxybenzotriazole monohydrate (75.4 mg) were added. Further, under ice cooling, N,N-diisopropylethylamine (0.316 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (98.2 mg) were added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by amination silica gel column chromatography (methanol / ethyl acetate = 10%), and the resulting solid was washed with diisopropyl ether to obtain N-[1-[[6-[(dimethylamino)methyl]pyridine-2-yl]methylamino]-1-oxohexane-2-yl]-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (155 mg). 11H-NMR (DMSO-D6, 400 MHz) δ: 0.86 (3H, t, J = 6.7 Hz), 1.01 (6H, s), 1.24 - 1.37 (4H, m), 1.60 - 1.71 (1H, m), 1.72 - 1.82 (1H, m), 2.15 (6H, s), 2.21 (2H, s), 2.47 (3H, s), 2.63 (2H, s), 3.45 (2H, s), 4.30 (1H, dd, J = 16.3, 6.1 Hz), 4.38 (1H, dd, J = 16.3, 6.1 Hz), 4.45 (1H, td, J = 8.5, 5.4 Hz), 7.14 (1H, d, J = 7.9 Hz), 7.26 (1H, d, J = 7.9 Hz), 7.47 (1H, d, J = 7.9 Hz), 7.70 (1H, t, J = 7.9 Hz), 8.61 (1H, t, J = 5.4 Hz), 11.64 (1H, s). HRMS (ESI + ): 482.31381 [M+H] +

[0645] <Reference Example 69>

[0646]

Chemical Structure

[0647] Under an argon atmosphere, 2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]hexanoic acid (500 mg) and N,N'-dicyclohexylcarbodiimide (339 mg) were dissolved in ethyl acetate (7.50 mL), to which pentafluorophenol (289 mg) was added at 50°C and the mixture was stirred for 2 hours. The reaction mixture was filtered with a cotton plug, and the filtrate was removed by reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed twice with saturated sodium bicarbonate aqueous solution and saturated brine, respectively. After drying with anhydrous sodium sulfate, insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was suspended and washed with diisopropyl ether to obtain (2,3,4,5,6-pentafluorophenyl) 2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]hexanoate (414 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: 0.86 (3H, t, J = 7.0 Hz), 1.00 (6H, s), 1.24-1.43 (4H, m), 1.65-1.76 (1H, m), 1.80-1.89 (1H, m), 2.24 (2H, s), 2.46 (3H, s), 2.65 (2H, s), 4.51-4.57 (1H, m), 11.44 (1H, brs), 12.07 (1H, s).

[0648] <Example 5-1>

[0649] [ka]

[0650] Under an argon atmosphere, a solution of (2,3,4,5,6-pentafluorophenyl) 2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]hexanoate (70.0 mg), 2-(difluoromethyl)aniline (27.6 mg), and N,N-diisopropylethylamine (48.7 μL) in N,N-dimethylacetamide (0.70 mL) was stirred at 50°C for 2 hours. After removing the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 6:1 to 0:1) to obtain N-[1-[2-(difluoromethyl)anilino]-1-oxohexane-2-yl]-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (14.0 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: 0.89 (3H, t, J = 7.0 Hz), 1.01 (6H, s), 1.25-1.45 (4H, m), 1.67-1.89 (2H, m), 2.21 (2H, s), 2.47 (3H, s), 2.64 (2H, s), 4.47-4.60 (1H, m), 7.02 (1H, t, J = 55.1 Hz), 7.31-7.43 (2H, m), 7.54 (1H, t, J = 7.6 Hz), 7.61 (2H, t, J = 7.3 Hz), 9.96 (1H, s), 11.66 (1H, s). HRMS (ESI + ): 460.24139 [M+H] +

[0651] Examples 5-2 to 5-3 were obtained using the corresponding starting materials and reagents by the same method as in Example 5-1, the method described in Step 2-2, or a similar method.

[0652] [Table 76]

[0653] [Table 77]

[0654] <Reference example 70-1>

[0655] [ka]

[0656] Under an argon atmosphere, 4-cyclopropyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid (214 mg) and 4-ethyl-6-methylpyridine-3-amine (120 mg) were dissolved in N,N-dimethylformamide (4.50 mL). Diisopropylamine (0.299 mL) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (368 mg) were added at room temperature and the mixture was stirred for 120 hours. The reaction mixture was added to water and extracted twice with ethyl acetate. The combined extract layers were washed with water and then saturated saline solution, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was purified by amination silica gel column chromatography (hexane:ethyl acetate = 3:1 to 0:1) to obtain tert-butyl N-[4-cyclopropyl-1-[(4-ethyl-6-methylpyridine-3-yl)amino]-1-oxobutan-2-yl]carbamate (288 mg). 1H-NMR (DMSO-D6, 400MHz) δ: -0.06-0.07 (2H, m), 0.32-0.43 (2H, m), 0.56-0.74 (1H, m), 1.09 (3H, t, J = 7.6 Hz), 1.20-1.29 (2H, m), 1.38 (9H, s), 1.60-1.86 (2H, m), 2.40 (3H, s), 2.47-2.54 (2H, m), 4.04-4.13 (1H, m), 7.03 (1H, d, J = 7.9 Hz), 7.12 (1H, s), 8.20 (1H, s), 9.38 (1H, s). MS (ESI + ): 362.2 [M+H] +

[0657] Using the corresponding starting materials and reagents, Reference Examples 70-2 to 70-58 were obtained by the same method as in Reference Example 70-1, the method described in Step 3-1, or a similar method.

[0658] [Table 78]

[0659] [Table 79]

[0660] [Table 80]

[0661] [Table 81]

[0662] [Table 82]

[0663] [Table 83]

[0664] Table 84

[0665] Table 85

[0666] Table 86

[0667] Table 87

[0668] Table 88

[0669] <Reference Example 71>

[0670]

change

[0671] Under an argon atmosphere, trifluoroacetic acid (0.663 mL) was added to a dichloromethane solution (0.663 mL) of tert-butyl N-[[6-[[2-(dimethylamino)ethyl-methylamino]methyl]pyridine-2-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (112 mg) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure. To a solution (1.33 mL) of the resulting crude product in N,N-dimethylformamide, 2-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid (61.3 mg) and 1-hydroxybenzotriazole monohydrate (43.0 mg) were added. Then, N,N-diisopropylethylamine (0.180 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (56.0 mg) were added under ice cooling, and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by amination silica gel column chromatography (ethyl acetate) to obtain tert-butyl N-[1-[[6-[[2-(dimethylamino)ethyl-methylamino]methyl]pyridine-2-yl]methylamino]-1-oxohexane-2-yl]carbamate (37.7 mg). 11H-NMR (CDCl3, 400 MHz) δ: 0.88 (3H, t, J = 6.7 Hz), 1.29 - 1.36 (4H, m), 1.44 (9H, s), 1.55 - 1.65 (1H, m), 1.82 - 1.90 (1H, m), 2.23 (6H, s), 2.27 (3H, s), 2.41 - 2.51 (2H, m), 2.55 - 2.62 (2H, m), 3.68 (2H, s), 4.14 - 4.22 (1H, m), 4.51 (1H, dd, J = 16.3, 4.8 Hz), 4.59 (1H, dd, J = 16.3, 4.8 Hz), 5.34 - 5.56 (1H, m), 7.13 (1H, d, J = 7.9 Hz), 7.28 (1H, d, J = 7.9 Hz), 7.43 (1H, brs), 7.61 (1H, t, J = 7.9 Hz). HRMS (ESI + ): 436.32827 [M+H] +

[0672] <Example 6-1>

[0673]

Chemical Structure

[0674] Under an argon atmosphere, tert-butyl N-[4-cyclopropyl-1-[(4-ethyl-6-methylpyridine-3-yl)amino]-1-oxobutan-2-yl]carbamate (288 mg) was added to a solution of dichloromethane (4.00 mL) at room temperature, and the mixture was stirred for 20 minutes. After removing the solvent and other components from the reaction mixture under reduced pressure, the residue was added to a solution of N,N-dimethylformamide (4.00 mL) at room temperature, to which 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxylic acid (176 mg), 1-hydroxybenzotriazole monohydrate (146 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (168 mg), and N,N-diisopropylethylamine (0.679 mL) were added, and the mixture was stirred for 51 hours. The reaction mixture was added to water and extracted twice with ethyl acetate. The combined extract layers were washed with water and then saturated saline solution, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1 to 0:1) to obtain N-[4-cyclopropyl-1-[(4-ethyl-6-methylpyridine-3-yl)amino]-1-oxobutan-2-yl]-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (231 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: -0.02-0.06 (2H, m), 0.36-0.45 (2H, m), 0.65-0.80 (1H, m), 1.01 (6H, s), 1.09 (3H, t, J = 7.3 Hz), 1.27-1.36 (2H, m), 1.77-2.01 (2H, m), 2.21 (2H, s), 2.41 (3H, s), 2.47 (3H, s), 2.52 (2H, q, J = 7.3 Hz), 2.63 (2H, s), 4.59-4.70 (1H, m), 7.13 (1H, s), 7.58 (1H, d, J = 7.9 Hz), 8.24 (1H, s), 9.62 (1H, s), 11.66 (1H, s). HRMS (ESI+ ): 465.28697 [M+H] +

[0675] Examples 6-2 to 6-107 were obtained using the corresponding starting materials and reagents by the same method as in Example 6-1, the method described in step 3-2 or step 3-3, or a similar method.

[0676] [Table 89]

[0677] [Table 90]

[0678] [Table 91]

[0679] [Table 92]

[0680] [Table 93]

[0681] [Table 94]

[0682] [Table 95]

[0683] [Table 96]

[0684] [Table 97]

[0685] Table 98

[0686] Table 99

[0687] Table 100

[0688] Table 101

[0689] Table 102

[0690] Table 103

[0691] Table 104

[0692] Table 105

[0693] Table 106

[0694] Table 107

[0695] Table 108

[0696] Table 109

[0697] Table 110

[0698] Table 111

[0699] Table 112

[0700] <Example 7>

[0701]

change

[0702] Under an argon atmosphere, trifluoroacetic acid (0.458 mL) was added to a dichloromethane solution (0.458 mL) of tert-butyl N-[1-[(6-methoxypyridine-3-yl)amino]-1-oxohexane-2-yl]carbamate (61.8 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure. 2,2-diphenylacetyl chloride (46.4 mg) and N,N-diisopropylethylamine (0.125 mL) were added to a dichloromethane solution (0.916 mL) of the resulting crude product, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1), and the resulting solid was washed with diisopropyl ether to obtain 2-[(2,2-diphenylacetyl)amino]-N-(6-methoxypyridine-3-yl)hexaneamide (64.7 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: 0.79 (3H, t, J = 6.7 Hz), 1.17-1.28 (4H, m), 1.54-1.73 (2H, m), 3.79 (3H, s), 4.41 (1H, td, J = 7.9, 5.4 Hz), 5.13 (1H, s), 6.78 (1H, d, J = 9.1 Hz), 7.17-7.30 (10H, m), 7.86 (1H, dd, J = 9.1, 2.4 Hz), 8.33 (1H, d, J = 2.4 Hz), 8.58 (1H, d, J = 7.9 Hz), 10.12 (1H, s). HRMS (ESI + ):432.22900 [M+H] +

[0703] <Example 8>

[0704] [ka]

[0705] Under an argon atmosphere, trifluoroacetic acid (0.363 mL) was added to a dichloromethane solution (0.363 mL) of tert-butyl N-[4-cyclopropyl-1-[(6-methoxypyridine-3-yl)amino]-1-oxobutan-2-yl]carbamate (50.8 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure. To the resulting crude product in a dichloromethane solution (0.727 mL), 2-phenylacetyl chloride (0.021 mL) and N,N-diisopropylethylamine (0.099 mL) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 3:2), and the resulting solid was washed with diisopropyl ether to obtain 4-cyclopropyl-N-(6-methoxypyridine-3-yl)-2-[(2-phenylacetyl)amino]butanamide (32.3 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: -0.11--0.02 (2H, m), 0.34 (2H, d, J = 7.9 Hz), 0.59-0.68 (1H, m), 1.12-1.22 (2H, m), 1.63-1.82 (2H, m), 3.44 (1H, d, J = 13.9 Hz), 3.51 (1H, d, J = 13.9 Hz), 3.79 (3H, s), 4.37 (1H, td, J = 7.9, 5.4 Hz), 6.78 (1H, d, J = 8.5 Hz), 7.15-7.29 (5H, m), 7.87 (1H, dd, J = 8.5, 2.4 Hz), 8.31-8.38 (2H, m), 10.07 (1H, s). HRMS (ESI + ):368.19644 [M+H] +

[0706] <Example 9-1>

[0707] [ka]

[0708] Under an argon atmosphere, 10% palladium carbon (15.3 mg) was added at room temperature to a mixed solution of benzyl N-[1-oxo-1-(quinoline-4-ylamino)hexane-2-yl]carbamate (76.7 mg) in ethanol (0.50 mL) and tetrahydrofuran (0.50 mL). The mixture was stirred under a hydrogen atmosphere for 5 hours, after which the hydrogen in the reaction vessel was replaced with argon. The reaction mixture was filtered using Celite, and the solvent and other components of the filtrate were removed under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1.00 mL), and at room temperature, 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxylic acid (47.5 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (47.0 mg), 1-hydroxybenzotriazole (46.4 mg), and N,N-diisopropylethylamine (71.0 μL) were added and the mixture was stirred for 4 hours. The reaction mixture was added to water and extracted twice with ethyl acetate. The combined extract layers were washed twice with saturated saline solution, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol = 99:1 to 11:1) to obtain 3,6,6-trimethyl-4-oxo-N-[1-oxo-1-(quinoline-4-ylamino)hexane-2-yl]-5,7-dihydro-1H-indole-2-carboxamide (78.0 mg). 1H-NMR (DMSO-D6, 400MHz) δ: 0.89 (3H, t, J = 7.3 Hz), 1.02 (6H, s), 1.27-1.49 (4H, m), 1.73-1.95 (2H, m), 2.22 (2H, s), 2.50 (3H, s), 2.64 (2H, s), 4.80-4.94 (1H, m), 7.65 (1H, t, J = 7.9 Hz), 7.73-7.80 (2H, m), 8.00 (1H, d, J = 7.6 Hz), 8.04 (1H, d, J = 5.2 Hz), 8.34 (1H, d, J = 7.6 Hz), 8.80 (1H, d, J = 5.2 Hz), 10.44 (1H, s), 11.70 (1H, s). HRMS (ESI + ): 461.25486 [M+H] +

[0709] Using the corresponding starting materials and reagents, Example 9-2 was obtained by the same method as in Example 9-1, the method described in step 3-2 or step 3-3, or a similar method.

[0710] [Table 113]

[0711] <Example 10>

[0712] [ka]

[0713] Under an argon atmosphere, 100 mg of benzyl N-[1-[[6-(oxetane-3-yloxy)pyridine-3-yl]amino]-1-oxohexane-2-yl]carbamate was added to a 1.50 mL solution of ethanol at room temperature. The mixture was stirred under a hydrogen atmosphere for 2 hours, after which the hydrogen in the reaction vessel was replaced with argon. The reaction mixture was filtered using Celite, and the solvent and other components of the filtrate were removed under reduced pressure. Diisopropylamine (61.7 μL) and 2-phenylacetyl chloride (32.0 μL) were added to the residue in a 2.50 mL solution of dichloromethane at 0°C, and the mixture was stirred for 1.5 hours. The reaction mixture was added to water and extracted twice with ethyl acetate. The combined extract layers were washed with water and then saturated saline solution, dried with anhydrous sodium sulfate, and insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1 to 0:1) to obtain N-[6-(oxetane-3-yloxy)pyridine-3-yl]-2-[(2-phenylacetyl)amino]hexanamide (80.0 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: 0.82 (3H, t, J = 6.7 Hz), 1.14-1.35 (4H, m), 1.50-1.76 (2H, m), 3.45 (1H, d, J = 13.9 Hz), 3.51 (1H, d, J = 13.9 Hz), 4.30-4.41 (1H, m), 4.52 (2H, dd, J = 7.6, 5.1 Hz), 4.81-4.90 (2H, m), 5.46-5.52 (1H, m), 6.87 (1H, d, J = 8.5 Hz), 7.16-7.30 (5H, m), 7.92 (1H, dd, J = 8.5, 2.4 Hz), 8.29 (1H, d, J = 2.4 Hz), 8.37 (1H, d, J = 7.9 Hz), 10.11 (1H, s). HRMS (ESI + ): 398.20803 [M+H] +

[0714] <Reference example 72-1>

[0715] [ka]

[0716] The synthesis was carried out using benzyl N-[1-[[6-(1-methylpiperidine-4-yl)oxypyridine-3-yl]amino]-1-oxohexane-2-yl]carbamate, in the same manner as in Reference Example 5. 1 H-NMR (DMSO-D6, 400MHz) δ: 0.85 (3H, t, J = 7.0 Hz), 1.20-1.48 (5H, m), 1.54-1.68 (3H, m), 1.87-1.96 (2H, m), 2.06-2.18 (5H, m), 2.55-2.66 (2H, m), 3.25 (1H, dd, J = 7.9, 5.4 Hz), 4.83-4.94 (1H, m), 6.72 (1H, d, J = 9.1 Hz), 7.92 (1H, dd, J = 9.1, 2.4 Hz), 8.34 (1H, d, J = 2.4 Hz). MS (ESI + ): 321.2 [M+H] +

[0717] Using the corresponding starting materials and reagents, Reference Example 72-2 was obtained by the same method as in Reference Example 72-1, the method described in step 3-2, or a similar method.

[0718] [Table 114]

[0719] <Example 11-1>

[0720] [ka]

[0721] Under an argon atmosphere, 2-amino-N-[6-(1-methylpiperidine-4-yl)oxypyridine-3-yl]hexaneamide (50.0 mg) and 1-hydroxybenzotriazole monohydrate (25.3 mg) were added to a solution of 2-methyl-4-(4-methylpiperazine-1-yl)benzoic acid (36.5 mg) in N,N-dimethylformamide (0.780 mL). Then, under ice cooling, N,N-diisopropylethylamine (0.040 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (33.0 mg) were added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by amination silica gel column chromatography (ethyl acetate : methanol = 9:1), and the resulting solid was washed with hexane : ethyl acetate = 5:1 to obtain 2-methyl-4-(4-methylpiperazine-1-yl)-N-[1-[[6-(1-methylpiperidine-4-yl)oxypyridine-3-yl]amino]-1-oxohexane-2-yl]benzamide (26.5 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: 0.87 (3H, t, J = 6.7 Hz), 1.25-1.38 (4H, m), 1.57-1.75 (4H, m), 1.88-1.96 (2H, m), 2.07-2.13 (2H, m), 2.16 (3H, s), 2.20 (3H, s), 2.31 (3H, s), 2.42 (4H, t, J = 4.8 Hz), 2.57-2.64 (2H, m), 3.17 (4H, t, J = 4.8 Hz), 4.45 (1H, td, J = 7.9, 6.1 Hz), 4.85-4.93 (1H, m), 6.72-6.76 (3H, m), 7.31 (1H, d, J = 9.1 Hz), 7.89 (1H, dd, J = 9.1, 2.4 Hz), 8.11 (1H, d, J = 7.9 Hz), 8.32 (1H, d, J = 2.4 Hz), 10.05 (1H, s). HRMS (ESI+ ):537.35620 [M+H] +

[0722] Examples 11-2 to 11-11 were obtained using the same starting materials and reagents as in Example 11-1, the method described in step 3-3, or a similar method.

[0723] [Table 115]

[0724] [Table 116]

[0725] [Table 117]

[0726] [Table 118]

[0727] <Example 12-1>

[0728] [ka]

[0729] In an argon atmosphere, pyridine (18.9 μL) and 2,2-diphenylacetyl chloride (39.7 mg) were added to a solution of 2-amino-N-[6-(1-methylpiperidin-4-yl)oxypyridin-3-yl]hexanamide (50.0 mg) in tetrahydrofuran (1.00 mL) at 0 °C. After stirring at room temperature for 3 hours, the reaction solution was purified by aminated silica gel column chromatography (methanol:ethyl acetate = 0:1 to 1:9) to obtain 2-[(2,2-diphenylacetyl)amino]-N-[6-(1-methylpiperidin-4-yl)oxypyridin-3-yl]hexanamide (67.0 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: 0.79 (3H, t, J = 7.0 Hz), 1.10 - 1.31 (4H, m), 1.50 - 1.75 (4H, m), 1.86 - 1.96 (2H, m), 2.07 - 2.18 (5H, m), 2.55 - 2.64 (2H, m), 4.35 - 4.46 (1H, m), 4.83 - 4.93 (1H, m), 5.13 (1H, s), 6.73 (1H, d, J = 9.1 Hz), 7.16 - 7.35 (10H, m), 7.85 (1H, dd, J = 9.1, 3.0 Hz), 8.29 (1H, d, J = 3.0 Hz), 8.57 (1H, d, J = 7.3 Hz), 10.10 (1H, s). HRMS (ESI + ): 515.30139 [M+H] +

[0730] Using the corresponding starting materials and reactants, Example 12-2 below was obtained by the same method as in Example 12-1, the method described in Step 3-3, or a method analogous thereto.

[0731]

Table 119

[0732] <Reference Example 73-1>

[0733] [ka]

[0734] It was synthesized in the same manner as in Example 6-1 using 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxylic acid and tert-butyl N-[6-(2-aminohexanoylamino)-4-methyl-1,3-benzothiazole-2-yl]carbamate. 1 H-NMR (DMSO-D6, 400MHz) δ: 0.87 (3H, t, J = 7.0 Hz), 1.01 (6H, s), 1.27-1.42 (4H, m), 1.48 (9H, s), 1.66-1.86 (2H, m), 2.22 (2H, s), 2.47 (3H, s), 2.64 (2H, s), 3.30 (3H, s), 4.52-4.60 (1H, m), 7.32 (1H, d, J = 1.8 Hz), 7.57 (1H, d, J = 7.3 Hz), 8.09 (1H, d, J = 1.8 Hz), 10.15 (1H, s), 11.68 (1H, s), 11.72 (1H, s). MS (ESI + ): 596.3 [M+H] +

[0735] Using the corresponding starting materials and reagents, Reference Examples 73-2 to 73-4 were obtained using the same method as in Reference Example 73-1, the method described in step 3-2 or step 3-3, or a similar method.

[0736] [Table 120]

[0737] <Example 13-1>

[0738] [ka]

[0739] tert-Butyl (4-cyclopropyl-1-oxo-1-(((S)-1-phenylethyl)amino)butan-2-yl)carbamate was used to synthesize in the same manner as in Example 6-1, and N-((S)-4-cyclopropyl-1-oxo-1-(((S)-1-phenylethyl)amino)butan-2-yl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide and its isomers were obtained. 1 H-NMR (270 MHz, CDCl3) δ: -0.23--0.07 (2H, m), 0.23-0.43 (2H, m), 0.45-0.65 (1H, m), 0.93-1.29 (8H, m), 1.38 (3H, d, J = 6.9 Hz), 1.65-2.01 (2H, m), 2.29 (2H, s), 2.51 (2H, s), 2.65 (3H, s), 4.69 (1H, dd, J = 13.5, 7.6 Hz), 4.99-5.10 (1H, m), 7.18-7.40 (7H, m), 10.34 (1H, s). MS (ESI + ): 450.37 [M+H] +

[0740] <Example 13-2>

[0741]

Chemical formula

[0742] N-((R)-4-cyclopropyl-1-oxo-1-(((S)-1-phenylethyl)amino)butan-2-yl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide 1H-NMR (270 MHz, CDCl3) δ: -0.05-0.10 (2H, m), 0.38-0.50 (2H, m), 0.57-0.80 (1H, m), 1.08 (6H, s), 1.17-1.42 (2H, m), 1.50 (3H, d, J = 6.9 Hz), 1.72-1.92 (1H, m), 1.97-2.18 (1H, m), 2.32 (2H, s), 2.57-2.64 (5H, m), 4.48-4.68 (1H, m), 5.02-5.19 (1H, m), 6.34 (1H, d, J = 7.6 Hz), 6.50 (1H, d, J = 7.9 Hz), 7.17-7.40 (5H, m), 9.28 (1H, s). MS (ESI + ): 450.37 [M+H] +

[0743] Examples 13-3 to 13-6 were obtained using the same starting materials and reagents as in Example 13-1, the method described in step 3-2 or step 3-3, or a similar method.

[0744] [Table 121]

[0745] [Table 122]

[0746] <Reference example 74-1>

[0747] [ka]

[0748] Under an argon atmosphere, 2.43 mL of a 1,2-dimethoxyethane solution of tert-butyl N-[1-(2-bromo-4-methylanilino)-4-cyclopropyl-1-oxobutan-2-yl]carbamate (200 mg) was mixed with 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.100 mL), 2 mol / L aqueous sodium carbonate solution (0.730 mL), and bis(triphenylphosphine)palladium(II) dichloride (34.1 mg), and the mixture was stirred at 80°C for 3 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0%-33%) to obtain tert-butyl N-[4-cyclopropyl-1-(2-ethenyl-4-methylanilino)-1-oxobutan-2-yl]carbamate (86.7 mg). 1 H-NMR (CDCl3, 400 MHz) δ:0.03-0.07 (2H, m), 0.43-0.48 (2H, m), 0.66-0.72 (1H, m), 1.30-1.38 (2H, m), 1.47 (9H, s), 1.74-1.81 (1H, m), 2.04-2.14 (1H, m), 2.32 (3H, s), 4.15-4.30 (1H, m), 4.85-5.05 (1H, m), 5.36 (1H, d, J = 10.9 Hz), 5.66 (1H, d, J = 17.0 Hz), 6.78 (1H, dd, J = 17.0, 10.9 Hz), 7.09 (1H, dd, J = 8.5, 1.8 Hz), 7.25 (1H, d, J = 1.8 Hz), 7.69 (1H, d, J = 8.5 Hz), 7.93 (1H, brs). HRMS (ESI + ):359.23318 [M+H] +

[0749] Using the corresponding starting materials and reagents, Reference Example 74-2 was obtained by the same method as in Reference Example 74-1, the method described in step 36-1, or a similar method.

[0750] [Table 123]

[0751] <Reference example 75-1>

[0752] [ka]

[0753] Under an argon atmosphere, 17.3 mg of 5% palladium carbon was added to a tetrahydrofuran-ethanol mixture (1.21 mL, 1:1) of tert-butyl N-[4-cyclopropyl-1-(2-ethenyl-4-methylanilino)-1-oxobutan-2-yl]carbamate (86.7 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 9 hours. After replacing the reaction system with an argon atmosphere, the reaction mixture was filtered through Celite. After solvent removal, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0%-30%) to obtain tert-butyl N-[4-cyclopropyl-1-(2-ethyl-4-methylanilino)-1-oxobutan-2-yl]carbamate (76.1 mg). 1H-NMR (CDCl3, 400 MHz) δ:0.03-0.07 (2H, m), 0.43-0.48 (2H, m), 0.65-0.74 (1H, m), 1.21 (3H, t, J = 7.3 Hz), 1.31-1.38 (2H, m), 1.46 (9H, s), 1.73-1.83 (1H, m), 2.07-2.15 (1H, m), 2.30 (3H, s), 2.56 (2H, q, J = 7.3 Hz), 4.15-4.30 (1H, m), 4.95 (1H, brs), 6.99-7.03 (2H, m), 7.66 (1H, d, J = 8.6 Hz), 7.87 (1H, brs). HRMS (ESI + ):361.24877 [M+H] +

[0754] Using the corresponding starting materials and reagents, Reference Example 75-2 was obtained by the same method as in Reference Example 75-1, the method described in step 36-2, or a similar method.

[0755] [Table 124]

[0756] <Example 14-1>

[0757] [ka]

[0758] Under an argon atmosphere, trifluoroacetic acid (0.528 mL) was added to a dichloromethane solution (0.528 mL) of tert-butyl N-[4-cyclopropyl-1-(2-ethyl-4-methylanilino)-1-oxobutan-2-yl]carbamate (76.1 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure. To a solution (1.06 mL) of the resulting crude product in N,N-dimethylformamide, 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxylic acid (46.7 mg), 1-hydroxybenzotriazole monohydrate (38.7 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44.5 mg), and N,N-diisopropylethylamine (0.144 mL) were added, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 10%-50%), and the resulting solid was washed with diisopropyl ether to obtain N-[4-cyclopropyl-1-(2-ethyl-4-methylanilino)-1-oxobutan-2-yl]-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (61.6 mg). 1H-NMR (DMSO-D6, 400MHz) δ: 0.00-0.05 (2H, m), 0.39-0.44 (2H, m), 0.69-0.77 (1H, m), 1.02 (6H, s), 1.08 (3H, t, J = 7.3 Hz), 1.28-1.35 (2H, m), 1.81-1.99 (2H, m), 2.22 (2H, s), 2.26 (3H, s), 2.48 (3H, s), 2.49-2.55 (2H, m), 2.64 (2H, s), 4.65 (1H, td, J = 7.9, 6.1 Hz), 6.97 (1H, dd, J = 7.9, 1.8 Hz), 7.04 (1H, d, J = 1.8 Hz), 7.16 (1H, d, J = 7.9 Hz), 7.56 (1H, d, J = 7.9 Hz), 9.41 (1H, s), 11.69 (1H, br s). HRMS (ESI + ):464.29052 [M+H] +

[0759] Using the corresponding starting materials and reagents, Example 14-2 was obtained by the same method as in Example 14-1, the method described in step 3-2 or step 3-3, or a similar method.

[0760] [Table 125]

[0761] <Reference example 76-1>

[0762] [ka]

[0763] Under an argon atmosphere, zinc cyanide (363 mg) was added to a 1.55 mL solution of tert-butyl N-[(2S)-4-cyclopropyl-1-(4-iodoanilino)-1-oxobutan-2-yl]carbamate (275 mg) in N,N-dimethylformamide and stirred at 90°C for 15 minutes. Then, dibenzylideneacetone palladium (0) (72.0 mg) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (51.0 mg) were added and stirred at 90°C for 3 hours. Further addition of dibenzylideneacetone palladium (0) (72.0 mg) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (51.0 mg) was added and stirred at 90°C for 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 8%-33%) to obtain tert-butyl N-[(2S)-1-(4-cyanoanilino)-4-cyclopropyl-1-oxobutan-2-yl]carbamate (145 mg). 1 H-NMR (CDCl3, 400 MHz) δ:-0.01-0.03 (2H, m), 0.41-0.44 (2H, m), 0.61-0.69 (1H, m), 1.27-1.32 (2H, m), 1.43 (9H, s), 1.68-1.78 (1H, m), 2.03-2.08 (1H, m), 4.16-4.22 (1H, m), 4.88 (1H, brs), 7.55 (2H, d, J = 8.5 Hz), 7.60 (2H, d, J = 8.5 Hz), 8.79 (1H, brs). HRMS (ESI + ):344.19695 [M+H] +

[0764] Using the corresponding starting materials and reagents, Reference Example 76-2 was obtained by the same method as in Reference Example 76-1, the method described in step 37-1, or a similar method.

[0765] [Table 126]

[0766] <Example 15-1>

[0767] [ka]

[0768] Under an argon atmosphere, trifluoroacetic acid (1.06 mL) was added to a dichloromethane solution (1.06 mL) of tert-butyl N-[(2S)-1-(4-cyanoanilino)-4-cyclopropyl-1-oxobutan-2-yl]carbamate (145 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure. To a solution (2.11 mL) of the resulting crude product in N,N-dimethylformamide, 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxylic acid (93.4 mg), 1-hydroxybenzotriazole monohydrate (77.6 mg), N,N-diisopropylethylamine (0.287 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (88.9 mg) were added, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 10%-66%), and the resulting solid was washed with diisopropyl ether to obtain N-[(2S)-1-(4-cyanoanilino)-4-cyclopropyl-1-oxobutan-2-yl]-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (150 mg). 1H-NMR (DMSO-D6, 400MHz) δ: -0.01-0.02 (2H, m), 0.36-0.40 (2H, m), 0.66-0.74 (1H, m), 1.00 (6H, s), 1.21-1.33 (2H, m), 1.77-1.90 (2H, m), 2.20 (2H, s), 2.44 (3H, s), 2.62 (2H, s), 4.55 (1H, td, J = 7.9, 5.4 Hz), 7.71 (1H, d, J = 7.9 Hz), 7.76 (2H, d, J = 9.1 Hz), 7.79 (2H, d, J = 9.1 Hz), 10.58 (1H, s), 11.66 (1H, s). HRMS (ESI + ):447.23893 [M+H] +

[0769] Examples 15-2 to 15-4 were obtained using the corresponding starting materials and reagents, by the same method as in Example 15-1, the method described in step 3-2 or step 3-3, or a similar method.

[0770] [Table 127]

[0771] [Table 128]

[0772] <Reference example 77>

[0773] [ka]

[0774] Under an argon atmosphere, 1.00 mL of tetrahydrofuran solution of methyl 4-[[2-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoylamino]methyl]benzoate (133 mg) was added to 0.760 mL of tetrahydrofuran solution of lithium aluminum hydride (26.7 mg) under ice cooling, and the mixture was stirred at room temperature for 3 hours. Water (0.027 mL), 15% aqueous sodium hydroxide solution (0.027 mL), and water (0.080 mL) were added to the reaction mixture, and the mixture was filtered using Celite. After solvent removal, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 50%) to obtain tert-butyl N-[1-[[4-(hydroxymethyl)phenyl]methylamino]-1-oxohexane-2-yl]carbamate (81.4 mg). 1 H-NMR (CDCl3, 400 MHz) δ:0.87 (3H, t, J = 6.7 Hz), 1.28-1.33 (4H, m), 1.40 (9H, s), 1.55-1.61 (1H, m), 1.80-1.89 (1H, m), 4.03 (1H, brs), 4.42 (2H, s), 4.66 (2H, s), 4.93 (1H, brs), 6.40 (1H, brs), 7.24 (2H, d, J = 7.9 Hz), 7.30 (2H, d, J = 7.9 Hz). HRMS (ESI + ):351.22875 [M+H] +

[0775] <Example 16>

[0776] [ka]

[0777] Under an argon atmosphere, trifluoroacetic acid (0.581 mL) was added to a dichloromethane solution (0.581 mL) of tert-butyl N-[1-[[4-(hydroxymethyl)phenyl]methylamino]-1-oxohexane-2-yl]carbamate (81.4 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure. To a solution (1.16 mL) of the resulting crude product in N,N-dimethylformamide, 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxylic acid (51.3 mg), 1-hydroxybenzotriazole monohydrate (42.7 mg), N,N-diisopropylethylamine (0.158 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (48.9 mg) were added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by silica gel column chromatography (ethyl acetate) to obtain N-[1-[[4-(hydroxymethyl)phenyl]methylamino]-1-oxohexane-2-yl]-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (73.8 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: 0.84 (3H, t, J = 7.0 Hz), 1.01 (6H, s), 1.24-1.31 (4H, m), 1.59-1.77 (2H, m), 2.21 (2H, s), 2.46 (3H, s), 2.63 (2H, s), 4.23 (1H, dd, J = 15.1, 6.1 Hz), 4.29 (1H, dd, J = 15.1, 6.1 Hz), 4.40-4.43 (1H, m), 4.44 (2H, d, J = 5.4 Hz), 5.12 (1H, t, J = 5.4 Hz), 7.19 (2H, d, J = 7.9 Hz), 7.23 (2H, d, J = 7.9 Hz), 7.48 (1H, d, J = 7.9 Hz), 8.54 (1H, t, J = 6.1 Hz), 11.72 (1H, s). HRMS (ESI + ):454.27086 [M+H] +

[0778] <Reference example 78-1>

[0779] [ka]

[0780] 194 mg of tert-butyl (S)-(1-oxo-1-(phenylamino)hexane-2-yl)carbamate was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (1 mL) was added and stirred overnight. 2N sodium hydroxide aqueous solution was added to adjust the pH to 13-14, and the mixture was extracted three times with dichloromethane. After drying over anhydrous sodium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was dissolved in 10 mL of tetrahydrofuran, and 2.3 mL of borane-tetrahydrofuran complex (1 M tetrahydrofuran solution) was added and stirred at 75°C for 1 day. 1 mL of 2N hydrochloric acid aqueous solution was added and stirred at 75°C for 1 hour. 2N sodium hydroxide aqueous solution was added to adjust the pH to 13-14, and the mixture was extracted three times with dichloromethane. After drying over anhydrous sodium sulfate, the mixture was filtered and concentrated under reduced pressure. (S)-N1-phenylhexane-1,2-diamine (116 mg) was obtained. 1 H-NMR (CDCl3, 270 MHz) δ: 0.92 (3H, t, J = 6.9 Hz), 1.25-1.59 (6H, m), 2.83 (1H, dd, J = 11.9, 8.2 Hz), 2.89-3.03 (1H, m), 3.18 (1H, dd, J = 11.9, 3.6 Hz), 4.10 (1H, br, s), 6.58-6.73 (3H, m), 7.10-7.22 (2H, m). MS (ESI + ): 193.23 [M+H] +

[0781] Using the corresponding starting materials and reagents, Reference Example 78-2 was obtained by the same method as in Reference Example 78-1, step 3-2, and the method described in step 46-1 or a similar method.

[0782] [Table 129]

[0783] <Example 17-1>

[0784] [ka]

[0785] (S)-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxylic acid and (S)-N1-phenylhexane-1,2-diamine were used in the same manner as in Example 6-1 to obtain (S)-3,6,6-trimethyl-4-oxo-N-(1-(phenylamino)hexane-2-yl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (153 mg). 1 H-NMR (CDCl3, 270 MHz) δ: 0.92 (3H, t, J = 7.1 Hz), 1.08 (6H, s), 1.30-1.51 (4H, m), 1.53-1.82 (2H, m), 2.32 (2H, s), 2.54 (3H, s), 2.65 (2H, s), 3.38-3.20 (2H, m), 3.99-4.20 (1H, m), 4.27-4.49 (1H, m), 5.77 (1H, d, J = 8.6 Hz), 6.53-6.76 (3H, m), 7.07-7.22 (2H, m), 9.84 (1H, brs). MS (ESI + ): 396.59 [M+H] +

[0786] Using the corresponding starting materials and reagents, Example 17-2 was obtained by the same method as in Example 17-1, the method described in step 46-2, or a similar method.

[0787] [Table 130]

[0788] <Reference example 79-1>

[0789] [ka]

[0790] Under an argon atmosphere, triphenylphosphine (86.0 mg) and carbon tetrabromide (127 mg) were added to a tetrahydrofuran-dichloromethane mixture (1.37 mL, 1:1) of N-[1-[3-(bromomethyl)anilino]-1-oxohexane-2-yl]-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (120 mg) at room temperature, and the mixture was stirred for 7 hours at room temperature. After concentrating the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 8%-66%) to obtain N-[1-[3-(bromomethyl)anilino]-1-oxohexane-2-yl]-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (85.1 mg). 1H-NMR (DMSO-D6, 400MHz) δ: 0.88 (3H, t, J = 6.7 Hz), 1.03 (6H, s), 1.29-1.37 (4H, m), 1.70-1.83 (2H, m), 2.23 (2H, s), 2.48 (3H, s), 2.65 (2H, s), 4.55 (1H, td, J = 7.9, 4.9 Hz), 4.68 (2H, s), 7.14 (1H, d, J = 7.9 Hz), 7.30 (1H, t, J = 7.9 Hz), 7.53 (1H, d, J = 7.9 Hz), 7.60 (1H, d, J = 7.9 Hz), 7.75 (1H, s), 10.22 (1H, s), 11.68 (1H, s). HRMS (ESI + ):502.17119 [M+H] +

[0791] Using the corresponding starting materials and reagents, Reference Examples 79-2 to 79-3 were obtained by the same method as in Reference Example 79-1, the method described in Step 4-1, or a similar method.

[0792] [Table 131]

[0793] [Table 132]

[0794] <Example 18-1>

[0795] [ka]

[0796] Under an argon atmosphere, dimethylamine (0.047 mL, 2 mol / L tetrahydrofuran solution) and potassium carbonate (12.9 mg) were added to a solution of N-[1-[3-(bromomethyl)anilino]-1-oxohexane-2-yl]-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (42.5 mg) in N,N-dimethylformamide (0.211 mL), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by amination silica gel column chromatography (ethyl acetate : methanol = 1 : 0 - 4 : 1), and the resulting solid was washed with diisopropyl ether to obtain N-[1-[3-[(dimethylamino)methyl]anilino]-1-oxohexane-2-yl]-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (14.3 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: 0.88 (3H, t, J = 6.7 Hz), 1.02 (6H, s), 1.32-1.39 (4H, m), 1.70-1.78 (2H, m), 2.13 (6H, s), 2.23 (2H, s), 2.48 (3H, s), 2.65 (2H, s), 3.34 (2H, s), 4.54 (1H, td, J = 8.6, 4.9 Hz), 6.96 (1H, d, J = 7.3 Hz), 7.24 (1H, t, J = 7.3 Hz), 7.52 (1H, d, J = 8.6 Hz), 7.56-7.62 (2H, m), 10.10 (1H, s), 11.71 (1H, s). HRMS (ESI + ):467.30234 [M+H] +

[0797] Examples 18-2 to 18-14 were obtained using the corresponding starting materials and reagents by the same method as in Example 18-1, the method described in step 4-2, or a similar method.

[0798] [Table 133]

[0799] [Table 134]

[0800] [Table 135]

[0801] [Table 136]

[0802] <Reference example 80>

[0803] [ka]

[0804] Under an argon atmosphere, 50.0 mg of N-[1-[[4-(3-hydroxypropyl)phenyl]methylamino]-1-oxohexane-2-yl]-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide was dissolved in 1.00 mL of dichloromethane. Triethylamine (21.7 μL) and methanesulfonyl chloride (9.67 μL) were added at 0°C and the mixture was stirred for 1 hour. The reaction mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1 to 0:1) to obtain 50.0 mg of 3-[4-[[2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]hexanoylamino]methyl]phenyl]propyl methanesulfonate. 11H-NMR (DMSO-D6, 400 MHz) δ: 0.84 (3H, t, J = 7.0 Hz), 1.01 (6H, s), 1.21 - 1.35 (4H, m), 1.57 - 1.78 (2H, m), 1.88 - 1.97 (2H, m), 2.20 (2H, s), 2.46 (3H, s), 2.59 - 2.66 (4H, m), 3.16 (3H, s), 4.17 (2H, t, J = 6.4 Hz), 4.19 - 4.31 (2H, m), 4.38 - 4.47 (1H, m), 7.13 - 7.19 (4H, m), 7.47 - 7.55 (1H, m), 8.48 - 8.56 (1H, m), 11.75 (1H, s). MS (ESI + ): 560.3 [M+H] +

[0805] <Reference Example 81>

[0806]

Chemical Structure

[0807] Under an argon atmosphere, potassium carbonate (37.0 mg) was added at room temperature to a solution of 3-[4-[[2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]hexanoylamino]methyl]phenyl]propyl methanesulfonate (50.0 mg) and iminodicarboxylate di-tert-butyl (58.2 mg) in N,N-dimethylformamide (1.00 mL), and the mixture was stirred at 50°C for 8 hours. The reaction mixture was added to water, extracted twice with ethyl acetate, and then washed with water and saturated brine in that order. After drying with anhydrous sodium sulfate, insoluble matter was filtered off. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1 to 0:1) to obtain tert-butyl N-[(2-methylpropan-2-yl)oxycarbonyl]-N-[3-[4-[[2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]hexanoylamino]methyl]phenyl]propyl]carbamate (46.0 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: 0.79-0.89 (3H, m), 1.01 (6H, s), 1.20-1.31 (6H, m), 1.40 (18H, s), 1.70-1.79 (2H, m), 2.20 (2H, s), 2.46 (3H, s), 2.50-2.54 (2H, m), 2.62 (2H, s), 3.40-3.48 (2H, m), 4.16-4.31 (2H, m), 4.38-4.48 (1H, m), 7.08-7.18 (4H, m), 7.46 (1H, d, J = 7.9 Hz), 8.52 (1H, t, J = 6.1 Hz), 11.70 (1 H, s). MS (ESI + ): 681.4 [M+H] +

[0808] <Example 19>

[0809] [ka]

[0810] To a solution of tert-butyl N-[(2-methylpropan-2-yl)oxycarbonyl]-N-[3-[4-[[2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]hexanoylamino]methyl]phenyl]propyl]carbamate (40.0 mg) in dichloromethane (0.250 mL), trifluoroacetic acid (0.250 mL) was added at room temperature and the mixture was stirred for 2 hours. After removing the solvent from the reaction mixture under reduced pressure, the residue was purified by amination silica gel column chromatography (ethyl acetate : methanol = 1:0 to 4:1) to obtain N-[1-[[4-(3-aminopropyl)phenyl]methylamino]-1-oxohexane-2-yl]-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (29.0 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: 0.83-0.91 (3H, m), 1.04 (6H, s), 1.23-1.37 (4H, m), 1.56-1.83 (4H, m), 2.24 (2H, s), 2.49 (3H, s), 2.53-2.60 (4H, m), 2.66 (2H, s), 4.20-4.34 (2H, m), 4.42-4.50 (1H, m), 7.12-7.20 (4H, m), 7.52 (1H, d, J = 7.9 Hz), 8.54 (1H, t, J = 5.8 Hz). HRMS (ESI + ): 481.31785 [M+H] +

[0811] <Reference example 82-1>

[0812] [ka]

[0813] Under an argon atmosphere, lithium hydroxide monohydrate (60.0 mg) was added to a tetrahydrofuran-methanol-water mixture (1.43 mL, 3:3:1) of methyl 4-[2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]hexanoylamino]benzoate (134 mg), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and neutralized with 1 mol / L hydrochloric acid. The resulting solid was filtered to obtain 4-[2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]hexanoylamino]benzoic acid (122 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: 0.88 (3H, t, J = 6.7 Hz), 1.02 (6H, s), 1.30-1.44 (4H, m), 1.70-1.84 (2H, m), 2.23 (2H, s), 2.47 (3H, s), 2.65 (2H, s), 4.56 (1H, td, J = 8.6, 4.9 Hz), 7.68 (1H, d, J = 8.6 Hz), 7.74 (2H, d, J = 8.6 Hz), 7.90 (2H, d, J = 8.6 Hz), 10.46 (1H, s), 11.69 (1H, s), 12.71 (1H, s). HRMS (ESI + ):454.23456 [M+H] +

[0814] Using the corresponding starting materials and reagents, Reference Example 82-2 was obtained by the same method as in Reference Example 82-1, the method described in Step 5-1, or a similar method.

[0815] [Table 137]

[0816] <Example 20-1>

[0817] [ka]

[0818] Under an argon atmosphere, ammonium chloride (29.5 mg), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (50.2 mg), and N,N-diisopropylethylamine (0.094 mL) were added to a 0.551 mL solution of 4-[2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]hexanoylamino]benzoic acid (50.0 mg) in N,N-dimethylformamide and stirred at room temperature for 8 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 25%-100% - methanol / ethyl acetate = 20%), and the resulting solid was washed with diisopropyl ether to obtain N-[1-(4-carbamoylanilino)-1-oxohexane-2-yl]-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (34.7 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: 0.88 (3H, t, J = 6.7 Hz), 1.03 (6H, s), 1.32-1.42 (4H, m), 1.71-1.82 (2H, m), 2.23 (2H, s), 2.48 (3H, s), 2.65 (2H, s), 4.57 (1H, td, J = 8.6, 4.9 Hz), 7.25 (1H, br s), 7.67 (2H, d, J = 8.6 Hz), 7.84 (2H, d, J = 8.6 Hz), 7.95 (2H, br s), 10.36 (1H, s), 11.69 (1H, s). HRMS (ESI + ):453.24986 [M+H] +

[0819] Using the corresponding starting materials and reagents, Example 20-2 was obtained by the same method as in Example 20-1, the method described in step 5-2, or a similar method.

[0820] [Table 138]

[0821] <Example 21>

[0822] [ka]

[0823] Under an argon atmosphere, 30.0 mg of 3,6,6-trimethyl-N-[1-(4-nitroanilino)-1-oxohexane-2-yl]-4-oxo-5,7-dihydro-1H-indole-2-carboxamide was mixed with methanol (0.500 mL) and tetrahydrofuran (0.500 mL). 10% palladium carbon (3.00 mg) was added at room temperature, and the mixture was stirred under a hydrogen atmosphere for 2 hours. After stirring, the hydrogen in the reaction vessel was replaced with argon. The reaction mixture was filtered using Celite, and the solvent and other components of the filtrate were removed under reduced pressure to obtain N-[1-(4-aminoanilino)-1-oxohexane-2-yl]-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (27.0 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: 0.88 (3H, t, J = 7.0 Hz), 1.04 (6H, s), 1.24-1.43 (4H, m), 1.62-1.85 (2H, m), 2.23 (2H, s), 2.49 (3H, s), 2.65 (2H, s), 4.50-4.58 (1H, m), 4.87 (2H, s), 6.51 (2H, d, J = 8.5 Hz), 7.24 (2H, d, J = 8.5 Hz), 7.54 (1H, d, J = 7.9 Hz), 9.71 (1H, s), 11.75 (1H, s). HRMS (ESI + ): 425.25574 [M+H] +

[0824] <Example 22-1>

[0825] [ka]

[0826] (S)-3,6,6-trimethyl-4-oxo-N-(1-oxo-1-((4-(piperazin-1-yl)benzyl)amino)hexane-2-yl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (62 mg), isobutyraldehyde (110 μL), and N,N-diisopropylethylamine (72 μL) were dissolved in dichloromethane (630 μL). Sodium triacetoxyborohydride (51 mg) was added to the solution under ice cooling, and the mixture was heated to room temperature and stirred overnight. 2 mL of saturated sodium bicarbonate aqueous solution and 1 mL of 2M potassium carbonate aqueous solution were added, and the mixture was extracted twice with dichloromethane. The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (dichloromethane-methanol) to obtain (S)-N-(1-((4-(4-isopropylpiperazin-1-yl)benzyl)amino)-1-oxohexane-2-yl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (28.2 mg). 1H-NMR (399 MHz,CDCl3) δ: 0.88 (3H, t, J = 7.3 Hz), 0.93 (6H, d, J = 6.4 Hz), 1.09 (6H, s), 1.28-1.40 (4H, m), 1.63-1.99 (3H, m), 2.17 (2H, d, J = 7.8 Hz), 2.33 (2H, s), 2.53-2.60 (4H, m), 2.62 (2H, s), 2.66 (3H, s), 3.18 (4H, t, J = 4.8 Hz), 4.32 (1H, dd, J = 14.6, 5.5 Hz), 4.42 (1H, dd, J = 14.6, 5.7 Hz), 4.55 (1H, q, J = 6.9 Hz), 6.27 (1H, s), 6.57 (1H, d, J = 7.8 Hz), 6.85 (2H, d, J = 8.7 Hz), 7.15 (2H, d, J = 8.7 Hz), 9.35 (1H, s) MS (ESI + ): 565.23 [M+H] +

[0827] Examples 22-2 to 22-5 were obtained using the corresponding starting materials and reagents by the same method as in Example 22-1, the method described in step 7-1, or a similar method.

[0828] [Table 139]

[0829] [Table 140]

[0830] <Reference example 83>

[0831] [ka]

[0832] (S)-3,6,6-trimethyl-4-oxo-N-(1-oxo-1-((4-(piperazin-1-yl)benzyl)amino)hexane-2-yl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (187 mg), 2-(benzyloxy)acetaldehyde (68 mg), and N,N-diisopropylethylamine (10.5 μL) were dissolved in dichloromethane (1.5 mL). Sodium triacetoxyborohydride (153 mg) was added to the solution under ice cooling, and the mixture was heated to room temperature and stirred overnight. Saturated sodium bicarbonate aqueous solution (2 mL) and 2M potassium carbonate aqueous solution (2 mL) were added, and the mixture was extracted twice with dichloromethane. The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (dichloromethane-methanol) to isolate (S)-N-(1-((4-(4-(2-(benzyloxy)ethyl)piperazin-1-yl)benzyl)amino)-1-oxohexane-2-yl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (177.9 mg). 1 H-NMR (399 MHz, CDCl3) δ: 0.88 (3H, t, J = 7.2 Hz), 1.09 (6H, s), 1.26-1.38 (4H, m), 1.63-1.80 (1H, m), 1.88-2.00 (1H, m), 2.33 (2H, s), 2.61 (2H, t, J = 5.3 Hz), 2.62 (2H, s), 2.65-2.70 (9H, m), 3.19 (4H, t, J = 5.2 Hz), 3.67 (2H, t, J = 6.4 Hz), 4.31 (1H, dd, J = 14.6, 4.8 Hz), 4.42 (1H, dd, J = 14.6, 4.8 Hz), 4.5- 4.56 (1H, m), 6.20 (1H, m), 6.55 (1H, d, J = 8.0 Hz), 6.86 (2H, d, J = 8.8 Hz), 7.15 (2H, d, J = 8.8 Hz), 7.35 (5H, m), 9.30 (1H brs). MS (ESI+ ): 642.18 [M+H] +

[0833] <Example 23>

[0834] [ka]

[0835] (S)-N-(1-((4-(4-(2-(benzyloxy)ethyl)piperazin-1-yl)benzyl)amino)-1-oxohexane-2-yl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (154 mg), 10% palladium carbon (50% aqueous solution) (150 mg), and trifluoroacetic acid (55 μL) mixed with methanol (40 mL) were stirred at room temperature under a hydrogen atmosphere for 2 days. The reaction mixture was filtered by Celite, concentrated under reduced pressure, and the residue was separated by adding dichloromethane-saturated sodium bicarbonate aqueous solution. The aqueous layer was extracted twice, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane-methanol) to obtain (S)-N-(1-((4-(4-(2-hydroxyethyl)piperazin-1-yl)benzyl)amino)-1-oxohexane-2-yl)-3,6,6-trimethyl-1-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (58.3 mg). 11H-NMR (399 MHz, CDCl3) δ: 0.88 (3H, t, J = 7.1 Hz), 1.08 (6H, s), 1.29 - 1.38 (4H, m), 1.73 (1H, td, J = 14.6, 7.2 Hz), 1.88 - 2.00 (1H, m), 2.32 (2H, s), 2.61 (2H, t, J = 5.3 Hz), 2.61 (2H, s), 2.65 (3H, s), 2.67 (4H, t, J = 4.8 Hz), 3.17 (4H, t, J = 5.0 Hz), 3.67 (2H, t, J = 5.3 Hz), 4.31 (1H, dd, J = 14.6, 5.5 Hz), 4.42 (1H, dd, J = 14.6, 5.5 Hz), 4.56 (1H, dt, J = 6.9, 6.9 Hz), 6.39 (1H, t, J = 5.5 Hz), 6.63 (1H, d, J = 7.8 Hz), 6.85 (2H, d, J = 8.7 Hz), 7.15 (2H, d, J = 8.7 Hz), 9.55 (1H, brs). MS (ESI + ): 552.13 [M+H] +

[0836] <Example 24-1>

[0837]

Chemical Structure

[0838] Under an argon atmosphere, trifluoroacetic acid (1.41 mL) was added to a dichloromethane solution (1.41 mL) of tert-butyl N-methyl-N-[2-[5-[2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]hexanoylamino]pyridin-2-yl]oxyethyl]carbamate (330 mg), and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was filtered off. After evaporating the solvent, 3,6,6-trimethyl-N-[1-[[6-[2-(methylamino)ethoxy]pyridin-3-yl]amino]-1-oxohexan-2-yl]-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (210 mg) was obtained. 1 H-NMR (DMSO-D6, 400 MHz) δ: 0.87 (3H, t, J = 6.7 Hz), 1.01 (6H, s), 1.25 - 1.42 (4H, m), 1.65 - 1.81 (2H, m), 2.21 (2H, s), 2.30 (3H, s), 2.46 (3H, s), 2.63 (2H, s), 2.77 (2H, t, J = 5.8 Hz), 4.22 (2H, t, J = 5.8 Hz), 4.53 (1H, td, J = 8.6, 5.5 Hz), 6.77 (1H, d, J = 8.6 Hz), 7.74 (1H, brs), 7.90 (1H, dd, J = 8.6, 2.4 Hz), 8.35 (1H, d, J = 2.4 Hz), 10.20 (1H, s), 11.80 (1H, brs). HRMS (ESI + ):484.29239 [M+H] +

[0839] Using the corresponding starting materials and reagents, Examples 24-2 to 24-5 below were obtained by the same method as in Example 24-1, the method described in Step 8-1, or a method analogous thereto.

[0840] [Table 141]

[0841] [Table 142]

[0842] <Example 25-1>

[0843] [ka]

[0844] To a solution of tert-butyl 5-[2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]hexanoylamino]-3,4-dihydro-1H-isoquinoline-2-carboxylate (55.0 mg) in dichloromethane (0.50 mL), trifluoroacetic acid (0.50 mL) was added at room temperature and the mixture was stirred for 2 hours. After removing the solvent from the reaction mixture under reduced pressure, the residue was purified by amination silica gel column chromatography (ethyl acetate : methanol = 97 : 3 ~ 4 : 1) to obtain 3,6,6-trimethyl-4-oxo-N-[1-oxo-1-(1,2,3,4-tetrahydroisoquinoline-5-ylamino)hexane-2-yl]-5,7-dihydro-1H-indole-2-carboxamide (31.8 mg). 1H-NMR (DMSO-D6, 400 MHz) δ: 0.96 (3H, t, J = 6.7 Hz), 1.09 (6H, s), 1.30-1.52 (4H, m), 1.74-1.96 (2H, m), 2.29 (2H, s), 2.55 (3H, s), 2.58-2.63 (2H, m), 2.71 (2H, s), 2.93-3.03 (2H, m), 3.89 (2H, s), 4.66-4.74 (1H, m), 6.92 (1H, d, J = 7.3 Hz), 7.14 (1H, t, J = 7.6 Hz), 7.27 (1H, d, J = 7.9 Hz), 7.64 (1H, d, J = 7.9 Hz), 9.43 (1H, s), 11.78 (1H, s). HRMS (ESI + ): 465.2857 [M+H] +

[0845] Examples 25-2 to 25-3 were obtained using the corresponding starting materials and reagents by the same method as in Example 25-1, the method described in step 9-1, or a similar method.

[0846] [Table 143]

[0847] <Example 26-1>

[0848] [ka]

[0849] It was synthesized in the same manner as in Example 19 using tert-butyl 3-[5-[2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]hexanoylamino]pyridine-2-yl]oxyazetidine-1-carboxylate. 1H-NMR (DMSO-D6, 400 MHz) δ: 0.87 (3H, t, J = 7.3 Hz), 1.01 (6H, s), 1.25-1.41 (4H, m), 1.64-1.83 (2H, m), 2.21 (2H, s), 2.46 (3H, s), 2.63 (2H, s), 3.44-3.52 (2H, m), 3.68-3.75 (2H, m), 4.50-4.58 (1H, m), 5.22-5.30 (1H, m), 6.80 (1H, d, J = 8.5 Hz), 7.56-7.64 (1H, m), 7.90 (1H, dd, J = 8.5, 3.0 Hz), 8.31 (1H, d, J = 3.0 Hz), 10.16 (1H, s), 11.66 (1H, br s). HRMS (ESI + ): 482.27709 [M+H] +

[0850] Examples 26-2 to 26-8 were obtained using the corresponding starting materials and reagents, by the same method as in Example 26-1, the method described in step 10-1, or a similar method.

[0851] [Table 144]

[0852] [Table 145]

[0853] <Example 27>

[0854] [ka]

[0855] It was synthesized in the same manner as in Example 19 using tert-butyl 7-[5-[2-[(3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carbonyl)amino]hexanoylamino]pyridine-2-yl]-2,7-diazaspiro[3.4]octane-2-carboxylate. 1 H-NMR (DMSO-D6, 400 MHz) δ: 0.86 (3H, t, J = 6.7 Hz), 1.01 (6H, s), 1.21-1.42 (4H, m), 1.63-1.80 (2H, m), 2.03-2.12 (2H, m), 2.21 (2H, s), 2.46 (3H, s), 2.63 (2H, s), 3.32-3.37 (4H, m), 3.39-3.50 (4H, m), 4.48-4.57 (1H, m), 6.39 (1H, d, J = 9.1 Hz), 7.63-7.74 (2H, m), 8.22 (1H, d, J = 2.4 Hz), 9.91 (1H, s). HRMS (ESI + ): 521.32408 [M+H] +

[0856] <Example 28>

[0857] [ka]

[0858] To a solution of tert-butyl 4-[4-[[4-cyclopropyl-1-[(6-methoxypyridine-3-yl)amino]-1-oxobutan-2-yl]carbamoyl]phenyl]piperidine-1-carboxylate (52.0 mg) in dichloromethane (0.500 mL), trifluoroacetic acid (0.500 mL) was added at room temperature and the mixture was stirred for 15 minutes. After removing the solvent from the reaction mixture under reduced pressure, diisopropylamine (0.100 mL) was added to the residue in a solution of tetrahydrofuran (0.500 mL) at room temperature and the mixture was stirred for 15 minutes. After removing the solvent under reduced pressure, the residue was purified by amination silica gel column chromatography (ethyl acetate : methanol = 1:0 to 9:1) to obtain N-[4-cyclopropyl-1-[(6-methoxypyridine-3-yl)amino]-1-oxobutan-2-yl]-4-piperidine-4-ylbenzamide (39.0 mg). 1 H-NMR (DMSO-D6, 400 MHz) δ: -0.05-0.08 (2H, m), 0.32-0.43 (2H, m), 0.64-0.76 (1H, m), 1.19-1.38 (2H, m), 1.50 (2H, ddd, J = 24.5, 12.2, 3.7 Hz), 1.62-1.72 (2H, m), 1.84-1.95 (2H, m), 2.52-2.68 (3H, m), 2.96-3.06 (2H, m), 3.80 (3H, s), 4.56 (1H, q, J = 7.9 Hz), 6.78 (1H, d, J = 8.6 Hz), 7.30 (2H, d, J = 8.6 Hz), 7.84 (2H, d, J = 8.6 Hz), 7.90 (1H, dd, J = 8.6, 2.4 Hz), 8.36 (1H, d, J = 2.4 Hz), 8.48 (1H, d, J = 7.9 Hz), 10.09 (1H, s). HRMS (ESI + ): 437.25501 [M+H] +

[0859] <Example 29>

[0860] [ka]

[0861] It was synthesized using N-[6-(1-methylpiperidine-4-yl)oxypyridine-3-yl]-2-[[2-(2-nitrophenyl)acetyl]amino]hexaneamide in the same manner as in Reference Example 5. 1 H-NMR (DMSO-D6, 400 MHz) δ: 0.82 (3H, t, J = 7.0 Hz), 1.17-1.33 (4H, m), 1.52-1.75 (4H, m), 1.88-1.97 (2H, m), 2.12-2.24 (5H, m), 2.58-2.70 (2H, m), 3.32-3.35 (1H, m), 3.38 (1H, d, J = 13.9 Hz), 4.30-4.40 (1H, m), 4.85-4.94 (1H, m), 5.04 (2H, s), 6.49 (1H, td, J = 7.3, 1.2 Hz), 6.62 (1H, d, J = 7.3 Hz), 6.73 (1H, d, J = 9.1 Hz), 6.91 (1H, td, J = 7.6, 1.2 Hz), 7.00 (1H, dd, J = 7.6, 1.2 Hz), 7.86 (1H, dd, J = 9.1, 2.4 Hz), 8.30 (1H, d, J = 2.4 Hz), 8.35 (1H, d, J = 7.9 Hz), 10.05 (1H, s). HRMS (ESI + ): 454.28121 [M+H] +

[0862] <Reference example 84-1>

[0863] [ka]

[0864] Under an argon atmosphere, 2-N-methylbenzene-1,2-diamine (0.047 mL), 1-hydroxybenzotriazole monohydrate (75.5 mg), N,N-diisopropylethylamine (0.105 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86.6 mg) were added to a 2.06 mL N,N-dimethylformamide solution (100 mg) of 4-cyclopropyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid (100 mg), and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, acetic acid (1.37 mL) was added, and the mixture was stirred at 60°C for 4 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain tert-butyl N-[3-cyclopropyl-1-(1-methylbenzimidazol-2-yl)propyl]carbamate (96.1 mg). 1 H-NMR (CDCl3, 400 MHz) δ: -0.03-0.06 (2H, m), 0.40-0.43 (2H, m), 0.67-0.75 (1H, m), 1.20-1.33 (2H, m), 1.43 (9H, s), 2.01-2.19 (2H, m), 3.83 (3H, s), 5.11 (1H, td, J = 7.9, 6.1 Hz), 5.29 (1H, d, J = 8.6 Hz), 7.24-7.31 (2H, m), 7.32-7.36 (1H, m), 7.73 (1H, dd, J = 7.3, 1.8 Hz). HRMS (ESI + ):330.21755 [M+H] +

[0865] Using the corresponding starting materials and reagents, Reference Examples 84-2 to 84-6 were obtained by the same method as in Reference Example 84-1, the method described in step 39-1, or a similar method.

[0866] [Table 146]

[0867] [Table 147]

[0868] <Example 30-1>

[0869] [ka]

[0870] Under an argon atmosphere, trifluoroacetic acid (0.729 mL) was added to a dichloromethane solution (0.729 mL) of tert-butyl N-[3-cyclopropyl-1-(1-methylbenzimidazol-2-yl)propyl]carbamate (96.1 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure. To a solution (1.46 mL) of the resulting crude product in N,N-dimethylformamide, 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxylic acid (64.6 mg), 1-hydroxybenzotriazole monohydrate (53.6 mg), N,N-diisopropylethylamine (0.199 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61.5 mg) were added, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1), and the resulting solid was washed with diisopropyl ether to obtain N-[3-cyclopropyl-1-(1-methylbenzimidazol-2-yl)propyl]-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (92.8 mg). 1H-NMR (DMSO-D6, 400MHz) δ: 0.00-0.10 (2H, m), 0.43 (2H, dd, J = 7.9, 1.8 Hz), 0.74-0.82 (1H, m), 1.04 (6H, s), 1.26-1.37 (2H, m), 2.11-2.21 (2H, m), 2.24 (2H, s), 2.48 (3H, s), 2.65 (2H, s), 3.85 (3H, s), 5.50 (1H, td, J = 8.6, 6.1 Hz), 7.22 (1H, ddd, J = 8.6, 7.3, 1.2 Hz), 7.27 (1H, ddd, J = 8.6, 7.3, 1.2 Hz), 7.56 (1H, dd, J = 7.3, 1.2 Hz), 7.63 (1H, dd, J = 7.3, 1.2 Hz), 8.05 (1H, d, J = 8.6 Hz), 11.61 (1H, s). HRMS (ESI + ):433.25981 [M+H] +

[0871] Examples 30-2 to 30-4 were obtained using the corresponding starting materials and reagents, by the same method as in Example 30-1, the method described in steps 39-2 to 39-3, or a similar method.

[0872] [Table 148]

[0873] [Table 149]

[0874] <Reference example 85>

[0875] [ka]

[0876] 604 mg of 3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid and 845 mg of (S)-1-(6-(benzyloxy)-1H-benz[d]imidazole-2-yl)pentan-1-amine were dissolved in tetrahydrofuran (10 mL), to which 906.5 mg of 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride was added under ice cooling. The mixture was allowed to return to room temperature and stirred overnight. Ethyl acetate, water, and saturated sodium bicarbonate aqueous solution were added to the reaction solution, and the organic layer was separated by liquid-liquid extraction. The aqueous layer was re-extracted once with ethyl acetate. The combined organic layers were washed with saturated brine-sodium bicarbonate aqueous solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane), crystallized while concentrating with chloroform, and washed with heptane to isolate (S)-N-(1-(6-(benzyloxy)-1H-benz[d]imidazole-2-yl)pentyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (990 mg). 1 H-NMR (399 MHz, CDCl3) δ: 0.83 (3H, t, J= 7.0 Hz), 0.99 (6H, s), 1.23-1.39 (4H, m), 1.83-1.95 (1H, m), 1.98-2.11 (1H, m), 2.19 (2H, s), 2.48 (3H, s), 261 (2H, s), 5.09 (2H, s), 5.19 (1H, q, J = 6.0 Hz), 6.85 (1H, m), 7.01 (0.6H, s), 7.17 (0.4H, s), 7.29 (1H, d, J = 7.2 Hz), 7.36 (3H, m), 7.43 (2H, d, J = 7.2 Hz), 7.80 (1H, d, J = 8.4 Hz), 11.59 (1H, s), 12.12 (1H, m). MS (ESI + ): 513.14 [M+H] +

[0877] <Reference example 86-1>

[0878] [ka]

[0879] Under an argon atmosphere, 200 mg of tert-butyl N-[3-cyclopropyl-1-(1,7-dimethylbenzimidazol-2-yl)propyl]carbamate was dissolved in carbon tetrachloride (5.82 mL) at room temperature, to which 104 mg of N-bromosuccinimide and 4.8 mg of 2,2'-azobis(isobutyronitrile) were added, and the mixture was stirred at 80°C for 5 hours. Saturated sodium thiosulfate aqueous solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to obtain 149 mg of tert-butyl N-[1-[7-(bromomethyl)-1-methylbenzimidazol-2-yl]-3-cyclopropylpropyl]carbamate. 1 H-NMR (CDCl3, 400 MHz) δ: -0.01-0.09 (2H, m), 0.42-0.47 (2H, m), 0.69-0.77 (1H, m), 1.25-1.36 (2H, m), 1.45 (9H, s), 2.13-2.20 (2H, m), 4.26 (3H, s), 4.87 (1H, d, J = 10.9 Hz), 4.93 (1H, d, J = 10.9 Hz), 5.15-5.23 (1H, m), 7.24-7.27 (2H, m), 7.77 (1H, t, J = 4.8 Hz). HRMS (ESI + ):422.14443 [M+H] +

[0880] Using the corresponding starting materials and reagents, Reference Examples 86-2 to 86-3 were obtained by the same method as in Reference Example 86-1, the method described in step 40-1, or a similar method.

[0881] [Table 150]

[0882] <Reference example 87-1>

[0883] [ka]

[0884] Under an argon atmosphere, 149 mg of tert-butyl N-[1-[7-(bromomethyl)-1-methylbenzimidazol-2-yl]-3-cyclopropylpropyl]carbamate (1.76 mL) was mixed with dimethylamine (0.353 mL, 2 mol / L tetrahydrofuran solution) at room temperature and stirred for 4 hours at room temperature. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to obtain 100 mg of tert-butyl N-[3-cyclopropyl-1-[7-[(dimethylamino)methyl]-1-methylbenzimidazol-2-yl]propyl]carbamate (1.76 mL). HRMS (ESI + ):387.27547 [M+H] +

[0885] Using the corresponding starting materials and reagents, Reference Examples 87-2 to 87-7 were obtained using the same method as in Reference Example 87-1, the method described in step 40-2, or a similar method.

[0886] [Table 151]

[0887] [Table 152]

[0888] <Example 31-1>

[0889] [ka]

[0890] Under an argon atmosphere, trifluoroacetic acid (0.647 mL) was added to a dichloromethane solution (0.647 mL) of tert-butyl N-[3-cyclopropyl-1-[7-[(dimethylamino)methyl]-1-methylbenzimidazol-2-yl]propyl]carbamate (100 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure. To a solution (1.29 mL) of the resulting crude product in N,N-dimethylformamide, 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxylic acid (57.3 mg), 1-hydroxybenzotriazole monohydrate (47.5 mg), N,N-diisopropylethylamine (0.175 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54.6 mg) were added, and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by amination silica gel column chromatography (hexane:ethyl acetate = 1:1), and the resulting solid was washed with diisopropyl ether to obtain N-[3-cyclopropyl-1-[7-[(dimethylamino)methyl]-1-methylbenzimidazol-2-yl]propyl]-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (73.6 mg). 1H-NMR (DMSO-D6, 400 MHz) δ: 0.00-0.11 (2H, m), 0.42-0.46 (2H, m), 0.75-0.83 (1H, m), 1.05 (6H, s), 1.28-1.39 (2H, m), 2.09-2.15 (2H, m), 2.19 (6H, s), 2.25 (2H, s), 2.50 (3H, s), 2.66 (2H, s), 3.64 (1H, d, J = 12.7 Hz), 3.75 (1H, d, J = 12.7 Hz), 4.15 (3H, s), 5.53 (1H, td, J = 8.5, 5.4 Hz), 7.03 (1H, d, J = 7.9 Hz), 7.13 (1H, t, J = 7.9 Hz), 7.58 (1H, dd, J = 7.9, 1.2 Hz), 8.05 (1H, d, J = 8.5 Hz), 11.62 (1H, s). HRMS (ESI + ):490.31795 [M+H] +

[0891] Examples 31-2 to 31-7 were obtained using the corresponding starting materials and reagents, by the same method as in Example 31-1, the method described in steps 39-2 to 39-3, or a similar method.

[0892] [Table 153]

[0893] [Table 154]

[0894] [Table 155]

[0895] <Reference example 88>

[0896] [ka]

[0897] Under an argon atmosphere, 3.00 mL of tetrahydrofuran solution of lithium aluminum hydride (49.0 mg) was mixed with 2.39 mL of tetrahydrofuran solution of methyl 2-[3-cyclopropyl-1-[(2-methylpropan-2-yl)oxycarbonylamino]propyl]-1-methylbenzimidazole-5-carboxylate (418 mg) under ice cooling, and the mixture was stirred at room temperature for 2 hours. Water (0.050 mL), 15% aqueous sodium hydroxide solution (0.050 mL), and water (0.150 mL) were added to the reaction mixture, and the mixture was filtered using Celite. After solvent removal, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 50%) to obtain tert-butyl N-[3-cyclopropyl-1-[5-(hydroxymethyl)-1-methylbenzimidazole-2-yl]propyl]carbamate (224 mg). 1 H-NMR (CDCl3, 400 MHz) δ: 0.00-0.08 (2H, m), 0.42-0.47 (2H, m), 0.65-0.73 (1H, m), 1.26-1.35 (2H, m), 1.38 (9H, s), 2.17-2.28 (1H, m), 2.47-2.57 (1H, m), 4.07 (3H, s), 4.84 (2H, s), 5.23-5.28 (1H, m), 7.51 (1H, d, J = 8.5 Hz), 7.58 (1H, dd, J = 8.5, 1.2 Hz), 7.93 (1H, d, J = 1.2 Hz). HRMS (ESI + ):360.22903 [M+H] +

[0898] <Reference example 89>

[0899] [ka]

[0900] Under an argon atmosphere, triphenylphosphine (130 mg) and carbon tetrabromide (191 mg) were added to a 2.06 mL dichloromethane solution of tert-butyl N-[3-cyclopropyl-1-[5-(hydroxymethyl)-1-methylbenzimidazol-2-yl]propyl]carbamate (148 mg) at room temperature, and the mixture was stirred at room temperature for 4 hours. After concentrating the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate : hexane = 1:2) to obtain tert-butyl N-[1-[5-(bromomethyl)-1-methylbenzimidazol-2-yl]-3-cyclopropylpropyl]carbamate (118 mg). 1 H-NMR (CDCl3, 400 MHz) δ: 0.01-0.07 (2H, m), 0.43-0.48 (2H, m), 0.66-0.72 (1H, m), 1.25-1.34 (2H, m), 1.38 (9H, s), 2.18-2.28 (1H, m), 2.49-2.59 (1H, m), 4.08 (3H, s), 4.59 (2H, s), 5.25 (1H, brs), 7.52 (1H, d, J = 8.5 Hz), 7.60 (1H, d, J = 8.5 Hz), 8.02 (1H, s). MS (ESI + ):422.2 [M+H] +

[0901] <Reference example 90>

[0902] [ka]

[0903] Under an argon atmosphere, 118 mg of tert-butyl N-[1-[5-(bromomethyl)-1-methylbenzimidazol-2-yl]-3-cyclopropylpropyl]carbamate (1.40 mL) was mixed with dimethylamine (0.279 mL, 2 mol / L tetrahydrofuran solution) at room temperature and stirred for 7 hours at room temperature. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by amination silica gel column chromatography (hexane:ethyl acetate = 1:1) to obtain tert-butyl N-[3-cyclopropyl-1-[5-[(dimethylamino)methyl]-1-methylbenzimidazol-2-yl]propyl]carbamate (98.4 mg). 1 H-NMR (CDCl3, 400 MHz) δ: 0.00-0.06 (2H, m), 0.40-0.44 (2H, m), 0.70-0.77 (1H, m), 1.25-1.29 (2H, m), 1.40 (9H, s), 1.96-2.06 (2H, m), 2.16 (6H, s), 3.49 (2H, s), 3.80 (3H, s), 4.94 (1H, td, J = 8.5, 6.1 Hz), 7.20 (1H, dd, J = 8.5, 1.2 Hz), 7.42-7.47 (2H, m). HRMS (ESI + ):387.27542 [M+H] +

[0904] <Example 32>

[0905] [ka]

[0906] Under an argon atmosphere, trifluoroacetic acid (0.636 mL) was added to a dichloromethane solution (0.636 mL) of tert-butyl N-[3-cyclopropyl-1-[5-[(dimethylamino)methyl]-1-methylbenzimidazol-2-yl]propyl]carbamate (98.4 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure. To a solution (1.27 mL) of the resulting crude product in N,N-dimethylformamide, 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxylic acid (56.4 mg), 1-hydroxybenzotriazole monohydrate (46.7 mg), N,N-diisopropylethylamine (0.173 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53.7 mg) were added, and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by amination silica gel column chromatography (methanol:ethyl acetate = 1:9), and the resulting solid was washed with diisopropyl ether to obtain N-[3-cyclopropyl-1-[5-[(dimethylamino)methyl]-1-methylbenzimidazol-2-yl]propyl]-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (81.5 mg). 1 H-NMR (DMSO-D6, 400MHz) δ: -0.01-0.10 (2H, m), 0.43 (2H, dd, J = 8.5, 1.8 Hz), 0.72-0.83 (1H, m), 1.03 (3H, s), 1.04 (3H, s), 1.24-1.39 (2H, m), 2.03-2.15 (2H, m), 2.16 (6H, s), 2.24 (2H, s), 2.48 (3H, s), 2.64 (2H, s), 3.49 (2H, s), 3.83 (3H, s), 5.43-5.51 (1H, m), 7.21 (1H, dd, J = 8.5, 1.8 Hz), 7.46-7.51 (2H, m), 8.07 (1H, d, J = 8.5 Hz), 11.67 (1H, brs). HRMS (ESI + ):490.31747 [M+H] +

[0907] <Example 33>

[0908] [ka]

[0909] Under an argon atmosphere, trifluoroacetic acid (0.487 mL) was added to a dichloromethane solution (0.487 mL) of tert-butyl N-[3-cyclopropyl-1-[5-(hydroxymethyl)-1-methylbenzimidazol-2-yl]propyl]carbamate (70.0 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure. To a solution (0.974 mL) of the resulting crude product in N,N-dimethylformamide, 3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxylic acid (43.1 mg), 1-hydroxybenzotriazole monohydrate (35.8 mg), N,N-diisopropylethylamine (0.132 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (41.0 mg) were added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. After solvent removal, the residue was purified by silica gel column chromatography (ethyl acetate), and the resulting solid was washed with diisopropyl ether to obtain N-[3-cyclopropyl-1-[5-(hydroxymethyl)-1-methylbenzimidazol-2-yl]propyl]-3,6,6-trimethyl-4-oxo-5,7-dihydro-1H-indole-2-carboxamide (40.8 mg). 11H-NMR (DMSO-D6, 400 MHz) δ: -0.01 - 0.09 (2H, m), 0.43 (2H, dd, J = 7.9, 2.4 Hz), 0.73 - 0.81 (1H, m), 1.04 (6H, s), 1.27 - 1.35 (2H, m), 2.08 - 2.22 (2H, m), 2.24 (2H, s), 2.47 (3H, s), 2.65 (2H, s), 3.84 (3H, s), 4.61 (2H, d, J = 5.4 Hz), 5.16 (1H, t, J = 5.4 Hz), 5.48 (1H, td, J = 8.5, 6.1 Hz), 7.24 (1H, d, J = 8.5 Hz), 7.49 (1H, d, J = 8.5 Hz), 7.56 (1H, s), 8.06 (1H, d, J = 8.5 Hz), 11.61 (1H, s). HRMS (ESI + ): 463.27046 [M+H] +

[0910] <Reference Example 91>

[0911]

Chemical formula

[0912] (S)-N-(1-(6-(benzyloxy)-1H-benzo[d]imidazole-2-yl)pentyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (100 mg) in 1.3 mL of dichloromethane (441) (μL) 4-dimethylaminopyridine (25 mg) was added under ice cooling and stirred for 1 hour. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate-heptane) to obtain (S)-6-(benzyloxy)-2-(1-(1-(tert-butoxycarbonyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide)pentyl)-1H-benzo[d]imidazole-1-carbonate tert-butyl (141 mg). (S)-6-(benzyloxy)-2-(1-(1-(tert-butoxycarbonyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide)pentyl)-1H-benzo[d]imidazole-1-carbonate. A mixture of tert-butyl (147 mg), 50% aqueous 10% palladium carbon (44.7 mg), and methanol (5 mL) was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered by Celite, concentrated under reduced pressure, and azeotropically heated with acetone to obtain (S)-2-(1-(1-(tert-butoxycarbonyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide)pentyl)-6-hydroxy-1H-benzo[d]imidazole-1-carbonate tert-butyl (127 mg). MS (ESI + ): 623.19 [M+H] +

[0913] <Example 34-1>

[0914] [ka]

[0915] (S)-2-(1-(1-(tert-butoxycarbonyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide)pentyl)-6-hydroxy-1H-benzo[d]imidazole-1-carbonate tert-butyl (125 mg) in toluene (1 mL solution), triphenylphosphine (131 mg), 3-(dimethylamino)propan-1-ol (51.6 mg), azodicarboxylate diisopropyl (97 mg) (μL) was added under ice-salt cooling, then returned to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane-methanol) to obtain (S)-2-(1-(1-(tert-butoxycarbonyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide)pentyl)-6-(3-(dimethylamino)propyloxy)-1H-benzo[d]imidazole-1-carbonate tert-butyl (81.6 mg). (S)-2-(1-(1-(tert-butoxycarbonyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide)pentyl)-6-(3-(dimethylamino)propyloxy)-1H-benzo[d]imidazole-1-carbonate tert-butyl (81.6 mg) was added to dichloromethane (3.7 mL) and trifluoroacetic acid (1.8 mL) and stirred overnight at room temperature. The mixture was concentrated under reduced pressure and azeotropically analyzed with dichloromethane. The residue was purified by silica gel column chromatography (dichloromethane-methanol) to obtain (S)-N-(1-(6-(3-(dimethylamino)propyloxy)-1H-benzo[d]imidazole-2-yl)pentyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (57.2 mg). 1H-NMR (400 MHz, DMSO-D6) δ: 0.87 (3H, t, J = 6.6 Hz), 1.02 (6H, s), 1.26-1.38 (4H, m), 1.78-1.96 (3H, m), 1.98-2.13 (1H, m), 2.16 (6H, s), 2.23 (2H, s), 2.38 (2H, t, J = 7.1 Hz), 2.49 (3H, s), 2.65 (2H, s), 3.99 (2H, t, J = 6.4 Hz), 5.22 (1H, dd, J = 13.7, 7.8 Hz), 6.75 (1H, dd, J = 8.7, 2.3 Hz), 6.93 (0.6H, d, J = 2.3 Hz), 7.07 (0.4H, d, J = 2.3 Hz), 7.30 (0.4H, d, J = 8.7 Hz), 7.42 (0.6H, d, J = 8.7 Hz), 7.86 (1H, d, J = 8.2 Hz), 11.64 (1H, s), 12.10 (0.6H, brs), 12.15 (0.4H, brs). MS (ESI + ): 508.15 [M+H] +

[0916] Examples 34-2 to 34-4 were obtained using the corresponding starting materials and reagents by the same method as in Example 34-1, the method described in steps 42-3 to 42-4, or a similar method.

[0917] [Table 156]

[0918] [Table 157]

[0919] <Example 35-1>

[0920] [ka]

[0921] (S)-2-(1-(1-(tert-butoxycarbonyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide)pentyl)-6-hydroxy-1H-benzo[d]imidazole-1-carbonate tert-butyl (249 mg) was mixed with triphenylphosphine (262 mg), 4-hydroxypiperidine-1-carboxylate benzyl (235 mg), and azodicarboxylate diisopropyl (194 μL) under ice-salt cooling, and then the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane-methanol) to obtain (S)-6-((1-((benzyloxy)carbonyl)piperidine-4-yl)oxy)-2-(1-(1-(tert-butoxycarbonyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide)pentyl)-1H-benzo[d]imidazole-1-carbonate tert-butyl (489 mg). (S)-6-((1-((benzyloxy)carbonyl)piperidine-4-yl)oxy)-2-(1-(1-(tert-butoxycarbonyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide)pentyl)-1H-benzo[d]imidazole-1-carbonate. A solution of tert-butyl (489 mg) in dichloromethane (38 μL) was mixed with trifluoroacetic acid (45 μL) and stirred overnight at room temperature. The mixture was concentrated under reduced pressure and azeotropically analyzed with dichloromethane. The residue was purified by silica gel column chromatography (dichloromethane-methanol) to obtain (S)-3,6,6-trimethyl-4-oxo-N-(1-(6-piperidine-4-yloxy)-1H-benzo[d]imidazole-2-yl)pentyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (127 mg). 1H-NMR (399 MHz, DMSO-D6) δ: 0.87 (3H, t, J = 6.9 Hz), 1.02 (6H, s), 1.22-1.40 (4H, m), 1.45-1.65 (2H, m), 1.80-2.10 (4H, m), 2.22 (2H, s), 2.49 (3H, s), 2.55-2.82 (2H, m), 2.65 (2H, s), 2.95-3.09 (2H, m), 3.35 (1H, brs), 4.21-4.47 (1H, m), 5.21 (1H, dd, J = 15.3, 7.1 Hz), 6.79 (1H, d, J = 6.9 Hz), 6.97 (0.6H, brs), 7.14 (0.4H, brs), 7.32 (0.4H, brs), 7.42 (0.6H, brs), 7.86 (1H, d, J = 7.8 Hz), 11.63 (1H, s), 12.10 (0.6H, brs), 12.16 (0.4H, brs). MS (ESI + ): 506.22 [M+H] +

[0922] Using the corresponding starting materials and reagents, Example 35-2 was obtained by the same method as in Example 35-1, the method described in steps 43-1 to 43-3, or a similar method.

[0923] [Table 158]

[0924] <Example 36>

[0925] [ka]

[0926] (S)-2-(1-(1-(tert-butoxycarbonyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide)pentyl)-6-hydroxy-1H-benzo[d]imidazole-1-carbonate tert-butyl (249 mg) was mixed with toluene (2.13 mL) and triphenylphosphine (262 mg), 2-((t-butyldimethylsilyl)oxy)ethanol (176 mg), and diisopropyl azodicarboxylate (194 μL) were added under ice-salt cooling, and the mixture was then returned to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane-methanol) to obtain (S)-2-(1-(1-(tert-butoxycarbonyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide)pentyl)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1H-benzo[d]imidazole-1-carbonate tert-butyl (260 mg). (S)-2-(1-(1-(tert-butoxycarbonyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide)pentyl)-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1H-benzo[d]imidazole-1-carbonate. A solution of tert-butyl (260 mg) in dichloromethane (2.14 mL) was mixed with trifluoroacetic acid (12.8 mL) and stirred overnight at room temperature. The mixture was concentrated under reduced pressure and azeotropically stirred twice with dichloromethane. The residue was purified by silica gel column chromatography (dichloromethane-methanol-ammonia) to obtain (S)-N-(1-(6-(2-hydroxyethoxy)-1H-benzo[d]imidazole-2-yl)pentyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (49.5 mg). 1H-NMR (399 MHz, DMSO-D6) δ: 0.87 (3H, t, J = 6.9 Hz), 1.03 (6H, s), 1.25 - 1.41 (4H, m), 1.85 - 2.14 (2H, m), 2.23 (2H, s), 2.49 (3H, s), 2.65 (2H, s), 3.34 (1H, brs), 3.73 (2H, t, J = 5.0 Hz), 3.99 (2H, t, J = 5.0 Hz), 4.87 (1H, brs), 5.23 (1H, dd, J = 14.2, 8.2 Hz), 6.84 (1H, dd, J = 8.7, 1.8 Hz), 7.04 (1H, d, J = 1.8 Hz), 7.43 (1H, d, J = 8.7 Hz), 7.90 (1H, d, J = 7.8 Hz), 11.65 (1H, s). MS (ESI + ): 467.18 [M+H] +

[0927] <Reference Example 92>

[0928]

Chemical formula

[0929] (S)-2-(1-(1-(tert-butoxycarbonyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide)pentyl)-6-hydroxy-1H-benzo[d]imidazole-1-carbonate tert-butyl (31.1 mg) was dissolved in toluene (230 μL), to which triphenylphosphine (26.2 mg), 2-bromoethanol (9.4 mg), and diisopropyl azodicarboxylate (20.2 μL) were added under ice-salt cooling, and the mixture was then returned to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane-methanol) to obtain (S)-6-(2-bromoethoxy)-2-(1-(1-(tert-butoxycarbonyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide)pentyl)-1H-benzo[d]imidazole-1-carbonate tert-butyl (48.4 mg). MS (ESI + ): 729.06 [M+H] +

[0930] <Reference example 93>

[0931] [ka]

[0932] (S)-6-(2-bromoethoxy)-2-(1-(1-(tert-butoxycarbonyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide)pentyl)-1H-benzo[d]imidazole-1-carbonate tert-butyl (48.4 mg) was added to a solution of dichloromethane (563 μL) under ice cooling with trifluoroacetic acid (51.1 μL) and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and azeotropically dissolved with dichloromethane. Ethyl acetate and saturated sodium bicarbonate were added, and the organic layer was separated. The aqueous layer was re-extracted twice, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane-methanol) to obtain (S)-N-(1-(6-(2-bromoethoxy)-1H-benzo[d]imidazole-2-yl)pentyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (37.5 mg). MS (ESI + ): 529.00 [M+H] +

[0933] <Example 37-1>

[0934] [ka]

[0935] (S)-N-(1-(6-(2-bromoethoxy)-1H-benzo[d]imidazole-2-yl)pentyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (53 mg) was dissolved in acetonitrile (2 mL) and piperidine (25.5 mg) was added, and the mixture was stirred overnight at 50°C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane-methanol) to obtain (S)-3,6,6-trimethyl-4-oxo-N-(1-(6-(2-(piperidine-1-yl)ethoxy)-1H-benzo[d]imidazole-2-yl)pentyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamide (17.5 mg). 1 H-NMR (500 MHz, DMSO-D6) δ: 0.87 (3H, s), 1.03 (6H, s), 1.12-1.43 (6H, m), 1.45- 1.58 (4H, m), 1.84-1.97 (1H, m), 1.97-2.15 (1H, m), 2.23 (2H, s), 2.45 (3H, s), 2.51 (4H, m), 2.66 (4H, m), 4.06 (2H, m), 5.23 (1H, m), 6.77 (1H, m), 6.95 (0.6H, m), 7.10 (0.4H, m), 7.32 (0.4H, m), 7.43 (0.6H, m), 7.87 (1H, m), 11.65 (1H, s), 12.12 (1H, s). MS (ESI + ): 534.13 [M+H] +

[0936] Examples 37-2 to 37-4 were obtained using the corresponding starting materials and reagents by the same method as in Example 37-1, the method described in step 45-3, or a similar method.

[0937] [Table 159]

[0938] <Reference example 94>

[0939] [ka]

[0940] Synthesis of benzyl 4-hydroxyindoline-1-carboxylate A solution of 4-hydroxyindole (5.32 g) in acetic acid (100 mL) was cooled on ice, and sodium borohydride cyanohydride (7.54 g) was added in portions over approximately 30 minutes at 15°C to 20°C. After removing the ice bath, the mixture was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The mixture was azeotropically mixed with methanol, ethanol, and toluene, and the residue was diluted with saturated sodium bicarbonate solution (150 mL) and tetrahydrofuran (30 mL). A solution of benzyl chloroformate (5.64 g) in ethyl acetate (5 mL) was added on ice, and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated and washed with saturated brine. After drying over sodium sulfate, the solid precipitated from the concentrated residue was washed with ethyl acetate / hexane (1 / 9) to obtain 7.16 g (66.5%) of benzyl 4-hydroxyindoline-1-carboxylate. 1 H-NMR (CDCl3, 400 MHz) δ: 3.05 (2H, t, J = 8.6 Hz), 4.09 (2H, t, J = 8.6 Hz), 5.09 (1H, s), 5.26 (2H, s), 6.44 (1H, d, J = 8.4 Hz), 7.05 (1H, br. s), 7.33-7.55 (6H, m). MS (ESI + ): 270[M+H] + ; (ESI - ): 268[MH] -

[0941] <Reference example 95>

[0942] [ka]

[0943] Synthesis of benzyl 4-(2-(dimethylamino)ethoxy)indoline-1-carboxylate A solution of benzyl 4-hydroxyindoline-1-carboxylate (269 mg) in tetrahydrofuran (5 mL) was cooled on ice, and 2-(dimethylamino)ethanol (267 mg), triphenylphosphine (918 mg), and azodicarboxylate bis(2-methoxyethyl) (703 mg) were added sequentially. After stirring overnight at room temperature, the concentrated residue of the reaction mixture was purified by aminosilica gel column chromatography (10-50% ethyl acetate-hexane) to obtain 252 mg (74.0%) of benzyl 4-(2-(dimethylamino)ethoxy)indoline-1-carboxylate. 1 H-NMR (CDCl3, 400 MHz) δ: 2.33 (6H, s), 2.72 (2H, t, J = 6.0 Hz), 3.04 (2H, t, J = 8.0 Hz), 4.05 (2H, t, J = 8.0 Hz), 4.10 (2H, t, J = 6.0 Hz), 5.25 (2H, s), 6.51 (1H, d, J = 8.4 Hz), 7.14 (1H, br. s), 7.32-7.55 (6H, m). MS (ESI + ): 341.3[M+H] +

[0944] <Reference example 96-1>

[0945] [ka]

[0946] Synthesis of 2-(indoline-4-yloxy)-N,N-dimethylethane-1-amine A methanol (5 mL) solution of benzyl 4-(2-(dimethylamino)ethoxy)indoline-1-carboxylate (240 mg) was cooled on ice, 20% palladium carbon (40% wet, 100 mg) was added, and the mixture was stirred for 30 minutes under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and 2-(indoline-4-yloxy)-N,N-dimethylethane-1-amine was obtained as the concentrated residue of the filtrate. This residue was used directly in the next condensation reaction step, the synthesis of the compound in Example 1-122. MS (ESI + ): 207[M+H] +

[0947] Using the corresponding starting materials and reagents, Reference Examples 96-2 to 96-9 were obtained by the same method as or similar to that used for Reference Examples 94 to 96-1.

[0948] [Table 160]

[0949] <Reference example 97>

[0950] [ka]

[0951] Synthesis of benzyl(S)-(4-cyclopropyl-1-(4-(2-(dimethylamino)ethoxy)indoline-1-yl)-1-oxobutan-2-yl)carbamate A solution of benzyl 4-hydroxyindoline-1-carboxylate (408 mg) in methanol (7.0 mL) was added to a suspension of 20% palladium carbon (40% wet, 106 mg) in methanol (3.0 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the residue. The resulting residue was diluted in dimethylformamide (8.0 mL) under a nitrogen stream, and (S)-2-(((benzyloxy)carbonyl)amino)-4-cyclopropylbutyrate (277 mg), 1-hydroxybenzotriazole monohydrate (230 mg), and diisopropylethylamine (261 μL) were added and the mixture was cooled on ice. To this mixed solution, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (288 mg) was added and the mixture was stirred at room temperature for 2.5 hours. Water (30 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (7 mL × 5). The organic layer was washed with saturated brine (20 mL) and dried over sodium sulfate. The concentrated residue was purified twice by silica gel column chromatography (0-8% methanol-dichloromethane) and amino silica gel chromatography (10-50% ethyl acetate-hexane) to obtain 268 mg (58%) of benzyl(S)-(4-cyclopropyl-1-(4-(2-(dimethylamino)ethoxy)indolin-1-yl)-1-oxobutan-2-yl)carbamate. 1 H-NMR (DMSO-d6, 400 MHz) δ: -0.07-0.09 (2H, m), 0.34-0.46 (2H, m), 0.60-0.73 (1H, m), 1.16-1.43 (2H, m), 1.66-1.80 (1H, m), 1.82-1.94 (1H, m), 2.33 (6H, s), 2.72 (2H, t, J= 5.8 Hz), 3.09-3.18 (2H, m), 4.10 (2H, t, J= 5.8 Hz), 4.05-4.14 (1H, m), 4.26-4.33 (1H, m), 4.59-4.66 (1H, m), 5.06 (1H, d, J= 12.3 Hz), 5.10 (1H, d, J= 12.3 Hz), 5.61 (1H, J= 9.0 Hz, d), 6.59 (1H, d, J= 8.2 Hz), 7.14 (1H, t, J = 8.2 Hz), 7.10-7.18 (5H, s), 7.81 (1H, d, J= 8.2 Hz). MS (ESI + ): 466[M+H] +

[0952] <Reference example 98>

[0953] [ka]

[0954] Synthesis of (S)-2-amino-4-cyclopropyl-1-(4-(2-dimethylamino)ethoxy)indoline-1-yl)butan-1-one A solution of benzyl(S)-(4-cyclopropyl-1-(4-(2-(dimethylamino)ethoxy)indolin-1-yl)-1-oxobutan-2-yl)carbamate (178 mg) in methanol (5.0 mL) was added to a methanol (3.0 mL) suspension of 20% palladium carbon (40% wet, 33.9 mg) and stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite to obtain (S)-2-amino-4-cyclopropyl-1-(4-(2-(dimethylamino)ethoxy)indolin-1-yl)butan-1-one. The vacuum-concentrated residue of the filtrate was used directly in the synthesis of the compound in Example 6-107 in the next step. MS (ESI + ): 332[M+H] +

[0955] <Test Example 1> G9a inhibitory activity test The G9a inhibitory activity of compounds was evaluated by measuring the enzyme activity of G9a using Amplified Luminescence Proximity Homogeneous Assay (ALPHA). First, 7.5 μL of recombinant human G9a protein (BPS Bioscience, #51001) diluted to 0.05-0.1 nM in Tris buffer (50 mM Tris-HCl [pH 9.0], 50 mM NaCl, 0.01% Tween-20, 1 mM DTT) and 0.5 μL of the test compound were added to a 384-well microplate (AlphaPlate-384 Shallow Well, PerkinElmer, #6008359), mixed by vortexing, and then allowed to stand at room temperature for 10 minutes. Biotinylated histone H3 peptide (1-21) (AnaSpec, #61702) 500 nM and SAM (SIGMA, #A7007) 150 μM were pre-mixed in a 1:1 ratio, 2 μL was added to each well, mixed by vortexing, and then allowed to stand at room temperature for 1 hour. AlphaLISA anti-H3K9me2 acceptor beads (PerkinElmer, #AL117C) and AlphaScreen streptavidin donor beads (PerkinElmer, #6760002B) were diluted in epigenetic buffer (PerkinElmer, AlphaLISA Epigenetics Buffer Kit #AL008C) to a final concentration of 10 μg / ml, added under light-shielding conditions, and then allowed to stand at room temperature under light-shielding conditions for 1 hour. Subsequently, measurements were taken using an EnSpire Alpha plate reader (PerkinElmer, Waltham, MA, USA). The G9a inhibitory activity of the test compound is determined by calculating the percentage of inhibition of the compound compared to the control without the compound (0%) and the control without the enzyme (100%), and then determining the compound concentration (IC) required to suppress G9a enzyme activity by 50%. 50 The value was calculated. The results are shown below. Note that in the table, IC 50 <50nM:+++, 50nM≦IC 50 <200nM:++, 200nM≦IC 50 It was written as :+.

[0956] Table 161

[0957] Table 162

[0958] Table 163

[0959] Table 164

[0960] Table 165

[0961] Table 166

[0962] Table 167

[0963] Table 168

[0964] Table 169

[0965] Table 170

[0966] <Test Example 2> Histone H3K9 dimethylation inhibitory activity test The inhibitory activity of a compound against G9a was evaluated by adding the compound to the human lung cancer cell line NCI-H460 and detecting changes in intracellular histone H3K9 dimethylation levels using Western blotting. NCI-H460 cells were cultured in DMEM medium (Fujifilm Wako Pure Chemical Industries, 044-29765) containing 10% fetal bovine serum and 4 mM glutamine. After washing the cultured cells with PBS, they were detached with trypsin / EDTA and measured at 2.5 × 10⁶. 4The cell saturation was prepared to a concentration of cells / mL. 500 μL / well of the cell saturation was seeded into 24-well microplates (Thermo Fisher Scientific, 142475) and incubated overnight at 37°C under 5% CO2 conditions. The following day, 0.5 μL / well of the test compound (DMSO solution) was added and the mixture was incubated at 37°C under 5% CO2 conditions for 72 hours. 0.5 μL / well of DMSO was added to the control wells (final DMSO concentration 0.1%). After removing the culture medium and washing the cells with PBS, 50 μL / well of 2× SDS-PAGE sample buffer (100 mM Tris-HCl (pH 6.8), 4% sodium lauryl sulfate, 2% 2-mercaptoethanol, 20% glycerol, 0.005% bromophenol blue) was added to each well to prepare the samples. The collected samples were heated at 95-100°C for 10 minutes, and proteins were separated by polyacrylamide gel electrophoresis (SDS-PAGE). Next, the isolated proteins were transferred to a polyvinylidene fluoride (PVDF) membrane by semi-dry blotting. The PVDF membrane was immersed in 3% skim milk (dissolved in PBS (PBST) containing 0.05% Tween 20) and blocked at room temperature for 30-60 minutes. Then, it was immersed in anti-dimethylated histone H3K9 antibody (Abcam, ab1220) diluted 1000-fold with 3% skim milk and reacted overnight at 4°C. The following day, the PVDF membrane was washed three times with PBST and then immersed in HRP (horseradish peroxidase)-labeled anti-mouse IgG antibody diluted 10000-fold with skim milk and reacted at room temperature for 1 hour. After washing the PVDF film three times with PBST, it was immersed in the chemiluminescent substrate solution Immobilon Western Chemiluminescent HRP substrate (Millipore, WBKLS0500) and left to stand at room temperature for 5 minutes, and then imaged using a lumino image analyzer (GE Healthcare, ImageQuant LAS4000). Subsequently, antibodies were stripped from the PVDF membrane using the EzReprobe reproubling reagent (ATTO, WSE-7240), and trimethylated histone H3K9 and histone H3 were detected using the same procedure as above. Active Motif anti-trimethylhistone H3K9 antibody (39161, 1000-fold dilution) and Abcam anti-histone H3 antibody (ab1791, 2000-fold dilution) were used for detection. From the captured images, the bands for each protein were quantified using the image processing software ImageJ (NIH). The ratio of dimethylated histone H3K9 and trimethylated histone H3K9 to histone H3 protein was calculated with the value of the sample without compound added set to 100%. Using the data analysis software Origin (LightStone), the concentration of the compound at which the ratio of dimethylated histone H3K9 becomes 50% was determined as the 50% inhibitory concentration (IC2). 50 The value was calculated. The results are shown below. Note that in the table, IC 50 <50nM:+++, 50nM≦IC 50 <500nM:++, 500nM≦IC 50 It was written as :+.

[0967] [Table 171]

[0968] <Test Example 3> Colony formation inhibition test The colony formation inhibitory activity of the compound against the human lung cancer cell line NCI-H460 was evaluated. NCI-H460 cells were cultured in DMEM medium (Fujifilm Wako Pure Chemical Industries, 044-29765) containing 10% fetal bovine serum and 4 mM glutamine. After washing the cultured cells with PBS, they were detached with trypsin / EDTA and 2 × 10⁶ cells were collected. 3Cell saturation was prepared to a concentration of cells / mL. Cell saturation was seeded at 1 mL / well in 12-well microplates (CORNING, 3513), and 1 μL / well of the test compound (DMSO solution) was added. The cells were cultured at 37°C under 5% CO2 conditions for 12 days. The final DMSO concentration was set to 0.1%, and 1 μL / well of DMSO was added to the control wells. Every 1 or 2 days, the culture medium was discarded, 1 mL / well of fresh medium was added, and either the test compound or DMSO was added at 1 μL / well. The percentage of colonies formed at the bottom of each well was measured using a high-speed cell imaging system (Tommy Digital Biology, Celigo). The ratio of colonies in each compound-added group was determined by setting the percentage of colonies formed in wells without the test compound solution to 1. The compound concentration (GI) required to suppress the colony formation rate to 50% of the control was then calculated. 50 The values ​​were calculated using the data analysis software Origin (LightStone). The results are shown below. Note that in the table, GI 50 <500nM:+++, 500nM≦GI 50 <1000nM:++, 1000nM≦GI 50 It was written as :+.

[0969] [Table 172]

[0970] <Test Example 4> Globin gene expression test The effect of the obtained compounds on the expression level of the fetal globin gene in the human erythroid cell line HUDEP-2 was evaluated by quantitative PCR. HUDEP-2 cells were cultured in Stemline II hematopoietic stem cell proliferation medium (Sigma) containing 1 μM dexamethasone (Sigma), 1 μg / ml doxycycline (Sigma), 50 ng / ml recombinant human SCF (R&D SYSTEMS), and 3 IU / mL epoetin alfa (Toho Pharmaceutical). Cultured cells were cultured in cell culture medium at a rate of 1 × 10⁶ 5Cell saturation was prepared to a concentration of cells / mL. Next, 2 mL / well of the cell saturation was seeded into 6-well plates (VIOLAMO), and 2 μL / well of the test compound (DMSO solution) (final DMSO concentration 0.1%) was added. The cells were cultured at 37°C under 5% CO2 conditions for 4 days. 2 μL / well of DMSO solution was added as a control. The cultured cells were collected by centrifugation at 7500 rpm, 4°C, and 5 minutes, and RNA was extracted using the Tissue Total RNA Mini Kit (Chiyoda Science). Subsequently, cDNA was synthesized using ReverTra Ace qPCR RT Master Mix (TOYOBO) by reverse transcription at 37°C for 15 minutes, followed by 50°C for 5 minutes. The diluted cDNA was used as a template and mixed with THUNDERBIRD SYBR qPCR (TOYOBO). Fetal β-globin gene, adult β-globin gene, and GAPDH gene (as a reference) were measured using the CFX Connect Real-Time PCR Detection System (BIORAD). The primers used for the genes were as follows: Fetal β-globin: Forward: 5'-TGGATGATCTCAAGGGCAC-3'; Reverse: 5'-TCAGTGGTATCTGGAGGACA-3'; Adult β-globin: Forward: 5'-CAGTGCAGGCTGCCTATC-3'; Reverse: 5'-ATACTTGTGGGCCAGGGCAT-3'; GAPDH: Forward: 5'-GCACCGTCAAGGCTGAGAAC-3'; Reverse: 5'-TGGTGAAGACGCCAGTGGA-3'. Gene expression analysis was performed using the ΔΔCt method, with a control (containing 0.1% DMSO solution) set as 1. [Industrial applicability]

[0971] The compounds according to the present invention are useful as therapeutic agents or preventive agents for proliferative diseases such as cancer, β-globin disorders, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy, autism, etc., due to their G9a enzyme inhibitory activity.

Claims

1. General formula (I): 【Chemistry 1】 [In formula (I), R １ is an oxygen atom, a nitrogen atom, or a hydrogen atom; R １ If the atoms are oxygen and nitrogen, １ The bond between the carbon atom and the carbon atom is a double bond; R １ If R is a hydrogen atom, １ The bond between the carbon atom and the carbon atom is a single bond; R ２ The following are A1), A2), or A3), where * indicates the bond position with -CO- in formula (I); 【Chemistry 2】 E is either an oxygen atom or a hydrogen atom; If E is an oxygen atom, the bond between E and the carbon atom is a double bond; If E is a hydrogen atom, the bond between E and the carbon atom is a single bond; R ２ａ 、 R ２ｂ and R ２ｃ are each independently a hydrogen atom, C １ -C ６ alkyl group, C ２ -C ６ alkenyl group, halo C １ -C ６ alkyl group, C １ -C ６ alkoxy group, C １ -C ６ alkylamino group, C １ -C ６ acyl group, C １ -C ６ alkoxycarbonyl group, C ３ -C １０ cycloalkyl group or hydroxy C １ -C ６ alkyl group (the C １ -C ６ alkyl group, C ２ -C ６ alkenyl group, halo C １ -C ６ alkyl group, C １ -C ６ alkoxy group, C １ -C ６ alkylamino group, C １ -C ６ acyl group, C １ -C ６ alkoxycarbonyl group, C ３ -C １０ cycloalkyl group and hydroxy C １ -C ６ alkyl group is C １ -C ６ alkyl group, C １ -C ６ alkoxy group, C １ -C ６ alkylamino group and hydroxy C １ -C ６ alkyl group may be substituted with one or more substituents selected from the group consisting of, and the substituents may be bonded to each other to form a ring); R ２ｂ and R ２ｃ These may also be joined together to form a ring; R ２ｄ and R ２ｅ Each is independently C １ ~C ６ Alkyl or hydroxy C １ ~C ６ It is an alkyl group; R ２ｄ and R ２ｅ These may be joined together to form a ring; R ６ and R ７ Each is independently a hydrogen atom, C １ ~C ６ Alkyl alkyl group, aromatic hydrocarbon ring group, C ３ ~C １０ The group is a cycloalkyl group, a 5-10 member heteroaryl group, or a 3-10 member heterocycloalkyl group; R ６ and R ７ These may also be joined together to form a ring; n is either 0 or 1; RingA is R ８ and R ９ Aromatic hydrocarbon ring group, C may be substituted with ３ ~C １０ The group is a cycloalkyl group, a 5-10 member heteroaryl group, or a 3-10 member heterocycloalkyl group; R ８ This includes hydrogen atoms, halogen atoms, cyano groups, amino groups, and aminosulfonyl groups (-SO ２ NH ２ ), C １ ~C ６ Alkyl, halo C １ ~C ６ Alkyl or C １ ~C ６ It is an alkoxy group; R ９ is -Y-Z; Y is a bond, -O-, -NR １０ - or - (CR １１ R １２ ) ｓ - and; R １０ 、 R １１ and R １２ are each independently a hydrogen atom or a C １ -C ６ alkyl group; s is an integer between 0 and 6; Z is a hydrogen atom, C １ -C ６ alkyl group, halo C １ -C ６ alkyl group, C １ -C ６ alkoxy group, C １ -C ６ alkylamino group, aromatic hydrocarbon ring group, C ３ -C １０ cycloalkyl group, 5- to 10-membered heteroaryl group or 3- to 10-membered heterocycloalkyl group (the C １ -C ６ alkyl group, aromatic hydrocarbon ring group, C ３ -C １０ cycloalkyl group, 5- to 10-membered heteroaryl group and 3- to 10-membered heterocycloalkyl group are C １ -C ６ alkyl group, halo C １ -C ６ alkyl group, C １ -C ６ alkoxy group, C １ -C ６ alkylamino group, C １ -C ６ acyl group and C １ -C ６ alkoxycarbonyl group and may be substituted with one or more substituents selected from the group consisting of).; R ３ ha*-(CH ２ ) ｘ -T-(CR １３ R １４ ) ｙ -U, where * indicates the bond position with -CH- in formula (I); T represents a bond, -NH-, -O-, or -S(O). ｐ - and; U is a hydrogen atom, C ３ ~C １０ It is a cycloalkyl group or an aromatic hydrocarbon ring group (the aromatic hydrocarbon ring group may be substituted with one or more halogen atoms); R １３ and R １４ Each is independently a hydrogen atom or C １ ~C ６ It is an alkyl group; x and y are independent integers between 0 and 4; p is an integer between 0 and 2; R ４ is a hydrogen atom or C １ ~C ６ It is an alkyl group; R ５ B1) or C below １ ~C ６ It is an alkyl group, and * indicates the bond position with -N- in formula (I); 【Transformation 3】 R １５ and R １６ Each is independently a hydrogen atom, C １ ~C ６ Alkyl or hydroxy C １ ~C ６ It is an alkyl group; R １５ and R １６ These may also be joined together to form a ring; R １５ and R １６ It may also bond with RingB to form a ring; m is either 0 or 1; RingB is R １７ , R １８ and R １９ Aromatic hydrocarbon ring group, C may be substituted with ３ ~C １０ It is a cycloalkyl group, a 5-10 membered heteroaryl group, or a 3-10 membered heterocycloalkyl group; R １７ and R １８ Each of these is independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a cyano group, and a carbamoyl group (-CONH ２ ), C １ ~C ６ Alkyl, halo C １ ~C ６ Alkyl alkyl groups, hydroxy C １ ~C ６ alkyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ Alkylamino group, C １ ~C ６ Alkyl sulfanyl group, halo C １ ~C ６ Alkyl sulfanyl group, C １ ~C ６ Acyl group, C １ ~C ６ Alkoxycarbonyl group, C １ ~C ６ Alkylaminocarbonyl group or C １ ~C ６ It is an acylamino group; R １９ Ha- (CR ２０ R ２１ ) ｒ -V-(CR ２２ R ２３ ) ｑ -Q is; V is bond, -O-, -NR ２４ - or -S(O) ｔ - and; t is an integer between 0 and 2; R ２０ , R ２１ , R ２２ , R ２３ and R ２４ Each is independently a hydrogen atom or C １ ~C ６ It is an alkyl group; q and r are each independent integers between 0 and 6; Q is a hydrogen atom, amino group, hydroxyl group, C １ ~C ６ alkyl group, C １ ~C ６ Alkylamino group, C ３ ~C １０ Cycloalkyl groups, 5-10 membered heteroaryl groups, or 3-10 membered heterocycloalkyl groups (the C １ ~C ６ Alkylamino group, C ３ ~C １０ Cycloalkyl groups, 5-10 membered heteroaryl groups, and 3-10 membered heterocycloalkyl groups contain halogen atoms and C １ ~C ６ alkyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ Alkylamino group, C １ ~C ６ Alkoxycarbonyl group, C １ ~C ６ Alkylaminocarbonyl group and hydroxy C １ ~C ６ (It may be substituted with one or more substituents selected from the group consisting of alkyl groups); R １７ , R １８ and R １９ They may also be joined to each other to form a ring; R ４ and R ５ These may also be joined together to form a ring; R １ is a nitrogen atom, m is 0, and RingB is R １７ , R １８ and R １９ If it is a phenyl group that may be substituted with, １ The phenyl group may bond to the benzimidazole ring. A compound represented by , or a pharmacologically acceptable salt thereof.

2. In formula (I), R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is an oxygen atom.

3. In formula (I), R ２ The following is A1) or A2): 【Chemistry 4】 The compound according to claim 2, or a pharmaceutically acceptable salt thereof.

4. In formula (I), R ２ This is A2) below; 【Transformation 5】 R ２ａ is C １ ~C ６ alkyl group, C ３ ~C １０ Cycloalkyl groups or hydroxyC １ ~C ６ It is an alkyl group. The compound according to claim 3, or a pharmaceutically acceptable salt thereof.

5. In formula (I), R ２ This is A2b) below, 【Transformation 6】 The compound according to claim 4, or a pharmaceutically acceptable salt thereof.

6. In formula (I), R ２ The following is A2b): 【Transformation 7】 R ２ａ is C １ ~C ６ Alkyl or C ３ ~C １０ It is a cycloalkyl group; R ２ｄ , R ２ｅ Each is independently C １ ~C ６ It is an alkyl group; R ２ｄ and R ２ｅ These may be joined together to form a ring. The compound according to claim 5, or a pharmaceutically acceptable salt thereof.

7. In formula (I), R ３ ha*-(CH ２ ) ｘ -T-(CR １３ R １４ ) ｙ -U, where * indicates the bond position with -CH- in formula (I); T is a bond or -S(O) ｐ - and; U is a hydrogen atom, C ３ ~C １０ It is a cycloalkyl group or an aromatic hydrocarbon ring group (the aromatic hydrocarbon ring group may be substituted with one or more halogen atoms); R １３ and R １４ Each is independently a hydrogen atom or C １ ~C ６ It is an alkyl group; x and y are independent integers between 0 and 2; p is 0; (However, R ３ (Except when it is a hydrogen atom or a methyl group) R ５ B1) or C below １ ~C ６ It is an alkyl group, and * indicates the bond position with -N- in formula (I); 【Transformation 8】 RingB is R １７ , R １８ and R １９ Aromatic hydrocarbon ring group, C may be substituted with ３ ~C １０ It is a cycloalkyl group, a 5-10 membered heteroaryl group, or a 3-10 membered heterocycloalkyl group; R １７ and R １８ Each of these is independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a cyano group, and C １ ~C ６ Alkyl, halo C １ ~C ６ Alkyl alkyl groups, hydroxy C １ ~C ６ alkyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ Alkylamino group, C １ ~C ６ Alkyl sulfanyl group, C １ ~C ６ Alkoxycarbonyl group, C １ ~C ６ Alkylaminocarbonyl group or C １ ~C ６ It is an acylamino group, The compound according to claim 6, or a pharmaceutically acceptable salt thereof.

8. In formula (I), R ３ ha*-(CH ２ ) ｘ -T-(CR １３ R １４ ) ｙ The group is represented by -U, and * indicates the bond position with -CH- in formula (I); T is a bond; U is a hydrogen atom or C ３ ~C １０ It is a cycloalkyl group; R １３ and R １４ is a hydrogen atom; x and y are independent integers between 1 and 2; R ５ B1) or C below １ ~C ６ It is an alkyl group, and * indicates the bond position with -N- in formula (I); 【Chemistry 9】 RingB is R １７ , R １８ and R １９ Aromatic hydrocarbon ring group, C may be substituted with ３ ~C １０ It is a cycloalkyl group, a 5-10 membered heteroaryl group, or a 3-10 membered heterocycloalkyl group; R １７ and R １８ Each of these is independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a cyano group, and C １ ~C ６ Alkyl, halo C １ ~C ６ Alkyl alkyl groups, hydroxy C １ ~C ６ Alkyl or C １ ~C ６ It is an alkoxy group, The compound according to claim 7, or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising an additive, and the compound described in claim 1 or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising an additive, and the compound described in claim 6 or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising an additive, and a compound having the following structure or a pharmaceutically acceptable salt thereof. 【Chemistry 10】

12. Additives, and the following 【Chemistry 11】 A pharmaceutical composition according to claim 11, comprising:

13. A pharmaceutical composition comprising an additive, and a compound having the following structure or a pharmaceutically acceptable salt thereof. 【Chemistry 12】

14. Additives, and the following 【Chemistry 13】 The pharmaceutical composition according to claim 13, comprising:

15. A pharmaceutical composition according to any one of claims 9 to 14 for the treatment of cancer, β-globin disorders, fibrosis, pain, neurodegenerative diseases, Prader-Willi syndrome, malaria, viral infections, myopathy, or autism.

16. A pharmaceutical composition according to any one of claims 9 to 14 for treating β-globin disorders.

17. The pharmaceutical composition according to claim 16, wherein the β-globin disorder is sickle cell anemia.

18. A pharmaceutical composition according to any one of claims 9 to 14 for inhibiting the G9a enzyme.

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