JP2020045306A - Amide derivatives comprising heterocycloalkyl ring - Google Patents

Abstract

To provide compounds or pharmacologically acceptable salts thereof that have excellent EP300 and/or CREBBP histone acetyltransferase inhibitory activity.SOLUTION: The invention provides compounds represented by the formula (1) in the figure or pharmacologically acceptable salts thereof. (In the formula (1), ring Q, ring Q, ring Q, X and L are as defined in the specification.)SELECTED DRAWING: None

Description

  The present invention relates to a low molecular weight compound having excellent inhibitory activity on EP300 and / or CREBBP histone acetyltransferase, or a pharmaceutically acceptable salt thereof.

  The chromosome changes its higher-order structure by methylation modification of its constituent DNA or various modifications of histones (histones H2A, H2B, H3, H4) (acetylation, methylation, phosphorylation, ubiquitination, etc.). And dynamically controls gene replication and transcription (Non-Patent Document 1).

  Reversible acetylation of histones or non-histone proteins is a common post-translational modification in eukaryotes. Histone acetyltransferase is an enzyme that transfers an acetyl group to the lysine side chain of histone, and histone deacetylase is an enzyme that removes an acetyl group from a lysine residue. Histone acetyltransferases are roughly classified into four groups based on amino acid sequence homology, higher-order structure, and their functions, and they are classified into EP300 / CREBBP (E1A binding protein p300 / CREB Binding Protein), GCN5 / PCAF (general control nonrepressed-). Protein 5 / P300 / CBP-associated factor), MYST (MOZ, Ybf2 / Sas3, Sas2, and Tip60), and Rtt109 (Regulator of Tyl Transduction generation product 109). EP300 and its paralog, CREBBP, have 90% or more amino acid sequence homology, and include a HAT domain, a CH1 / CH2 / CH3 domain (cysteine-histidine rich domains), a KIX domain, and a bromo domain (Non-patented). Reference 2).

  EP300 and CREBPP were found as binding partners of E1A adenoviral protein and cAMP-regulated enhancer binding protein, respectively (Non-Patent Documents 3-5). Subsequently, it was found that EP300 / CREBBP has histone acetyltransferase activity (Non-patent Documents 6 and 7), and its substrate specificity was also examined. Lysine residues of histones (H2A, H2B, H3 and H4) were also examined. In addition, p53 (Non-patent document 8), MyoD (Non-patent document 9), STAT3 (Non-patent document 10), Androgen receptor (Non-patent document 11) and the like have also been reported to be acetylated. EP300 not only functions as a histone acetyltransferase, but also participates in the activation of transcription as a component of a transcription factor or by linking a transcription factor to another protein involved in transcription (Non-Patent Documents 12 and 13). EP300 / CREBBP is also involved in many biological reactions such as division, proliferation, and differentiation (Non-Patent Document 12).

  It has been reported that high expression, mutation or enhanced function of EP300 / CREBBP is associated with various cancers. Examples include prostate cancer (Non-Patent Documents 14 and 15), liver cancer (Non-Patent Documents 16 and 17), lung cancer (Non-Patent Documents 18, 19 and 20), breast cancer (Non-Patent Document 21), and large intestine. Cancer and stomach cancer (Non-patent document 22), blood cancer (Non-patent documents 23 and 24), pancreatic cancer (Non-patent document 25), bladder cancer (Non-patent document 26), gastrointestinal stromal tumor (Non-patent document 26) Reference 27), NUT midline carcinoma (Non-patent Document 28) or ovarian cancer (Non-patent Document 29).

  From the above, a drug that inhibits the histone acetyltransferase activity of EP300 / CREBBP is expected to be useful as an antitumor agent. However, it is difficult to search for a compound having a strong inhibitory activity and a more specific histone acetyltransferase inhibitory activity (Non-Patent Document 30). Recently, C646 was found as a specific EP300 inhibitor (Non-Patent Document 31), but development of a compound having a novel structure having stronger inhibitory activity and selectivity has been demanded.

Genes Dev. 2002, 16 (14): 1739-1742. Mol Genet Metab. 2016, 119 (1-2): 37-43. Virology. 1985, 147 (1): 142-153. Mol Cell Biol. 1986, 6 (5): 1579-1589. Nature. 1993, 365 (6449): 855-859. Cell. 1996, 87 (5): 953-959. Nature. 1996, 384 (6610): 641-643. Cell. 1997, 90 (4): 595-606. J Biol Chem. 2000, 275 (44): 34359-34364. Science. 2005, 307 (5707): 269-273. J Biol Chem. 2000, 275 (27), 20853-20860. J Cell Sci. 2001, 114 (Pt 13): 2363-2373. Epigenetics. 2011, 6 (8): 957-961. Adv Exp Med Biol. 2008; 617: 535-540. Prostate. 2008, 68 (10): 1097-1104. Cancer Lett. 2011, 310 (2): 140-147. J Trans Med. 2011, 9: 5. Int J Clin Exp Pathol. 2014, 7 (2): 760-767. Nat Genet. 2012, 44 (10): 1104-1110. Clin Cancer Res. 2005, 11 (2 Pt 1): 512-519. Genes Cancer. 2016, 7 (3-4): 98-109. Oncogene. 1996, 12 (7): 1565-1569. Proc Natl Acad Sci USA. 1997, 94 (16): 8732-8737. Blood. 2012, 120 (15) 3058-3068. Nat Genet. 2000, 24 (3): 300-303. Nat Genet. 2011, 43 (9): 875-878. Oncol Rep. 2016, 36 (5): 2763-2770. J Biol Chem. 2015, 290 (5): 2744-2758. Oncotarget. 2016, 7 (14): 17790-17804. Nat Chem Biol. 2008, 4 (10): 590-597. Chem Biol. 2010, 17 (5): 471-482.

  The present invention provides a novel low-molecular-weight compound that has an effect of inhibiting both the histone acetyltransferase activities of EP300 and CREBBP, and has an anticancer effect against EP300 and / or CREBBP-dependent cancer. Is what you do.

The present invention relates to the following [1] to [21].
[1] a compound represented by the following general formula (1) or a pharmacologically acceptable salt thereof;

[Where,
Ring Q ¹ is, have from 1 to 3 substituents independently selected substituents independently selected from the following group A 1 to 3 optionally having phenyl group or the following group A, A nitrogen atom, an oxygen atom, and a 5- or 6-membered aromatic heterocyclic group having 1 or 2 hetero atoms in a ring independently selected from the group consisting of a sulfur atom;
The ring Q ² may have one or two substituents independently selected from the following group B. In addition to the nitrogen atom shown in the general formula (1), a nitrogen atom, an oxygen atom, and a sulfur A 5- to 8-membered heterocycloalkyl ring which may have one heteroatom in the ring independently selected from the group consisting of atoms,
Ring Q ³ has a phenyl group which may have 1 to 3 substituents independently selected from the following group C, and has 1 to 3 substituents independently selected from the following group C A 5- or 6-membered aromatic heterocyclic group having 1 or 2 heteroatoms in the ring independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; An 8- to 10-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom which may have 1 to 3 substituents selected A bicyclic aromatic heterocyclic group of
L _{is, - (CH 2) m -} , or indicates one of the following formulas (2A) to (2C),

(Where
* It is attached to the ring ^{Q 2,}
** is bonded to ring Q ³ ,
m represents an integer of 1 to 3,
n represents an integer of 0 to 2,
p represents an integer of 0 to 2,
R ¹ represents a hydrogen atom or a C _1-6 alkyl group,
R ² represents a hydrogen atom or a methyl group. )
X is, ^-CR 3 ^{R 4} - or -NR ⁵ - indicates,
R ³ and R ⁴ each independently represent a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group, or
R ³ and R ⁴ together with the carbon atom to which R ³ and R ⁴ are bonded may have 3 to 3 members which may have 1 to 3 substituent (s) independently selected from the following group D A 7-membered cycloalkyl ring, a tetrahydropyran ring optionally having 1 to 3 substituents independently selected from Group D below, or 1 to 3 substituents independently selected from Group D below Forming an indane ring which may have
R ⁵ represents a hydrogen atom or a C _1-6 alkyl group. ]
Group A: halogen atom, hydroxy group, carboxy group, C _1-6 alkyl group, hydroxy C _1-6 alkyl group, C _1-6 alkoxy group, halogeno C _1-6 alkoxy group, C _2-7 alkanoyl group, C _2-7 alkanoylamino group, phenyl group, carbamoyl group, (C _3-7 cycloalkyl) sulfonylcarbamoyl group, hydroxycarbamoyl group, tetrazolyl group, 1-benzyl-carboxy-4-oxo-3-pyridinyl group B: halogen Atom, C _1-6 alkyl group, oxo group Group C: halogen atom, cyano group, amino group, C _1-6 alkyl group, C _1-6 alkoxy group, hydroxy C _1-6 alkyl group, C _1-6 alkyl Amino group, C _1-6 alkoxy C _1-6 alkyl group, hydroxy group, halogeno C _1-6 alkyl group, C _2-7 Lucanoylamino group, halogeno C _1-6 alkoxy group, C _1-6 alkylsulfonylamino group, carbamoyl group D group: halogen atom, C _1-6 alkyl group [2] ring Q ² is a pyrrolidine ring, a piperidine ring, An azepan ring, an oxazepan ring, a diazepan ring, or an oxazocan ring (the pyrrolidine ring, piperidine ring, azepan ring, oxazepan ring, diazepan ring, or oxazocan ring has one oxo group or C _1-6 alkyl group; Or the pharmacologically acceptable salt thereof according to [1];
[3] The compound of [1], wherein ring Q ² represents any of the following formulas (3A) to (3G), or a pharmaceutically acceptable salt thereof;

[Where,
* Is attached to the carbon atom of the carbonyl group,
** is linked to L,
R ⁶ represents a hydrogen atom or a methyl group. ]
[4] L _{is, -CH 2 -, - NH -} , - N (CH 3) -, indicate either an oxygen atom or the following formula, (4A) to (4C), of [1] to [3] A compound according to any one of the above or a pharmacologically acceptable salt thereof;

[Where,
* It is attached to the ring ^{Q 2,}
** it is attached to the ring ^{Q 3.} ]
[5] The compound according to any one of [1] to [4], wherein the ring Q ¹ represents ^one of the following formulas (5A) to (5C), or a pharmaceutically acceptable salt thereof;

[Where,
* Indicates a bond,
R ⁷ , R ⁸ , and R ⁹ each independently represent a hydrogen atom, a halogen atom, a hydroxy group, a C _1-6 alkoxy group, a hydroxycarbamoyl group, or a tetrazolyl group;
R ¹⁰ represents a hydrogen atom or a C _1-6 alkoxy group,
R ¹¹ represents a hydrogen atom or a 1-benzyl-carboxy-4-oxo-3-pyridinyl group. ]
[6] When ring Q ¹ is a 4-hydroxyphenyl group, a 4-methoxyphenyl group, a 4-chlorophenyl group, a 4-hydroxycarbamoyl group, a 3,4-dimethoxyphenyl group, a 3-pyridinyl group, a 4- (tetrazole-5 The compound according to any one of [1] to [4], which is a -yl) phenyl group or a 5- (1-benzyl-5-carboxy-4-oxo-3-pyridinyl) -2-thienyl group. Or a pharmacologically acceptable salt thereof;
[7] Ring Q ³ is a phenyl group (the phenyl group may have one carbamoyl group), a thiazolyl group (the thiazolyl group has one C _2-7 alkanoylamino group) Or a pyrazolyl group, or the pharmaceutically acceptable salt thereof according to any one of [1] to [6];
[8] ring ^{Q 3} is 3-carbamoyl phenyl group, 2-acetamide-4-yl group or 1H- pyrazol-4-yl group, according to any one of [1] to [6] Or a pharmacologically acceptable salt thereof;
[9] The compound according to any one of [1] to [6], wherein ring Q ³ represents the following formula (6A) or (6B), or a pharmaceutically acceptable salt thereof;

[Where,
* Indicates a bond,
Z represents a nitrogen atom or CR ¹³ ;
R ¹² represents a hydrogen atom or a halogen atom,
R ¹³ represents a hydrogen atom or a C _1-6 alkyl group. ]
[10] The compound according to any one of [1] to [6], wherein ring Q ³ represents any of the following formulas (7A) to (7F), or a pharmaceutically acceptable salt thereof;

[In the formula, * represents a bond. ]
[11] The compound according to any one of [1] to [10], wherein X is —CH ₂ — or —N (CH ₃ ) —, or a pharmaceutically acceptable salt thereof;
[12] X is —CR ³ R ⁴ —, and R ³ and R ⁴ are taken together with the carbon atom to which R ³ and R ⁴ are bonded to form a cyclopentane ring, a cyclohexane ring, a tetrahydropyran ring [3.3] The compound according to any one of [1] to [10], which forms a heptane ring or an indane ring, or a pharmaceutically acceptable salt thereof;
[13] X is —CR ³ R ⁴ —, and R ³ and R ⁴ are taken together with the carbon atom to which R ³ and R ⁴ are bonded to form a cyclopentane ring, cyclohexane ring, 4-tetrahydro The compound or the pharmaceutically acceptable salt thereof according to any one of [1] to [10], which forms a pyran ring;
[14] When ring Q ¹ is a 4-hydroxyphenyl group, a 4-methoxyphenyl group, a 4-chlorophenyl group, a 4-hydroxycarbamoyl group, a 3,4-dimethoxyphenyl group, a 3-pyridinyl group, a 4- (tetrazole-5 -Yl) phenyl or 5- (1-benzyl-5-carboxy-4-oxo-3-pyridinyl) -2-thienyl;
Ring Q ² represents any of formulas (3A) to (3G) below;

[Where,
* Is attached to the carbon atom of the carbonyl group,
** is linked to L,
R ⁶ represents a hydrogen atom or a methyl group. ]
Ring ^{Q 3} is 3-carbamoyl phenyl group, 2-acetamide-4-yl group, 1H-pyrazol-4-yl group, or indicates one of the following formulas (7A) to (7F),;

[In the formula, * represents a bond. ]
L _{is, -CH 2 -, - NH -} , - N (CH 3) -, indicates one of an oxygen atom or the following formula, (4A) to (4C);

[Where,
* It is attached to the ring ^{Q 2,}
** it is attached to the ring ^{Q 3.} ]
X is, ^-CR 3 ^{R 4} - a and,
R ³ and R ⁴ together with the carbon atom to which R ³ and R ⁴ are attached form a cyclopentane, cyclohexane, 4-tetrahydropyran ring;
The compound of [1] or a pharmacologically acceptable salt thereof;
[15] Any compound selected from the following group or a pharmacologically acceptable salt thereof;
[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] [4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] methanone,
1- [6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] -2- (4-methoxyphenyl) ethanone,
[3- (1H-indazol-4-ylmethyl) azepan-1-yl] [2- (4-methoxyphenyl) spiro [3.3] heptane-2-yl] methanone,
[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone,
[3- (1H-indazol-4-ylmethyl) piperidin-1-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone,
[1- (4-chlorophenyl) cyclohexyl] [6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] methanone,
[3- (1H-indazol-4-ylmethyl) azepan-1-yl] [2- (4-methoxyphenyl) -2,3-dihydro-1H-inden-2-yl] methanone,
3- (1H-indazol-4-ylmethyl) -1-{[1- (4-methoxyphenyl) cyclohexyl] carbonyl} piperidin-4-one,
{(2R) -2-[(1H-indazol-4-ylamino) methyl] pyrrolidin-1-yl} [1- (4-methoxyphenyl) cyclopentyl] methanone,
[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] [1- (pyridin-3-yl) cyclohexyl] methanone,
[6- (1H-indazol-4-ylmethyl) -1,4-diazepan-1-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone,
[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] {1- [4- (2H-tetrazol-5-yl) phenyl] cyclohexyl} methanone,
[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclopentyl] methanone,
(+)-[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclopentyl] methanone,
[1- (4-hydroxyphenyl) cyclohexyl] [3- (1H-indazol-4-ylmethyl) azepan-1-yl] methanone,
[1- (3,4-dimethoxyphenyl) cyclopentyl] [3- (1H-indazol-4-ylmethyl) azepan-1-yl] methanone,
1-benzyl-5- [5- (1-{[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] carbonyl} cyclohexyl) thiophen-2-yl] -4-oxo -1,4-dihydropyridine-3-carboxylic acid,
N-hydroxy-4- (1-{[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] carbonyl} cyclohexyl) benzamide;
[6- (1H-indazol-3-ylmethyl) -1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone,
[1- (4-methoxyphenyl) cyclohexyl] [6- (1H-pyrazolo [3,4-b] pyridin-4-ylmethyl) -1,4-oxazepan-4-yl] methanone,
[1- (4-methoxyphenyl) cyclohexyl] [6- (1H-pyrazolo [4,3-c] pyridin-4-ylmethyl) -1,4-oxazepan-4-yl] methanone,
[3- (1H-indazol-4-ylmethyl) -1,5-oxazocan-5-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone,
{6-[(6-fluoro-1H-indazol-4-yl) methyl] -1,4-oxazepan-4-yl} [1- (4-methoxyphenyl) cyclohexyl] methanone,
[6- (1H-indazol-4-ylmethyl) -2-methyl-1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone,
[1- (4-methoxyphenyl) cyclohexyl] {3-[(7-methyl-1H-indazol-4-yl) methyl] azepan-1-yl} methanone,
2-acetamido-N- (4-{[4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] carbonyl} -1,4-oxazepan-6-yl) -1,3-thiazole-4 -Carboxamide,
[6- (1H-indazol-4-ylamino) -1,4-oxazepan-4-yl] [4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] methanone,
[6- (1H-indazol-4-yloxy) -1,4-oxazepan-4-yl] [4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] methanone,
[1- (4-methoxyphenyl) cyclohexyl] {6-[(1H-pyrazol-4-yloxy) methyl] -1,4-oxazepan-4-yl} methanone,
6- (1H-indazol-4-ylmethyl) -N- (4-methoxyphenyl) -N-methyl-1,4-oxazepan-4-carboxamide;
3-[(4-{[1- (4-methoxyphenyl) cyclohexyl] carbonyl} -1,4-oxazepan-6-yl) methyl] benzamide [16] [1] to [15] A pharmaceutical composition comprising, as an active ingredient, the compound of the above or a pharmacologically acceptable salt thereof;
[17] An EP300 and / or CREBPP inhibitor comprising the compound according to any one of [1] to [15] or a pharmaceutically acceptable salt thereof as an active ingredient;
[18] an antitumor agent comprising, as an active ingredient, the compound according to any one of [1] to [15] or a pharmacologically acceptable salt thereof;
[19] tumor is prostate cancer, liver cancer, lung cancer, breast cancer, colorectal cancer, stomach cancer, blood cancer, pancreatic cancer, esophageal cancer, bladder cancer, gastrointestinal stromal tumor, NUT midline carcinoma, Or the antitumor agent according to [18], which is an ovarian cancer;
[20] a method for treating a tumor, which comprises administering the compound according to any one of [1] to [15] or a pharmaceutically acceptable salt thereof;
[21] The tumor is prostate cancer, liver cancer, lung cancer, breast cancer, colon cancer, stomach cancer, blood cancer, pancreatic cancer, esophageal cancer, bladder cancer, gastrointestinal stromal tumor, NUT midline carcinoma, Or the method of treatment according to [20], wherein the cancer is ovarian cancer;
It is.

  The compound of the present invention or a pharmaceutically acceptable salt thereof exhibits excellent EP300 and / or CREBPP inhibitory activity. That is, by administering a pharmaceutical composition containing the compound of the present invention or a pharmacologically acceptable salt thereof to a mammal (human, cow, horse, pig, etc.) or bird (chicken, etc.), EP300 and / or It can be used for the treatment of CREBBP-dependent cancer. Therefore, the compound of the present invention or a pharmacologically acceptable salt thereof can be used as an active ingredient of an antitumor agent. Examples of the tumor include prostate cancer, liver cancer, lung cancer, breast cancer, colon cancer, stomach cancer, blood cancer, pancreatic cancer, esophageal cancer, bladder cancer, gastrointestinal stromal tumor, NUT midline carcinoma, Or ovarian cancer.

  In the present invention, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom.

In the present invention, the “C _1-6 alkyl group” refers to a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethyl Propyl group, n-hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, Examples thereof include a 1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,3-dimethylbutyl group, and a 2-ethylbutyl group.

In the present invention, the “C _1-6 alkoxy group” refers to a group in which the above “C _1-6 alkyl group” is bonded to an oxygen atom. For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, n-hexyloxy And the like.

In the present invention, the “hydroxy C _1-6 alkyl group” refers to a group in which one or two hydrogen atoms of the above “C _1-6 alkyl group” have been substituted with a hydroxyl group. For example, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydroxypropyl group, a 2-hydroxypropyl group, a 1-hydroxyisopropyl group, a 1-hydroxybutyl group, a 2-hydroxybutyl group, Examples thereof include a hydroxypentyl group, a 2-hydroxypentyl group, 1-hydroxyhexyl, and a 1,2-dihydroxyethyl group.

In the present invention, the “halogeno C _1-6 alkyl group” refers to a group in which one to three hydrogen atoms of the above “C _1-6 alkyl group” are substituted with the above “halogen atom”. For example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 1-fluoroethyl, 1-chloroethyl, 2-fluoroethyl, 1,2-difluoropropyl And 2,2,2-trifluoroethyl groups.

In the present invention, the “halogeno C _1-6 alkoxy group” refers to a group in which one to three hydrogen atoms of the above “C _1-6 alkoxy group” have been substituted with the above “halogen atom”. For example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, 1-fluoroethoxy, 1-chloroethoxy, 2-fluoroethoxy, 1,2-difluoro Examples thereof include a propoxy group and a 2,2,2-trifluoroethoxy group.

In the present invention, the “C _2-7 alkanoyl group” refers to a group in which the “C _1-6 alkyl group” and the carbon atom of the carbonyl group are bonded. Examples include acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, isovaleryl, hexanoyl, heptanoyl and the like.

In the present invention, the “C _2-7 alkanoylamino group” refers to a group in which the “C _2-7 alkanoyl group” is bonded to an amino group. For example, an acetylamino group, a propionylamino group, a butyrylamino group, an isobutyrylamino group, a pentanoylamino group and the like can be mentioned.

In the present invention, the “C _1-6 alkylsulfonylamino group” refers to a group in which a group in which the above “C _1-6 alkyl group” and a sulfur atom of a sulfonyl group are bonded to an amino group. For example, methylsulfonylamino group, ethylsulfonylamino group, n-propylsulfonylamino group, isopropylsulfonylamino group, n-butylsulfonylamino group, sec-butylsulfonylamino group, tert-butylsulfonylamino group, n-pentylsulfonylamino And the like.

In the present invention, the “C _1-6 alkylamino group” refers to a group in which one hydrogen atom of an amino group is substituted with the above “C _1-6 alkyl group”. Examples thereof include a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, an n-butylamino group, a sec-butylamino group, a tert-butylamino group, and an n-pentylamino group.

In the present invention, _{"C 1-6} alkoxy _{C 1-6} alkyl group", one of the hydrogen atoms of the aforementioned _{"C 1-6} alkyl group", a substituted group in the above _{"C 1-6} alkoxy group" Show. For example, methoxymethyl group, ethoxymethyl group, n-propoxymethyl group, isopropoxymethyl group, methoxyethyl group, ethoxyethyl group, propoxyethyl group, isopropoxyethyl group and the like can be mentioned.

  In the present invention, the “3- to 7-membered cycloalkyl ring” refers to a 3- to 7-membered monocyclic or spiro-cyclic saturated hydrocarbon group (ring). For example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a spiro [3.3] heptyl group and the like can be mentioned.

In the present invention, the “C _3-7 cycloalkylsulfonylcarbamoyl group” refers to a group in which the above “3- to 7-membered cycloalkyl ring” and a group in which a sulfur atom of a sulfonyl group is bonded to a nitrogen atom of a carbamoyl group. Show. Examples thereof include a cyclopropylsulfonylcarbamoyl group, a cyclobutylsulfonylcarbamoyl group, a cyclopentylsulfonylcarbamoyl group, a cyclohexylsulfonylcarbamoyl group, and a cycloheptylsulfonylcarbamoyl group.

  In the present invention, “1-benzyl-carboxy-4-oxo-3-pyridinyl group” refers to a 1-benzyl-2-carboxy-4-oxo-3-pyridinyl group (8A), -Benzyl-5-carboxy-4-oxo-3-pyridinyl group (8B) or 1-benzyl-6-carboxy-4-oxo-3-pyridinyl group (8C).

[In the formula, * represents a bond. ]
In the present invention, “a 5- or 6-membered aromatic heterocyclic group having one or two hetero atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in a ring” refers to a ring Represents a group derived from a 5- or 6-membered monocyclic aromatic compound containing one or two hetero atoms (a nitrogen atom, an oxygen atom, or a sulfur atom) other than a carbon atom as a constituent atom. Examples thereof include a pyridinyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, an oxopyridinyl group, a thiophenyl group, a furanyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, and an isoxazolyl group. The “5- or 6-membered aromatic heterocyclic group having 1 or 2 hetero atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom” in the ring Q ¹ is preferably Is a pyridinyl group or a thiophenyl group. The “5- or 6-membered aromatic heterocyclic group having one or two hetero atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom” in the ring Q ³ is preferably Is a pyrazolyl group or a thiazolyl group.

In the present invention, it is preferable that "in the ring, one heteroatom independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in addition to the nitrogen atom represented by the general formula (1)" The "good 5- to 8-membered heterocycloalkyl ring" means, in addition to the nitrogen atom shown in the general formula (1), one hetero atom (nitrogen atom, oxygen atom, Or a ring (group) derived from a 5- to 8-membered monocyclic non-aromatic compound which may contain a sulfur atom), and may have an unsaturated bond in part of the ring. For example, pyrrolidinyl group, oxazolidinyl group, thiazolidinyl group, piperidinyl group, oxadinanyl group, thiazinyl group, hexahydropyrimidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, azepanyl group, oxazepanyl group, diazepanyl group, oxazocanyl group, thiazocanyl group, thiazocanyl group Pyrrolyl group, dihydroimidazolyl group, dihydrooxazinyl group, dihydrothiazinyl group, tetrahydropyrimidinyl group, tetrahydropyrazinyl group, tetrahydrooxazepinyl group, tetrahydrodiazepinyl group, tetrahydrothiazepinyl group, dihydropyrazinyl Group, dihydropyrazinyl group, oxazinyl group, thiazinyl group and the like. In addition to the nitrogen atom of a nitrogen atom that is displayed in the "general formula (1) in the ring Q ^2, oxygen atoms, and even heteroatoms selected independently from the group consisting of a sulfur atom have one in the ring A good 5- to 8-membered heterocycloalkyl ring is preferably a pyrrolidinyl, piperidinyl, azepanyl, oxazepanyl, diazepanyl, or oxazocanyl group.

In the present invention, “an 8- to 10-membered bicyclic aromatic heterocyclic group having 1 to 4 hetero atoms in a ring independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom” The term “is a group derived from an 8- to 10-membered condensed aromatic compound containing 1 to 4 heteroatoms (nitrogen, oxygen, or sulfur) in addition to carbon atoms as ring constituent atoms. A part of the cyclic ring may have a saturated bond. For example, a pyrrolopyrazolyl group, an indazolyl group, a quinolyl group, a benzimidazolyl group, a pyrrolopyridinyl group, a 2-oxo-2,3-dihydro-1H-pyrrolopyridinyl group, a 2-oxo-2,3-dihydro-1H-benzimidazolyl group, Zolopyridinyl group, 3-oxo-3,4-dihydro-2H-pyrido [1,4] oxazinyl group, 2-oxo-1,2,3,4-tetrahydroquinolinyl group, isoindolinyl group, indolinyl group , Indolizinyl, purinyl, quinolizinyl, isoquinolyl, naphthyridinyl, phthalazinyl, quinoxalinyl, quinazolinyl, pteridinyl and the like. In ring Q ³ 'nitrogen atom, an oxygen atom, and bicyclic aromatic heterocyclic group having 8-membered to 10-membered to 1 to 4 Yes to the hetero atom in the ring independently selected from the group consisting of sulfur atoms " Is preferably an indazolyl group or a pyrazolopyridinyl group.

  In the present invention, tumors, malignant tumors, cancers, malignant neoplasms, carcinomas, sarcomas, and the like are collectively referred to as “tumor” or “cancer”.

  In the present invention, “inhibition of EP300” means inhibition of histone acetyltransferase activity of EP300.

  In the present invention, “inhibition of CREBBP” means inhibition of histone acetyltransferase activity of CREBBP.

  In the present invention, the “histone acetyltransferase activity of EP300 and / or CREBBP” means an enzymatic activity of EP300 and / or CREBBP that acetylates lysine 27 of histone H3.

  Preferred substituents in the compound of the present invention are described below.

Ring ^{Q 1} is, preferably, is any one of the following (5A) to (5C).

[Where,
* Indicates a bond,
R ⁷ , R ⁸ , and R ⁹ each independently represent a hydrogen atom, a halogen atom, a hydroxy group, a C _1-6 alkoxy group, a hydroxycarbamoyl group, or a tetrazolyl group;
R ¹⁰ represents a hydrogen atom or a C _1-6 alkoxy group,
R ¹¹ represents a hydrogen atom or a 1-benzyl-carboxy-4-oxo-3-pyridinyl group. ]

Ring Q ¹ is more preferably a 4-hydroxyphenyl group, a 4-methoxyphenyl group, a 4-chlorophenyl group, a 4-hydroxycarbamoyl group, a 3,4-dimethoxyphenyl group, a 3-pyridinyl group, or a 4- (tetrazole -5-yl) phenyl group or 5- (1-benzyl-5-carboxy-4-oxo-3-pyridinyl) -2-thienyl group.

Ring Q ² is preferably an oxo group or a pyrrolidine ring, a piperidine ring, an azepane ring, an oxazepane ring, a diazepane ring, or an oxazocane ring which may have one C _1-6 alkyl group. is there.

Ring ^{Q 2} are more preferably either below (3A) to (3G).

[Where,
* Is attached to the carbon atom of the carbonyl group,
** is linked to L,
R ⁶ represents a hydrogen atom or a methyl group. ]

Ring Q ³ is preferably a phenyl group (the phenyl group may have one carbamoyl group), a thiazolyl group (the thiazolyl group has one C _2-7 alkanoylamino group). Or a pyrazolyl group.

Ring ^{Q 3} are more preferred, 3-carbamoyl phenyl group, 2-acetamide-4-yl group or 1H- pyrazol-4-yl group.

Ring ^{Q 3} are preferably a following (6A) or (6B).

[Where,
* Indicates a bond,
Z represents a nitrogen atom or CR ¹³ ;
R ¹² represents a hydrogen atom or a halogen atom,
R ¹³ represents a hydrogen atom or a C _1-6 alkyl group. ]

Ring ^{Q 3} are more preferably either of the following formulas (7A) to (7F).

[In the formula, * represents a bond. ]
X is preferably, -CH ₂ - or -N (CH ₃₎ - is.
X is preferably X is —CR ³ R ⁴ —, and R ³ and R ⁴ are taken together with the carbon atom to which R ³ and R ⁴ are attached to a cyclopentane ring, a cyclohexane ring, Form a tetrahydropyran ring, a [3.3] heptane ring, or an indane ring.
X is more preferably X is —CR ³ R ⁴ —, and R ³ and R ⁴ are taken together with the carbon atom to which R ³ and R ⁴ are bonded to form a cyclopentane ring, a cyclohexane ring Or a 4-tetrahydropyran ring.
L is _{preferably, -CH 2 -, - NH -} , - N (CH 3) -, forms an oxygen atom or the following formula, (4A) to (4C).

[Where,
* It is attached to the ring ^{Q 2,}
** it is attached to the ring ^{Q 3.} ]

The compound of the present invention is preferably one selected from the following compounds or pharmacologically acceptable salts thereof:
[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] [4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] methanone,
1- [6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] -2- (4-methoxyphenyl) ethanone,
[3- (1H-indazol-4-ylmethyl) azepan-1-yl] [2- (4-methoxyphenyl) spiro [3.3] heptane-2-yl] methanone,
[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone,
[3- (1H-indazol-4-ylmethyl) piperidin-1-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone,
[1- (4-chlorophenyl) cyclohexyl] [6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] methanone,
[3- (1H-indazol-4-ylmethyl) azepan-1-yl] [2- (4-methoxyphenyl) -2,3-dihydro-1H-inden-2-yl] methanone,
3- (1H-indazol-4-ylmethyl) -1-{[1- (4-methoxyphenyl) cyclohexyl] carbonyl} piperidin-4-one,
{(2R) -2-[(1H-indazol-4-ylamino) methyl] pyrrolidin-1-yl} [1- (4-methoxyphenyl) cyclopentyl] methanone,
[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] [1- (pyridin-3-yl) cyclohexyl] methanone,
[6- (1H-indazol-4-ylmethyl) -1,4-diazepan-1-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone,
[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] {1- [4- (2H-tetrazol-5-yl) phenyl] cyclohexyl} methanone,
[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclopentyl] methanone,
(+)-[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclopentyl] methanone,
[1- (4-hydroxyphenyl) cyclohexyl] [3- (1H-indazol-4-ylmethyl) azepan-1-yl] methanone,
[1- (3,4-dimethoxyphenyl) cyclopentyl] [3- (1H-indazol-4-ylmethyl) azepan-1-yl] methanone,
1-benzyl-5- [5- (1-{[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] carbonyl} cyclohexyl) thiophen-2-yl] -4-oxo -1,4-dihydropyridine-3-carboxylic acid,
N-hydroxy-4- (1-{[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] carbonyl} cyclohexyl) benzamide;
[6- (1H-indazol-3-ylmethyl) -1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone,
[1- (4-methoxyphenyl) cyclohexyl] [6- (1H-pyrazolo [3,4-b] pyridin-4-ylmethyl) -1,4-oxazepan-4-yl] methanone,
[1- (4-methoxyphenyl) cyclohexyl] [6- (1H-pyrazolo [4,3-c] pyridin-4-ylmethyl) -1,4-oxazepan-4-yl] methanone,
[3- (1H-indazol-4-ylmethyl) -1,5-oxazocan-5-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone,
{6-[(6-fluoro-1H-indazol-4-yl) methyl] -1,4-oxazepan-4-yl} [1- (4-methoxyphenyl) cyclohexyl] methanone,
[6- (1H-indazol-4-ylmethyl) -2-methyl-1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone,
[1- (4-methoxyphenyl) cyclohexyl] {3-[(7-methyl-1H-indazol-4-yl) methyl] azepan-1-yl} methanone,
2-acetamido-N- (4-{[4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] carbonyl} -1,4-oxazepan-6-yl) -1,3-thiazole-4 -Carboxamide,
[6- (1H-indazol-4-ylamino) -1,4-oxazepan-4-yl] [4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] methanone,
[6- (1H-indazol-4-yloxy) -1,4-oxazepan-4-yl] [4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] methanone,
[1- (4-methoxyphenyl) cyclohexyl] {6-[(1H-pyrazol-4-yloxy) methyl] -1,4-oxazepan-4-yl} methanone,
6- (1H-indazol-4-ylmethyl) -N- (4-methoxyphenyl) -N-methyl-1,4-oxazepan-4-carboxamide;
3-[(4-{[1- (4-methoxyphenyl) cyclohexyl] carbonyl} -1,4-oxazepan-6-yl) methyl] benzamide.

  In the compounds of the present invention, geometric isomers or tautomers may exist depending on the type of the substituent. When the compound of the present invention has an asymmetric carbon atom, optical isomers may exist. The present invention includes separated forms of these isomers (eg, enantiomers or diastereomers) or mixtures (eg, racemic or diastereomeric mixtures). Also, the present invention includes a labeled compound, that is, a compound in which one or more atoms of the compound of the present invention are substituted with a corresponding radioactive isotope or non-radioactive isotope at an arbitrary ratio.

  When the compound of the present invention has a basic group such as an amino group, it is possible to form a pharmacologically acceptable acid addition salt, if desired. Such acid addition salts include, for example, hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrates, perchlorates, sulfates, phosphates Inorganic acid salts such as methanesulfonic acid salt, trifluoromethanesulfonic acid salt, ethanesulfonic acid salt and the like; arylsulfonic acid salts such as benzenesulfonic acid salt and p-toluenesulfonic acid salt; Organic acid salts such as malate, fumarate, succinate, citrate, tartrate, oxalate, and maleate; or amino acid salts such as ornithate, glutamate, and aspartate. Preferably, hydrohalides and organic acid salts are preferred.

  When the compound of the present invention has an acidic group such as a carboxy group, it is possible to form a pharmacologically acceptable base addition salt, if desired. Such base addition salts include, for example, alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; inorganic salts such as ammonium salt; or dibenzylamine salt; Morpholine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, diethanolamine salt, N-benzyl- Organic amine salts such as N- (2-phenylethoxy) amine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt and the like can be mentioned.

  The compounds of the present invention may exist as unsolvated or solvated forms. The solvate is not particularly limited as long as it is pharmacologically acceptable. Specifically, hydrates, ethanol solvates and the like are preferable. When a nitrogen atom is present in the compound represented by the general formula (1), the compound may be in the form of an N-oxide, and these solvates and N-oxides are also included in the scope of the present invention. .

  In the compound of the present invention, various isomers such as geometric isomers such as cis- and trans-forms, tautomers, and optical isomers such as d- and l-forms may be present depending on the types and combinations of substituents. The compounds of the present invention include all isomers and mixtures of these isomers in any ratio unless otherwise specified.

Also, the compounds of the present invention may contain unnatural proportions of isotopes at one or more of the atoms that constitute such compounds. Examples of the isotope include deuterium ( ² H; D), tritium ( ³ H; T), iodine-125 ( ¹²⁵ I), and carbon-14 ( ¹⁴ C). The compounds of the present invention, for example, tritium ⁽³ H), iodine--125 ⁽¹²⁵ I), or may be radiolabeled with radioactive isotopes such as carbon -14 ⁽¹⁴ C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents (eg, assay reagents), and diagnostic agents (eg, in vivo diagnostic imaging agents). Compounds of the present invention that contain all proportions of radioactive or non-radioactive isotopes are included within the scope of the invention.

[Production method]
Next, a typical method for producing the compound represented by the general formula (1) will be described. The compound of the present invention can be produced by various production methods, and the production methods shown below are examples, and the present invention should not be construed as being limited thereto.

  The compound represented by the general formula (1), a pharmacologically acceptable salt thereof and a production intermediate thereof are applied to various known production methods utilizing characteristics based on their basic skeleton or types of substituents. Can be manufactured. Known methods include, for example, “ORGANIC FUNCTIONAL GROUP PREPARATIONS”, 2nd edition, ACADEMIC PRESS, INC. 1989, "Comprehensive Organic Transformations", VCH Publishers Inc. , 1989, and the like.

  At that time, depending on the type of the functional group present in the compound, the functional group is protected with an appropriate protecting group at the stage of a raw material or an intermediate, or is replaced with a group that can be easily converted to the functional group. May be effective in manufacturing technology.

  Examples of such a functional group include an amino group, a hydroxyl group, a carboxy group, and the like. G. FIG. Wuts, "Protective Groups in Organic Synthesis (Fifth Edition, 2014)".

  The protecting group or the group that can be easily converted to the functional group may be appropriately selected and used depending on the respective reaction conditions in the production method for producing the compound.

  According to such a method, a desired compound can be obtained by removing the protecting group or converting it to a desired group, if necessary, after the introduction of the group and the reaction.

  The compound represented by the general formula (1) can be produced, for example, by the following methods A to G. Various compounds which are production intermediates are known or can be produced by known methods or similar methods using known compounds as starting materials, and can also be produced, for example, by the following H to M methods.

  The compound serving as a reaction substrate in the reaction of each of the following methods A to M has a functional group or a partial structure that inhibits the intended reaction, such as an amino group, a hydroxy group, a carboxy group, or a heteroatom on a cyclic compound. In such a case, if necessary, a protective group may be introduced into them and the introduced protective group may be removed. Such a protecting group is not particularly limited as long as it is a commonly used protecting group, and may be, for example, the protecting group described in the above-mentioned “Protective Groups in Organic Synthesis (5th edition, 2014)”. The reaction for introducing and removing those protecting groups can be carried out according to a conventional method described in the above literature.

  Each compound of the following methods A to M can be replaced with a group that can be easily converted to a desired functional group at the stage of a raw material or an intermediate depending on the type of the functional group present in the compound. The conversion to the desired functional group can be performed at an appropriate stage according to a known method. Known methods include, for example, methods described in the above-mentioned “ORGANIC FUNCTIONAL GROUP PREPARATIONS”, “Comprehensive Organic Transformations”, and the like.

  Each compound of the following methods A to M is isolated and purified as various solvates such as a non-solvate, a salt thereof and a hydrate. The salt can be produced by a usual method. Examples of the salt include a hydrochloride, a sulfate and the like, or a sodium salt and a potassium salt.

  The solvent used in the reaction of each of the following processes A to M is not particularly limited as long as it does not inhibit the reaction and partially dissolves the starting materials. For example, it is selected from the following solvent group. The solvent group includes aliphatic hydrocarbons such as n-hexane, pentane, petroleum ether, and cyclohexane; aromatic hydrocarbons such as benzene, toluene, and xylene; dichloromethane (methylene chloride), chloroform, carbon tetrachloride, and dichloroethane. Halogenated hydrocarbons such as chlorobenzene and dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone; Esters such as ethyl acetate, propyl acetate and butyl acetate; nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; Carboxylic acids such as pionic acid; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol; formamide Amides such as N, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide, tetrahydrothiophene 1,1-dioxide; Water; and mixtures thereof.

  The acid used in the reaction of each of the following methods A to M is not particularly limited as long as it does not inhibit the reaction, and is selected from the following acid group. The acid group includes inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, and nitric acid, organic acids such as acetic acid, propionic acid, trifluoroacetic acid, and pentafluoropropionic acid, and methanesulfonic acid. Organic sulfonic acids such as trifluoromethanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and boron tribromide, indium (III) bromide, boron trifluoride, aluminum (III) chloride, trifluoromethane sulfone It consists of a Lewis acid such as trimethylsilyl acid.

  The base used in the reaction of each of the following methods A to M is not particularly limited as long as it does not inhibit the reaction, and is selected from the following base group. The base group includes alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; alkali metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; lithium hydroxide, sodium hydroxide Alkali metal hydroxides such as calcium hydroxide and barium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; Alkali metal amides such as lithium amide, sodium amide, potassium amide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide; lithium diisopropylamide Such as lithium bistrimethylsilylamide and sodium bistrimethylsilylamide; alkyllithiums such as n-butyllithium, sec-butyllithium and tert-butyllithium; methylmagnesium chloride (methylmagnesium chloride), methylmagnesium Bromide (methyl magnesium bromide), methyl magnesium iodide (methyl magnesium iodide), ethyl magnesium chloride (ethyl magnesium chloride), ethyl magnesium bromide (ethyl magnesium bromide), isopropyl magnesium chloride (isopropyl magnesium chloride), isopropyl magnesium bromide (Isopropyl magnesium bromide), isobutyl magnesium chloride (isobuty chloride) Magnesium halides such as magnesium); and triethylamine, tributylamine, N, N-diisopropylethylamine, 1-methylpiperidine, 4-methylmorpholine, 4-ethylmorpholine, pyridine, picoline, 4-dimethylaminopyridine, -Pyrrolidinopyridine, 2,6-di-tert-butyl-4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4,3,0] -5 -From organic amines such as nonene (DBN), 1,4-diazabicyclo [2,2,2] octane (DABCO), 1,8-diazabicyclo [5,4,0] -7-undecene (DBU), imidazole Become.

  In the reactions in each of the following methods A to M, the reaction temperature varies depending on the solvent, the starting material, the reagent, and the like, and the reaction time varies depending on the solvent, the starting material, the reagent, the reaction temperature, and the like.

  In the reactions in each of the following methods A to M, after completion of the reaction, the target compound in each step is isolated from the reaction mixture according to a conventional method. For the target compound, for example, (i) insoluble substances such as a catalyst are filtered off if necessary, and (ii) water and a water-immiscible solvent (eg, dichloromethane, diethyl ether, ethyl acetate, etc.) are added to the reaction mixture. To extract the desired compound, (iii) washing the organic layer with water, drying using a desiccant such as anhydrous magnesium sulfate, and (iv) distilling off the solvent. The obtained target compound is further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, distillation, column chromatography using silica gel or alumina (including normal phase and reverse phase) and the like. Can be. The obtained target compound is identified by standard analysis techniques such as elemental analysis, NMR, mass spectroscopy, and IR analysis, and its composition or purity can be analyzed. Further, the target compound in each step can be used for the next reaction without purification.

  In each step of the following methods A to M, an optically active amine such as (R)-(+)-or (S)-(-)-1-phenethylamine, (+)-or (-)-10-camphorsulfone The optical isomer can be separated and purified by fractional recrystallization using an optically active carboxylic acid such as an acid or separation using an optically active column.

  The raw materials and reagents used in the production of the compounds of the present invention can be purchased from commercial suppliers, or can be synthesized by methods described in the literature or methods analogous thereto.

  Hereinafter, the A to M methods will be described.

Method A When the compound represented by the general formula (1) is the compound 1a, it can be produced, for example, by Method A or B.

[In the formula, Q ¹ , Q ² , Q ³ , m and X have the same meanings as described above. R ¹⁴ represents a protecting group on the nitrogen atom, and examples thereof include a tert-butoxycarbonyl group (Boc group), a benzyloxycarbonyl group (Cbz group), and a 2-nitrobenzenesulfonyl group (Ns group). R ¹⁵ represents a methylidene group, a vinyl group or an allyl group. Y represents a leaving group, such as a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group (MsO group), and a p-toluenesulfonyloxy group (TsO group). ]

(A-1) Conversion of Compound 2a to Compound 4a In a solvent inert to the reaction of compound 2a (eg, tetrahydrofuran, 1,4-dioxane, etc.), a boron reagent (eg, 9-borabicyclo [3.3.1]) is used. ] Nonane (preferably, the reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is 10 minutes to 24 hours), and then a solvent inert to the reaction (eg, N, N-dimethylformamide, etc.). Compound 3a in the presence of water, a base (eg, potassium carbonate, tripotassium phosphate, etc.) and a palladium catalyst (eg, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex). (Preferably, the reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is 5 minutes to 48 hours).

Conversion of (A-2) converting compound 4a from compound 4a to compound 5a to compound 5a has a different way depending on the type of ^{R 14.}

(A-2-1)
When R ¹⁴ is a Boc group, the compound 4a containing the functional group is converted into an acid in a solvent inert to the reaction (eg, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, dichloromethane, tert-butyl alcohol, water, etc.). It can be carried out by treating with a catalyst (for example, hydrogen chloride, trifluoroacetic acid, pyridinium p-toluenesulfonate, etc.). Alternatively, treatment with an acid (such as trimethylsilyl trifluoromethanesulfonate) may be performed in the presence of a base (such as 2,6-lutidine). In any case, the reaction temperature is preferably from -15 ° C to room temperature, and the reaction time is from 30 minutes to 6 days.

(A-2-2)
When R ¹⁴ is a Cbz group, the compound 4a containing the functional group is converted into a reduction catalyst (eg, palladium-carbon, palladium hydroxide, Raney nickel, platinum) in a solvent inert to the reaction (eg, methanol, ethanol, ethyl acetate, etc.). -Carbon, platinum oxide, etc.) in the presence of a hydrogen atmosphere. Preferably, the reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 24 hours.

(A-3) Conversion of Compound 5a to Compound 1a In a solvent inert to the reaction (eg, dichloromethane, tetrahydrofuran, N, N-dimethylformamide, etc.), a base (eg, triethylamine, N, N-diisopropyl) is used. (Ethylamine, pyridine, 4-dimethylaminopyridine, etc.) in the presence of a carboxylic acid halide or a carboxylic acid active ester derived from compound 6a. Preferably, the reaction temperature is from -30C to the boiling point of the solvent, and the reaction time is from 5 minutes to 4 days.

B method

Wherein Q ¹ , Q ² , Q ³ , m, X, Y and R ¹⁵ are as defined above. ]

(B-1) Conversion of Compound 2b to Compound 3b Conversion of Compound 2b to Compound 3b can be carried out in the same manner as in Step A-3.

(B-2) Conversion of Compound 3b to Compound 1a Conversion of Compound 3b to Compound 1a can be carried out in the same manner as in Step A-1.

  Known literatures on the methods A and B include, for example, Med. Chem. , 57, 8307-8318 (2014).

Method C When the compound represented by the general formula (1) is the compound 1c, it can be produced, for example, by the method C.

[In the formula, Q ¹ , Q ² , Q ³ , R ² and X have the same meanings as described above. ]

(C-1) Conversion of Compound 2c to Compound 3c Conversion of Compound 2c to Compound 3c can be carried out in the same manner as in Step A-3.

(C-2) Conversion of Compound 3c to Compound 1c Conversion of Compound 3c to Compound 1c can be carried out in the same manner as in Step A-3.

Method D When the compound represented by the general formula (1) is the compound 1d, it can be produced, for example, by the method D.

[In the formula, Q ¹ , Q ² , Q ³ , R ¹ , R ¹⁴ , X, Y and p are as defined above. ]

(D-1) Conversion of Compound 2d to Compound 3d Conversion of Compound 2d to Compound 3d can be carried out in the same manner as in Step A-3.

(D-2) Conversion of Compound 3d to Compound 4d Conversion of Compound 3d to Compound 4d can be carried out in the same manner as in Step A-2.

(D-3) Conversion of Compound 4d to 1d Compound 4d is reacted with a phosphorus compound (eg, 4,5-bis (diphenylphosphino)) in a solvent inert to the reaction (eg, 1,4-dioxane, toluene, etc.). -9,9-dimethylxanthene, 2- (dicyclohexylphosphino) biphenyl and the like), a base (for example, cesium carbonate, sodium tert-butoxide and the like), a palladium catalyst (for example, tris (dibenzylideneacetone) dipalladium (0) and the like) ) In the presence of a compound 3a. Preferably, the reaction temperature is from room temperature to 250 ° C., the reaction time is from 5 minutes to 48 hours, and a microwave heating synthesizer may be used.

  Known methods for the method D include, for example, Org. Chem. , 69, 8893-8902 (2004); Am. Chem. Soc. , 118, 7215-7216 (1996).

Method E When the compound represented by the general formula (1) is the compound 1e, it can be produced, for example, by the method E.

[In the formula, Q ¹ , Q ² , Q ³ , R ¹ , R ¹⁴ and X are as defined above. q represents 0 or 1. ]

(E-1) Conversion of Compound 2e to Compound 4e Conversion of Compound 2e to Compound 4e can be carried out in the same manner as in Step A-3.

(E-2) Conversion of Compound 4e to Compound 5e The reaction can be carried out by reacting compound 4e with a boron compound (eg, borane-tetrahydrofuran complex) in a solvent inert to the reaction (eg, tetrahydrofuran). Preferably, the reaction temperature is from -20C to the boiling point of the solvent, and the reaction time is from 5 minutes to 48 hours.

(E-3) Conversion of Compound 5e to Compound 6e Conversion of Compound 5e to Compound 6e can be carried out in the same manner as in Step A-2.

(E-4)
Conversion of compound 6e to compound 1e can be carried out in the same manner as in step A-3.

Method F When the compound represented by the general formula (1) is the compound 1f, it can be produced, for example, by the method F.

[In the formula, Q ¹ , Q ² , Q ³ , X, R ¹⁵ and n have the same meanings as described above. ]

(F-1) Conversion of Compound 2f to Compound 3f Conversion of Compound 2f to Compound 3f can be carried out in the same manner as in Step A-3.

(F-2) Conversion of Compound 3f to Compound 1f Compound 3f is reacted in a solvent inert to the reaction (for example, toluene and the like), a phosphorus compound (for example, triphenylphosphine, tri-n-butylphosphine and the like), an azo compound (Eg, diisopropyl azodicarboxylate, 1,1 ′-(azodicarbonyl) dipiperidine, etc.), and can be carried out by reacting with compound 4f. Preferably, the reaction temperature is from -30C to the boiling point of the solvent, and the reaction time is from 5 minutes to 3 days.

(F-3) Conversion of Compound 3b to Compound 3f Compound 3f can also be produced from compound 3b.
After reacting compound 3b with a boron reagent (eg, 9-borabicyclo [3.3.1] nonane, borane-tetrahydrofuran complex, etc.) in a solvent inert to the reaction (eg, tetrahydrofuran) (preferably the reaction The temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 10 minutes to 24 hours), treated with a basic aqueous solution (eg, aqueous sodium hydroxide solution, potassium hydroxide aqueous solution, etc.), and an oxidizing agent (eg, aqueous hydrogen peroxide solution). (Preferably, the reaction temperature is from −30 ° C. to the boiling point of the solvent, and the reaction time is from 5 minutes to 24 hours).

  Known literature on the method F includes, for example, Bioorg. Med. Chem. , 12, 4089-4100 (2004); Med. Chem. , 43, 3736-3745 (2000); Angew. Chem. Int. Ed. , 50, 9452-9455 (2011).

Method G When the compound represented by the general formula (1) is the compound 1g, it can be produced, for example, by the method G.

Wherein Q ¹ , Q ² , Q ³ , L and R ⁵ are as defined above. ]

  The reaction can be carried out by reacting compound 2g with compound 3g in a solvent inert to the reaction (eg, 1,2-dichloroethane, etc.) in the presence of a base (eg, triethylamine, etc.) and a carbonylating reagent (eg, triphosgene, etc.). . Preferably, the reaction temperature is from -30C to the boiling point of the solvent, and the reaction time is from 5 minutes to 48 hours.

  Known methods for the G method include, for example, Med. Chem. , 39, 3820-3836 (1996).

  Next, a method for producing compound 6a will be described.

  Compound 6a is known or is produced from a known compound as a starting material according to a known method or a method similar thereto. Known documents include, for example, J.I. Med. Chem. , 39, 968-981 (1996); Eur. J. Med. Chem. , 75, 438-447 (2014). Hereinafter, H and I methods are described as examples of the production method when compound 6a is compound 6h, but the synthesis method of 6a is not limited thereto.

H method

[Wherein Q ¹ , R ³ and R ⁴ have the same meanings as described above. R ¹⁶ represents a cyano group, a benzyloxycarbonyl group, or a C _1-6 alkyloxycarbonyl group, such as a methoxycarbonyl group, an ethoxycarbonyl group, and a tert-butoxycarbonyl group. ]

(H-1) Conversion of Compound 1h to Compound 2h In a solvent inert to the reaction (for example, N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, etc.), a base (for example, sodium hydride, hydrogenation) In the presence of potassium, etc., halides (eg, iodomethane, 1,3-dibromopropane, 1,4-dibromobutane, 1,5-dibromopentane, bis (2-bromoethyl) ether, α, α′-dichloro- (e.g., o-xylene). Preferably, the reaction temperature is from -30C to 70C and the reaction time is from 30 minutes to 3 days. Depending on the combination of the substituents (Q ¹ , R ³ , R ⁴ and R ¹⁶ ), a crown ether (for example, 18-crown 5-ether or the like) may be added as a reaction accelerator.

Conversion of (H-2) converting compound 2h from Compound 2h to Compound 6h to Compound 6h how different depending on the type of ^{R 16.}

(H-2-1)
When R ¹⁶ is a cyano group, a methoxycarbonyl group, an ethoxycarbonyl group, or the like, the compound 2h containing the functional group is reacted in a solvent inert to the reaction (for example, methanol, ethanol, ethylene glycol, water, tetrahydrofuran, dioxane, or the like, or These mixed solvents are mentioned, but an organic solvent which can be mixed with water at an arbitrary ratio is preferable), a base (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) or an acid (sulfuric acid, hydrochloric acid, etc.) Can be implemented. Preferably, the reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 5 minutes to 3 days.

(H-2-2)
When R ¹⁶ is a benzyloxycarbonyl group, the compound 2h containing the functional group is subjected to a reduction catalyst (eg, palladium-carbon, palladium hydroxide, Raney nickel) in a solvent inert to the reaction (eg, methanol, ethanol, ethyl acetate, etc.). , Platinum-carbon, platinum oxide, etc.) in a hydrogen atmosphere. Preferably, the reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 24 hours.

(H-2-3)
When R ¹⁶ is a tert-butoxycarbonyl group, the compound 2h containing the functional group is reacted with an acid (eg, hydrogen chloride) in a solvent inert to the reaction (eg, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, dichloromethane, etc.). , Trifluoroacetic acid, etc.). Alternatively, treatment with an acid (such as trimethylsilyl trifluoromethanesulfonate) may be performed in the presence of a base (such as 2,6-lutidine). In any case, the reaction temperature is preferably from -15 ° C to room temperature, and the reaction time is from 30 minutes to 12 hours.

(H-2-4)
When R ¹⁶ is a cyano group, compound 6h can also be produced via compound 3h.
Conversion of compound 2h to compound 3h is carried out by reacting compound 2h with a reducing agent (eg, diisobutylaluminum hydride, etc.) in a solvent inert to the reaction (eg, toluene, n-hexane, tetrahydrofuran, etc.). it can. Suitably the reaction temperature is from -100 <0> C to room temperature and the reaction time is from 5 minutes to 40 hours.

  The conversion of the compound 3h into the compound 6h is performed by reacting the compound 3h in a solvent inert to the reaction (for example, tert-butyl alcohol, water, acetonitrile or the like, or a mixed solvent thereof) with 2-methyl-2-butene and phosphoric acid The reaction can be carried out by reacting with an oxidizing agent (for example, sodium chlorite or the like) in the presence of sodium dihydrogen. Suitably the reaction temperature is from 0 ° C. to 50 ° C. and the reaction time is from 5 minutes to 2 days.

  As a publicly known document on the H method, for example, J. H. Med. Chem. , 58, 7341-7348 (2015); Org. Chem. , 59, 6464-6469 (1994), Bioorg. Med. Chem. Lett. , 21, 1438-1441 (2011), Bioorg. Med. Chem. Lett. , 12, 2141-2144 (2002); Chem. Pharm. Bull. , 53, 965-973 (2005); Chem. Pharm. Bull. , 59, 1376-1385 (2011).

I method

[In the formula, Q ¹ , R ³ , R ⁴ and Y have the same meanings as described above. R ¹⁷ represents a protecting group for a carboxy group, and examples thereof include a 2- (trimethylsilyl) ethoxymethyl group. ]

(I-1) Conversion of Compound 1i to Compound 3i In a solvent inert to the reaction (for example, toluene and the like), a base (for example, lithium dicyclohexylamide) and a metal catalyst (for example, tris (dibenzylideneacetone)) ) Dipalladium (0)) and a ligand (eg, tri-tert-butylphosphonium tetrafluoroborate) in the presence of compound 2i. Preferably, the reaction temperature is from -50 ° C to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

(I-2) Conversion of Compound 3i to Compound 6h This can be carried out by reacting compound 3i with a fluoride reagent (eg, tetrabutylammonium fluoride) in a solvent inert to the reaction (eg, tetrahydrofuran). . Preferably, the reaction temperature is from -20C to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

  As the well-known literature on the method I, for example, J.I. Am. Chem. Soc. , 124, 12557-12565 (2002); Org. Lett. , 10, 1545-1552 (2008); Org. Chem. , 78, 8250-8266 (2013).

  Next, a method for producing compound 2a will be described.

  Compound 2a is a known compound or is produced from a known compound as a starting material according to a known method or a method similar thereto. Known compounds can be purchased from commercial suppliers or can be readily synthesized by methods described in the literature or by methods analogous thereto. Known documents include, for example, Bioorg. Med. Chem. Lett. , 19, 4359-4363 (2009); Chem. Eur. J. , 21, 18589-18593 (2015); Chem. Soc. Perkin. Trans. , 15, 2163-2165 (1997); Heterocycl. Chem. , 29, 1663-1665 (1992); Org. Chem. , 69, 3783-3793 (2004).

  Hereinafter, J and K methods are described as examples of the production method of compound 2a, but the synthesis method of 2a is not limited thereto.

Method J When compound 2a is compound 2j, it can be produced, for example, by method J.

[Wherein, R ¹⁴ and Y are as defined above. T represents an oxygen atom or ^{-NR 18} - shows the. R ¹⁸ represents a protecting group on the nitrogen atom, for example, a tert-butoxycarbonyl group (Boc group), a benzyloxycarbonyl group (Cbz group), or the like, but a protecting group different from R ¹⁴ . r represents an integer of 1 to 3. ]

  The reaction can be carried out by reacting compound 1j with compound 3j in a solvent inert to the reaction (eg, N, N-dimethylformamide, tetrahydrofuran, etc.) in the presence of a base (eg, sodium hydride, potassium hydride, etc.). Preferably, the reaction temperature is from -50 ° C to the boiling point of the solvent, and the reaction time is from 10 minutes to 48 hours. Depending on the structure of 1j, an additive (for example, tetrabutylammonium iodide or the like) may be added. Since this reaction proceeds stepwise, an intermediate in the middle of the reaction may be isolated in some cases. The obtained intermediate can be converted to compound 2j by treating under the same conditions as described above.

  Known literature on the J method includes, for example, WO2015 / 109130A1, WO2016 / 149581A1, Chem. Pharm. Bull. , 49, 1653-1657 (2001).

Method K Compound 2a can be produced, for example, by Method K.

[Wherein, Q ² , R ¹⁴ and R ¹⁵ are as defined above. R ¹⁸ represents an oxo group, a formyl group or a 2-oxoethyl group. ]

  In a solvent inert to the reaction (eg, tetrahydrofuran), a phosphonium salt reagent (eg, methyltriphenylphosphonium bromide, methyltriphenylphosphonium iodide, etc.) and a base (eg, potassium tert-butoxide, n-butyllithium, etc.) Can be carried out by reacting the compound 1k with a phosphonium ylide obtained by reacting In any case, the reaction temperature is preferably from −20 ° C. to the boiling point of the solvent, and the reaction time is from 10 minutes to 48 hours.

  Known literature on the K method includes, for example, Tetrahedron Lett. , 56, 4119-4123 (2015), Eur. J. Med. Chem. , 53, 408-415 (2012); Org. Chem. , 66, 9056-9062 (2001), WO2010 / 144647 A1, and the like.

  Next, a method for producing compound 3a will be described.

  Compound 3a is a known compound or is produced from a known compound as a starting material according to a known method or a method analogous thereto. Known compounds can be purchased from commercial suppliers or can be readily synthesized by methods described in the literature or by methods analogous thereto. Known documents include, for example, Synlett. , 4, 615-619 (2009); Med. Chem. , 40, 2430-2433 (1997); Chem. Lett. , 6, 42-46 (2015), WO2014 / 026328 A1, WO2011 / 146287 A1, WO2016 / 201052 A1, WO2007 / 21937 A2, J. Am. Med. Chem. , 52, 4370-4379 (2009); Org. Chem. , 41, 1328-1331 (1976), Adv. Synth. Catal. , 352, 288-292 (2010).

  Next, a method for producing compound 2b will be described.

Compound 2b is a known compound or is produced from a known compound as a starting material according to a known method or a method analogous thereto. Known compounds can be purchased from commercial suppliers or can be readily synthesized by methods described in the literature or by methods analogous thereto. Compound 2b can also be easily produced by deprotecting the protecting group (R ¹⁴ ) of compound 2a by a known method.

  Next, a method for producing compound 2c will be described.

  Compound 2c is a known compound or is produced from a known compound as a starting material according to a known method or a method similar thereto. Known compounds can be purchased from commercial suppliers or can be readily synthesized by methods described in the literature or by methods analogous thereto. Known documents include, for example, J.I. Med. Chem. , 60, 3314-3334 (2017), WO2004 / 033455 A2, WO2011 / 029046 A1, Bioorg. Med. Chem. Lett. , 21, 928-931 (2011); Med. Chem. , 60, 1971-1993 (2017), WO 2004/014893 A2, Bioorg. Med. Chem. Lett. , 26, 5580-5590 (2016), WO 2006/123792 A1, Bioorg. Med. Chem. Lett. , 20, 918-921 (2010).

  Next, a method for producing compound 4c will be described.

  Compound 4c is a known compound or is produced from a known compound as a starting material according to a known method or a method similar thereto. Known compounds can be purchased from commercial suppliers or can be readily synthesized by methods described in the literature or by methods analogous thereto. Known documents include, for example, Fluid Phase Equil. , 430, 93-100 (2016); Compt. Theor. Nano. , 4, 1-5 (2007); Chem. Sci. , 8, 3349-3355 (2017); Org. Chem. , 70, 4314-4317 (2005), Bioorg. Med. Chem. , 9, 2035-2044 (2001); Heterocyclic. Chem. , 29, 1357-1359 (1992); Am. Chem. Soc. , 122, 10810-10820 (2000), Syn. Commun. , 42, 658-666 (2012); Med. Chem. , 59, 1556-1564 (2016), Bioorg. Med. Chem. Lett. , 27, 4370-4376 (2017), Heterocycles, 43, 2701-2712 (1996), WO2014 / 073904 A1, WO2004 / 046133 A1, and the like.

  Next, a method for producing compound 2d will be described.

  Compound 2d is a known compound or is produced from a known compound as a starting material according to a known method or a method similar thereto. Known compounds can be purchased from commercial suppliers or can be readily synthesized by methods described in the literature or by methods analogous thereto. Known documents include, for example, J.I. Med. Chem. , 44, 94-104 (2001); Antibiot. , 54, 1080-1092 (2001), WO 03/051797 A2, Bioorg. Med. Chem. , 16, 1431-1443 (2008), WO2017 / 103824 A1, WO2011 / 29046 A1, WO2013 / 184747 A1, WO2012 / 167423 A1, Bioorg. Med. Chem. Lett. , 14, 3675-3678 (2004).

  Next, a method for producing compound 2e will be described.

  Compound 2e is a known compound or is produced from a known compound as a starting material according to a known method or a method similar thereto. Known compounds can be purchased from commercial suppliers or can be readily synthesized by methods described in the literature or by methods analogous thereto. Known documents include, for example, WO2012 / 162635 A1, WO2015 / 118342 A1, J. Med. Chem. , 35, 2582-2591 (1992); Org. Chem. , 61, 566-572 (1996); Med. Chem. , 46, 2057-2073 (2003), Adv. Synth. Catal. , 354, 2635-2640 (2012), Eur. J. Med. Chem. , 41, 809-824 (2006), Org. Biomol. Chem. , 1, 3977-3988 (2003); Med. Chem. , 60, 1417-1431 (2017), Eur. J. Org. Chem. , 3,476-486 (2007), Synlett, 4,631-634 (2005), WO2015 / 109130 A1, WO2012 / 101064 A1, and the like.

  Next, a method for producing compound 3e will be described.

  Compound 3e is a known compound or is produced from a known compound as a starting material according to a known method or a method analogous thereto. Known compounds can be purchased from commercial suppliers or can be readily synthesized by methods described in the literature or by methods analogous thereto. Known documents include, for example, Org. Lett. , 3, 3417-3419 (2001); Org. Lett. , 3, 2729-2732 (2001); Org. Lett. , 12, 5254-5257 (2010), US 2010/0063066 A1, Eur. J. Med. Chem. , 131, 1-13 (2017), WO2013 / 039988 A1, WO2015 / 058084 A1, J.I. Org. Chem. , 78, 3400-3404 (2013), WO2015 / 089337 A1, WO2015 / 074064 A2, J. Am. Org. Chem. , 72, 9815-9817 (2007) and the like.

  Next, a method for producing compound 2f will be described.

  Compound 2f is a known compound or is produced from a known compound as a starting material according to a known method or a method similar thereto. Known compounds can be purchased from commercial suppliers or can be readily synthesized by methods described in the literature or by methods analogous thereto. Known documents include, for example, WO2015 / 109130 A1, WO2011 / 026917 A1, Bioorg. Med. Chem. Lett. , 15, 809-812 (2005), US2003 / 0187002 A1, Bioorg. Med. Chem. Lett. , 24, 1983-1986 (2014), US Pat. No. 4,229,443 A, WO 2016/149581 A1, and the like.

  Next, a method for producing compound 4f will be described.

  Compound 4f is a known compound or is produced from a known compound as a starting material according to a known method or a method analogous thereto. Known compounds can be purchased from commercial suppliers or can be readily synthesized by methods described in the literature or by methods analogous thereto. Known documents include, for example, US 2010/0184766 A1, WO 2009/073300 A1, J. Pharm. Org. Chem. , 78, 5804-5809 (2013); Org. Chem. , 76, 2296-2300 (2011), US 2016/0095858 A1, WO 2009/114870 A2, WO 2016/037578 A1, Bioorg. Med. Chem. , 26, 1579-1587 (2018), WO2011 / 068560 A1, J. Am. Chem. Soc. , 2412-2419 (1955), Tetrahedron, 58, 10323-10328 (2002); Am. Chem. Soc. , 71, 367-368 (1949).

  Next, a method for producing compound 2g will be described.

  Compound 2g is a known compound or is produced from a known compound as a starting material according to a known method or a method similar thereto. Known compounds can be purchased from commercial suppliers or can be readily synthesized by methods described in the literature or by methods analogous thereto. Known documents include those described in the production method of compound 3e and, for example, Org. Lett. , 15, 3734-3737 (2013); Org. Lett. , 10, 1601-1604 (2008), Synthesis, 13, 2163-2170 (2009), ACS Med. Chem. Lett. , 3, 373-377 (2012); Heterocycl. Chem. , 33, 1367-1370 (1996).

  Next, a method for producing compound 3g will be described.

  Compound 3g is known or is produced from a known compound as a starting material according to a known method or a method similar thereto. Known compounds can be purchased from commercial suppliers or can be readily synthesized by methods described in the literature or by methods analogous thereto. 5a or 6e may be used as the compound 3g.

Method L When compound 3g is compound 31, it can be produced from compound 2c by method L.

Wherein Q ² , Q ³ , R ² and R ¹⁴ are as defined above. ]

(L-1) Conversion of Compound 2c to Compound 11 In a solvent inert to the reaction (for example, dichloromethane, 1,2-dichloroethane, methanol, etc.), a base catalyst (for example, triethylamine, N, N-diisopropyl) The reaction can be carried out by reacting a protective reagent (eg, di-tert-butyl dicarbonate, benzyl chloroformate, dibenzyl dicarbonate, etc.) in the presence of an ethylamine or an acid catalyst (eg, hydrochloric acid, sulfuric acid, etc.). Preferably, the reaction temperature is from -78 ° C to the boiling point of the solvent, and the reaction time is from 5 minutes to 4 days.

(L-2) Conversion of Compound 11 to Compound 21 Conversion of Compound 11 to Compound 21 can be carried out in the same manner as in Step A-3.

(L-3) Conversion of Compound 21 to Compound 31 Conversion of Compound 21 to Compound 31 can be carried out in the same manner as in Step A-2.

  Known literature on the L method includes, for example, Bioorg. Med. Chem. Lett. , 17, 2535-2539 (2007), WO2005 / 000811 A1, Bioorg. Med. Chem. Lett. , 17, 6779-6784 (2007), WO2005 / 75439 A1, US2007 / 0142349 A1, and the like.

Method M When compound 3g is compound 3m, it can be produced from compound 2f by method M.

Wherein Q ² , Q ³ , R ¹⁴ and n are as defined above. ]

(M-1) Conversion of Compound 2f to Compound 1m Conversion of Compound 2f to Compound 1m can be carried out in the same manner as in Step L-1.

(M-2) Conversion of Compound 1m to Compound 2m Conversion of Compound 1m to Compound 2m can be carried out in the same manner as in Step F-2.

(M-3) Conversion of Compound 2m to Compound 3m Conversion of Compound 2m to Compound 3m can be carried out in the same manner as in Step A-2.

  The histone acetyltransferase activity of EP300 or CREBBP can be measured using the histone acetyltransferase assay described in the following Test Examples. Alternatively, in the detection of histone acetyltransferase activity, for example, a method of detecting with a radioisotope (Lau OD, et al. J. Biol. Chem. 2000; 275: 21953-21959), is produced as a by-product during the histone acetyltransferase reaction. Method for detecting CoA-SH by fluorescence (Gao T, et al. Methods Mol Biol. 2013; 981: 229-38) and method for detecting by NADH (Bernsen CE, Denu JM. Methods. 2005; 36: 321-). 331) and the like can be used.

  Since the compound of the present invention or a pharmacologically acceptable salt thereof has an activity of inhibiting both EP300 and CREBBP's ahistone cetyltransferase activity, it is used for EP300 and / or CREBBP-dependent cancer. Is preferred. Examples of tumors in which the expression of EP300 and / or CREBBP is enhanced include prostate cancer, liver cancer, lung cancer, breast cancer, colon cancer, stomach cancer, blood cancer, pancreatic cancer, esophageal cancer, bladder cancer, Gastrointestinal stromal tumors, NUT midline carcinoma, or ovarian cancer are known.

  Whether the expression of EP300 and / or CREBBP is enhanced can be determined by examining EP300 and / or CREBBP in a patient's test tissue (eg, collected by blood sampling, biopsy, etc.) by Southern blot, Northern blot, Western blot, ELISA, DNA chip, FISH assay, tissue immunostaining, and other known gene analysis methods {e.g., PCR, LCR (Ligase chain reaction), SDA (Strand displacement and purification), NASBA (Nucleic acid-based artificial AMP). chinery primer-initiation amplification, LAMP method ( Analysis using oop-mediated isothernal amplification), etc.} and the like can be confirmed by using a pathological techniques such known methods.

  Whether a mutation exists in EP300 and / or CREBBP can be confirmed by examining the nucleotide sequence of genomic DNA.

  The compound of the present invention or a pharmacologically acceptable salt thereof may be used in combination with another antitumor agent. For example, alkylating agents, antimetabolites, antitumor antibiotics, antitumor plant components, BRMs (biological response regulators), hormones, vitamins, antitumor antibodies, molecular targeting drugs, and other antitumor agents Agents and the like.

  More specifically, examples of the alkylating agent include an alkylating agent such as nitrogen mustard, a nitrogen mustard N-oxide, chlorambutyl, an aziridine-based alkylating agent such as carbone and thiotepa, dibromomannitol, and dibromodarcy. Examples include epoxide-based alkylating agents such as toll, carmustine, lomustine, semustine, nimustine hydrochloride, nitrosourea-based alkylating agents such as streptozocin, chlorozotocin, and ranimustine, busulfan, improsulfan tosylate, and dacarbazine.

  As antimetabolites, for example, purine antimetabolites such as 6-mercaptopurine, 6-thioguanine and thioinosine; pyrimidine antimetabolites such as fluorouracil, tegafur, tegafur / uracil, carmofur, doxyfluridine, broxuridine, cytarabine and enocitabine And antifolates such as methotrexate and trimetrexate.

  Examples of the antitumor antibiotic include an anthracycline antibiotic antitumor agent such as mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4'-epidoxorubicin, epirubicin, and chromomycin A3. , Actinomycin D and the like.

  Examples of the antitumor plant component include vinca alkaloids such as vindesine, vincristine, and vinblastine, taxanes such as paclitaxel and docetaxel, and epipodophyllotoxins such as etoposide and teniposide.

  Examples of the BRM include tumor necrosis factor, indomethacin and the like.

  Examples of the hormone include hydrocortisone, dexamethasone, methylprednisolone, prednisolone, plasterone, betamethasone, triamcinolone, oxymetholone, nandrolone, metenolone, phosphfestrol, ethinyl estradiol, chlormadinone, medroxyprogesterone, and the like.

  Examples of the vitamin include vitamin C and vitamin A.

  Examples of antitumor antibodies and molecular targeted drugs include trastuzumab, rituximab, cetuximab, nimotuzumab, denosumab, bevacizumab, infliximab, imatinib mesylate, gefitinib, erlotinib, sunitinib, lapatinib, and sorafenib.

  Other antitumor agents include, for example, cisplatin, carboplatin, oxaliplatin, tamoxifen, camptothecin, ifosfamide, cyclophosphamide, melphalan, L-asparaginase, acecraton, schizophyllan, picibanil, procarbazine, pipobroman, neocarzinostatin, Hydroxyurea, ubenimex, krestin and the like.

  A preparation containing the compound of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is prepared using additives such as a carrier and an excipient used in usual preparations. Administration of the compound of the present invention includes oral administration in the form of tablets, pills, capsules, granules, powders, solutions, injections (eg, intravenous, intramuscular, etc.), suppositories, transdermals, Parenteral administration in the form of nasal preparations, inhalants and the like may be possible. The dose and frequency of administration of the compound of the present invention are appropriately determined depending on the individual case in consideration of symptoms, age, sex, and the like of the administration subject. The dose is generally 0.001 mg / kg to 100 mg / kg per adult for oral administration and 0.0001 mg / kg to 10 mg / kg per adult for intravenous administration. The frequency of administration is usually once to six times a day or once to seven times a day.

  Solid formulations for oral administration according to the present invention may be tablets, powders, granules and the like. Such formulations are prepared in a conventional manner by mixing one or more active substances with inert excipients, lubricants, disintegrants, solubilizing agents and the like. Excipients can be, for example, lactose, mannitol, glucose. The lubricant can be, for example, magnesium stearate. The disintegrant can be, for example, sodium carboxymethyl starch. Tablets or pills may be coated with sugar coating or a gastric or enteric coating, if necessary.

  Liquid preparations for oral administration can be pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like. Such formulations contain commonly used inert solvents (eg, purified water, ethanol), and further include solubilizing agents, wetting agents, suspending agents, sweetening agents, flavoring agents, flavoring agents, or preservatives. An agent may be contained.

  Injections for parenteral administration may be sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Aqueous solvents for injections can be, for example, distilled water or saline. Non-aqueous solvents for injections can be, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, or Polysorbate 80 (European name). Such formulations may also contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These preparations can be sterilized by, for example, filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation. In addition, a composition obtained by dissolving or suspending a sterile solid composition in sterile water or a solvent for injection before use can also be used as these preparations.

  Hereinafter, the present invention will be described in more detail by way of Examples and Test Examples, but the scope of the present invention is not limited thereto.

Elution in column chromatography in Reference Examples and Examples was performed under observation by thin layer chromatography (TLC). In the TLC observation, silica gel 60F ₂₅₄ or 60NH ₂ F ₂₅₄ S manufactured by Merck was used as a TLC plate, the solvent used as an elution solvent in column chromatography was used as a developing solvent, and a UV detector or a color detector was used as a detection method. Reagents were employed. Silica gel SK-85 manufactured by Merck or Chromatorex NH manufactured by Fuji Silysia Chemical Ltd. was used as the silica gel for the column. In addition to these, an automatic purification device of Yamazen, Shoko Science or Biotage was used.

The abbreviations used in Reference Examples and Examples have the following meanings.
Me = methyl, tBu = tert-butyl, Bn = benzyl, TBDMS = tert-butyldimethylsilyl, TBDPS = tert-butyldiphenylsilyl, SEM = 2- (trimethylsilyl) ethoxymethyl group, Cbz = benzyloxycarbonyl, Boc = tert -Butoxycarbonyl, Fmoc = 9-fluorenylmethyloxycarbonyl, Ms = methanesulfonyl, Ts = p-toluenesulfonyl, Ns = 2-nitrobenzenesulfonyl group, PyBrop = bromotripyrrolidinophosphonium hexafluorophosphate (CAS number: 132705-51-2), COMU = (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholinocarbenium hexafluorophosphate (CAS No. : 1075198-30-9), HATU = O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (CAS number: 148893- 10-) 1), EDCI = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (CAS No .: 25952-53-8), DBU = 1,8-diazabicyclo [5.4.0] -7-undecene (CAS number: 6672-22-2).

In the following examples, nuclear magnetic resonance ^{(hereinafter,} 1 H-NMR: 400MHz) spectrum, tetramethylsilane as a standard substance, described the chemical shift values in δ values (ppm). The splitting pattern is indicated by s for singlet, d for doublet, t for triplet, q for quadruple, m for multiplet, and br for broad. In mass spectrometry, any of the ESI method, the APCI method, or the ESI / APCI method was used as an ion source.

Reference example A-1
tert-butyl 4- (1,4-oxazepan-6-ylmethyl) -1H-indazole-1-carboxylate

(Step 1) To a suspension of tert-butyl 6-methylidene-1,4-oxazepan-4-carboxylate sodium hydride (purity> 55%, 11.4 g) in N, N-dimethylformamide (150 mL). Under ice-cooling, 3-chloro-2-chloromethyl-1-propene (12.7 mL, CAS number: 1871-57-4) was added, and the mixture was stirred at the same temperature for 10 minutes, and then added with 2- (tert-butoxycarbonyl). A solution of amino) -1-ethanol (19.3 g, CAS No .: 26690-80-2) in tetrahydrofuran (150 mL) was added dropwise over 1.5 hours, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was ice-cooled, water was added, and the mixture was extracted three times with diethyl ether. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (16.0 g) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.48-3.54 (2H, m), 3.69-3.76 (2H, m), 4.06-4.19 (4H, m), 4.95-5.06 (2H, m). MS (m / z): 114 (M + H-Boc) ⁺ .

(Step 2) Benzyl 6-methylidene-1,4-oxazepan-4-carboxylate Hydrogen chloride (2 mol / L, methanol solution, 100 mL) was added to the compound (5.00 g) obtained in the above step 1. And stirred at room temperature overnight. Hydrogen chloride (4 mol / L, 1,4-dioxane solution, 20 mL) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, N, N-diisopropylethylamine (10.2 mL) and benzyl chloroformate (3.67 mL) were added to a suspension of the obtained residue in dichloromethane (80 mL) under ice-cooling. The mixture was stirred at the same temperature for 30 minutes. 1 mol / L hydrochloric acid was added to the reaction solution, extracted with dichloromethane three times, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (5.70 g) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 3.56-3.62 (2H, m), 3.69-3.77 (2H, m), 4.16-4.21 (4H, m), 4.99-5.10 (2H, m), 5.15 (2H, m s), 7.29-7.38 (5H, m).

(Step 3) tert-butyl 4-({4-[(benzyloxy) carbonyl] -1,4-oxazepan-6-yl} methyl) -1H-indazole-1-carboxylate In the above step 2 under a nitrogen atmosphere. To the obtained compound (5.63 g), 9-borabicyclo [3.3.1] nonane (0.50 mol / L, tetrahydrofuran solution, 46 mL, CAS number: 280-64-8) was added, and the mixture was heated to reflux. After stirring for 3 hours, the mixture was allowed to cool to room temperature. N, N-dimethylformamide (92 mL), water (9.2 mL), potassium carbonate (3.93 g), tert-butyl 4-bromo-1H-indazole-1-carboxylate (5.64 g) were added to the reaction solution. , WO2007 / 21937 A2), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (0.775 g, CAS No. 95564-05-4), and added at 65 ° C. for 4 hours. Stirred. After allowing to cool to room temperature, water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate), and then purified by amino silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (7.53 g) as an oil. .
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.66 (9H, s), 2.27-2.33 (1H, m), 2.81-2.93 (2H, m), 3.27 (1H, dd, J = 14.2, 8.2 Hz), 3.44 (2H, dd, J = 12.4, 7.0 Hz), 3.61-3.71 (5H, m), 5.02 (2H, s), 7.14-7.33 (6H, m), 7.45 (1H, t, J = 7.9 Hz), 7.92 (1H, d, J = 8.5 Hz), 8.41 (1H, s) .MS (m / z): 366 (M + H-Boc) ⁺ .

(Step 4) tert-butyl 4- (1,4-oxazepan-6-ylmethyl) -1H-indazole-1-carboxylate This step was carried out by any of the following step 4A or step 4B.
(Step 4A)
To a solution of the compound (7.53 g) obtained in Step 3 above in ethanol (100 mL) was added 5% palladium-carbon (1.5 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure. The residue obtained was subjected to amino silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (5.02 g) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.73 (9H, s), 2.25-2.35 (1H, m), 2.67-2.72 (1H, m), 2.90-3.02 (5H, m), 3.53-3.60 (1H, m), 3.68-3.78 (2H, m), 3.86 (1H, dd, J = 12.4, 5.1 Hz), 7.11 (1H, d, J = 7.3 Hz), 7.44 (1H, dd, J = 8.5, 7.3 Hz) ), 8.03 (1H, d, J = 8.5 Hz), 8.22 (1H, s). MS (m / z): 332 (M + H) ⁺ .

(Step 4B)
To a solution of the compound (300 mg) obtained in the above step 3 (300 mg) in ethanol (10 mL) was added 10% palladium-carbon (100 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. After the reaction solution was filtered through celite, the solvent was distilled off under reduced pressure to obtain the title compound. This compound was used for the next reaction without further purification.

Reference Example A-2
4- (1,4-oxazepan-6-ylmethyl) -1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazole

(Step 1) Benzyl 6-[(1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazol-4-yl) methyl] -1,4-oxazepan-4-carboxylate Reference Example A-1 Compound obtained in step 2 (1.66 g), 9-borabicyclo [3.3.1] nonane (0.50 mol / L, tetrahydrofuran solution, 13.5 mL), potassium carbonate (1.10 g) , [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (0.250 g), 4-bromo-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazole (2 g, Synlett., 4,615-619 (2009)) to perform the same operation as in Step 3 of Reference Example A-1 to give the title compound. A (2.2 g) as an oil.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: -0.11 (9H, s), 0.79 (2H, t, J = 7.9 Hz), 2.29-2.40 (1H, m), 2.79-2.87 (2H, m), 3.22-3.32 (1H, m), 3.36-3.49 (2H, m), 3.55 (2H, t, J = 7.9 Hz), 3.70-3.85 (5H, m), 5.14 (2H, s), 5.80 (2H, s), 7.04-7.09 (1H, m), 7.33-7.48 (6H, m), 7.58-7.63 (1H, m), 8.23 (1H, s) .MS (m / z): 496 (M + H) ⁺ .

(Step 2) 4- (1,4-oxazepan-6-ylmethyl) -1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazole The compound obtained in the above step 1 (2.2 g) The same operation as in Step 4B of Reference Example A-1 was performed using 10% palladium-carbon (1 g) to give the title compound (1.62 g) as an oil.
¹ H-NMR (CDCl ₃ ) δ: -0.07 (9H, s), 0.86-0.91 (2H, m), 2.32-2.43 (1H, m), 2.73 (1H, dd, J = 13.3, 7.3 Hz), 2.89 (2H, d, J = 7.9 Hz), 2.93-2.99 (2H, m), 3.04 (1H, dd, J = 13.6, 5.1 Hz), 3.48 (1H, s), 3.52-3.63 (3H, m) , 3.71-3.77 (2H, m), 3.88 (1H, dd, J = 12.4, 5.1 Hz), 5.80 (2H, s), 7.05 (1H, d, J = 7.3 Hz), 7.40 (1H, dd, J) = 7.3, 8.5 Hz), 7.50 (1H, d, J = 8.5 Hz), 8.11-8.12 (1H, m) .MS (m / z): 362 (M + H) ⁺ .

Reference Example A-3
4- (piperidin-3-ylmethyl) -1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazole

(Step 1) tert-butyl 3-methylidenepiperidine-1-carboxylate potassium tert-butoxide (0.971 g), tetrahydrofuran (25 mL), methyltriphenylphosphonium iodide (3.50 g, CAS number: 2065) -66-9) was stirred at room temperature for 1 hour. Under ice-cooling, a solution of tert-butyl 3-oxopiperidine-1-carboxylate (1.50 g, CAS No. 98977-36-7) in tetrahydrofuran (15 mL) was added dropwise to the reaction solution, and the mixture was stirred overnight at room temperature. After adding a saturated aqueous solution of ammonium chloride to the reaction solution, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (0.994 g) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.59-1.65 (2H, m), 2.26 (2H, t, J = 6.3 Hz), 3.44 (2H, t, J = 5.7 Hz), 3.87 (2H, s), 4.75 (1H, s), 4.82 (1H, br s).

(Step 2) Benzyl 3-methylidenepiperidine-1-carboxylate The compound obtained in the above step 1 (0.990 g), hydrogen chloride (2 mol / L, methanol solution, 25 mL), N, N-diisopropyl The title compound (1.01 g) was obtained as an oil by performing the same operation as in Step 2 of Reference Example A-1 using ethylamine (2.19 mL) and benzyl chloroformate (0.785 mL). Was.
¹ H-NMR (CDCl ₃ ) δ: 1.65 (2H, br s), 2.28 (2H, t, J = 6.0 Hz), 3.51-3.54 (2H, m), 3.96 (2H, s), 4.77-4.83 ( 2H, m), 5.13 (2H, s), 7.29-7.37 (5H, m) .MS (m / z): 232 (M + H) ⁺ .

(Step 3) Benzyl 3-[(1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazol-4-yl) methyl] piperidine-1-carboxylate The compound obtained in the above step 2 (253 mg) ), 9-borabicyclo [3.3.1] nonane (0.50 mol / L, tetrahydrofuran solution, 2.2 mL), potassium carbonate (207 mg), [1,1′-bis (diphenylphosphino) ferrocene ] Palladium (II) dichloride dichloromethane complex (40.8 mg), 4-bromo-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazole (327 mg, see Reference Example A-2, Step 1). By performing the same operation as in Step 3 of Reference Example A-1 to give a mixture containing the title compound (253 mg) as an oil. .
MS (m / z): 480 (M + H) ⁺ .

(Step 4) 4- (piperidin-3-ylmethyl) -1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazole The compound obtained in the above Step 3 (245 mg), 10% palladium-carbon ( 100 mg) to give the title compound by performing the same operation as in Step 4B of Reference Example A-1. This compound was used for the next reaction without further purification.

Reference Example A-4
tert-butyl 4-{[1- (tert-butoxycarbonyl) -1,4-diazepan-6-yl] methyl} -1H-indazole-1-carboxylate

(Step 1) tert-butyl (2-{[2- (chloromethyl) prop-2-en-1-yl] [(2-nitrophenyl) sulfonyl] amino} ethyl) carbamate 3-chloro-2-chloromethyl To a solution of -1-propene (2.89 g) in N, N-dimethylformamide (70 mL) was added sodium hydride (purity> 55%, 1.55 g) under ice-cooling, and tert-butyl (2 A solution of-{[(2-nitrophenyl) sulfonyl] amino} ethyl) carbamate (6.14 g, Tetrahedron Letters, 50, 4050-4053 (2009)) in tetrahydrofuran (70 mL) was added dropwise over 30 minutes, followed by 60 minutes. Stirred at C for 3 hours. After returning to room temperature, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (3.44 g) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.41 (9H, s), 3.26-3.33 (2H, m), 3.42 (2H, t, J = 6.0 Hz), 3.96 (2H, s), 4.11 (2H, s) ), 4.76 (1H, br s), 5.27 (1H, s), 5.34 (1H, s), 7.65-7.75 (3H, m), 8.11 (1H, d, J = 7.9 Hz) .MS (m / z ): 334 (M + H-Boc) ⁺ .

(Step 2) tert-butyl 6-methylidene-4-[(2-nitrophenyl) sulfonyl] -1,4-diazepan-1-carboxylate The compound obtained in the above step 1 (3.08 g), N, Sodium hydride (purity> 55%, 403 mg) was added to a mixture of N-dimethylformamide (70 mL) and tetrabutylammonium iodide (262 mg, CAS No .: 311-28-4), and the mixture was added at room temperature for 3 hours. Stirred. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (2.75 g) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.44-1.45 (9H, m), 3.44-3.47 (2H, m), 3.57-3.64 (2H, m), 3.97 (2H, d, J = 19.3 Hz), 4.09 (2H, d, J = 17.5 Hz), 5.03-5.12 (2H, m), 7.64-7.74 (3H, m), 8.01-8.06 (1H, m) .MS (m / z): 298 (M + H -Boc) ⁺ .

(Step 3) tert-butyl 6-methylidene-1,4-diazepan-1-carboxylate To a solution of the compound (2.75 g) obtained in the above Step 2 in acetonitrile (35 mL) was added 4-bromobenzenethiol ( 1.44 g, CAS number: 106-53-6) and potassium carbonate (2.10 g) were added, and the mixture was stirred at room temperature for 6.5 hours. After water was added to the reaction solution, the reaction mixture was extracted with a mixed solvent of chloroform / methanol = 9/1. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to amino silica gel column chromatography (n-hexane / ethyl acetate) to give a mixture (1.35 g) containing the title compound. Obtained as an oil. This compound was used for the next reaction without further purification.
MS (m / z): 213 (M + H) ⁺ .

(Step 4) Benzyl tert-butyl 6-methylidene-1,4-diazepan-1,4-dicarboxylate The compound obtained in the above Step 3 (1.35 g), dichloromethane (30 mL), N, N- A solution of benzyl chloroformate (1.20 g) in dichloromethane (5.0 mL) was added to a mixture of diisopropylethylamine (1.66 mL) under ice-cooling, followed by stirring at the same temperature for 30 minutes. After a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, the reaction mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (1.57 g) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.41-1.49 (9H, m), 3.44-3.59 (4H, m), 3.89 (1H, s), 3.97-4.05 (3H, m), 4.94-5.11 (2H, m), 5.14 (2H, s), 7.31-7.38 (5H, m) .MS (m / z): 247 (M + H-Boc) ⁺ .

(Step 5) Benzyl tert-butyl 6-{[1- (tert-butoxycarbonyl) -1H-indazol-4-yl] methyl} -1,4-diazepan-1,4-dicarboxylate Obtained in Step 4 above. Compound (1.00 g), 9-borabicyclo [3.3.1] nonane (0.50 mol / L, tetrahydrofuran solution, 5.8 mL), potassium carbonate (0.261 g), [1, 1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (0.118 g) and tert-butyl 4-bromo-1H-indazole-1-carboxylate (431 mg) using Reference Example The same operation as in step 3 of A-1 was performed to obtain the title compound (0.717 g) as an oil.
MS (m / z): 565 (M + H) ⁺ .

(Step 6) tert-butyl 4-{[1- (tert-butoxycarbonyl) -1,4-diazepan-6-yl] methyl} -1H-indazole-1-carboxylate The compound obtained in the above step 5 ( A mixture of 717 mg), 10% palladium-carbon (400 mg), and methanol (20 mL) was stirred at room temperature for 2.5 hours under a hydrogen atmosphere. After removing insoluble matter by filtration through Celite, the solvent was distilled off under reduced pressure. A mixture of the obtained residue, methanol (20 mL), and 10% palladium-carbon (400 mg) was stirred under a hydrogen atmosphere at room temperature for 1 hour and at 50 ° C for 40 minutes. After returning the reaction solution to room temperature, it was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a mixture (468 mg) containing the title compound as an oil. This compound was used for the next reaction without further purification.
MS (m / z): 431 (M + H) ⁺ .

Reference Example A-5
tert-butyl 4- (azepan-3-ylmethyl) -1H-indazole-1-carboxylate

(Step 1) A suspension of tert-butyl 3-methylideneazepan-1-carboxylate methyltriphenylphosphonium bromide (7.54 g, CAS No .: 1779-49-3) in tetrahydrofuran (50 mL) was ice-cooled. Below, n-butyl lithium (2.6 mol / L, n-hexane solution, 7.96 mL) was added dropwise. After stirring at the same temperature for 1 hour, a solution of tert-butyl 3-oxoazepan-1-carboxylate (3.00 g, CAS No .: 870842-23-2) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred at room temperature overnight. An aqueous ammonium chloride solution was added to the reaction solution, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (0.766 g) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.45-1.47 (9H, m), 1.54-1.68 (4H, m), 2.17-2.23 (2H, m), 3.22-3.32 (2H, m), 3.98-4.06 ( 2H, m), 4.80-4.87 (2H, m).

(Step 2) Benzyl 3-methylideneazepan-1-carboxylate The compound obtained in the above step 1 (2.82 g), hydrogen chloride (4 mol / L, 1,4-dioxane solution, 45 mL), The title compound (2.42 g) was obtained by performing the same operation as in Step 2 of Reference Example A-1 using N, N-diisopropylethylamine (5.81 mL) and benzyl chloroformate (2.09 mL). Was obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.59-1.70 (4H, m), 2.19-2.23 (2H, m), 3.32-3.39 (2H, m), 4.09-4.13 (2H, m), 4.83-4.90 ( 2H, m), 5.14-5.16 (2H, m), 7.28-7.37 (5H, m).

(Step 3) tert-butyl 4-({1-[(benzyloxy) carbonyl] azepan-3-yl} methyl) -1H-indazole-1-carboxylate
Compound (0.510 g) obtained in the above step 2, 9-borabicyclo [3.3.1] nonane (0.50 mol / L, tetrahydrofuran solution, 4.2 mL), potassium carbonate (0.359 g) ), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (0.0708 g), tert-butyl 4-bromo-1H-indazole-1-carboxylate (0.515 g) )) To obtain the title compound (0.638 g) as an oily product by performing the same operation as in Step 3 of Reference Example A-1.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.22-1.27 (2H, m), 1.55-1.81 (13H, m), 2.09 (1H, br s), 2.85-2.99 (3H, br m) , 3.24 (1H, br s), 3.51-3.63 (2H, br m), 5.00 (2H, br s), 7.13-7.46 (7H, br m), 7.91 (1H, d, J = 7.9 Hz), 8.41 (1H, s). MS (m / z): 464 (M + H) ⁺ .

(Step 4) tert-butyl 4- (azepan-3-ylmethyl) -1H-indazole-1-carboxylate The compound (1.09 g) obtained in the above Step 3 and 10% palladium-carbon (500 mg) were obtained. The title compound (0.727 g) was obtained as an oil by performing the same operation as in Step 4B of Reference Example A-1.
¹ H-NMR (CDCl ₃ ) δ: 1.29-1.91 (16H, m), 1.97-2.07 (1H, m), 2.55 (1H, dd, J = 13.6, 8.2 Hz), 2.77-2.98 (5H, m) , 7.09 (1H, d, J = 7.3 Hz), 7.44 (1H, dd, J = 7.3, 8.5 Hz), 8.02 (1H, d, J = 8.5 Hz), 8.21 (1H, s) .MS (m / z): 330 (M + H) ⁺ .

Reference Example A-6
tert-butyl 4-{[(2R) -pyrrolidin-2-ylmethyl] amino} -1H-indazole-1-carboxylate

(Step 1) Sodium nitrite (1.13) was added to a solution of 4-nitro-1H-indazole 2-methyl-3-nitroaniline (2.27 g, CAS number: 603-83-8) in acetic acid (60.0 mL). g) in water (5.00 mL) was added and stirred at room temperature for 2 hours. Ice water was added to the reaction solution, and the precipitated solid was collected by filtration and dried to obtain the title compound (1.91 g) as a solid.
MS (m / z): 164 (M + H) ⁺ .

(Step 2) tert-butyl 4-nitro-1H-indazole-1-carboxylate Triethylamine (10.2 mL) was added to a solution of the compound (10.0 g) obtained in the above step 1 in dichloromethane (200 mL). Di-tert-butyl carbonate (14.7 g, CAS number: 24424-99-5) was added, and the mixture was stirred at room temperature for 6 hours. Partitioned between water and dichloromethane, the organic layer was dried over anhydrous sodium sulfate. The residue obtained by concentration was purified by silica gel column chromatography (n-hexane / ethyl acetate) and then recrystallized (n-hexane / diethyl ether) to obtain the title compound (15.1 g) as a solid. .
¹ H-NMR (CDCl ₃ ) δ: 1.75 (9H, s), 7.66-7.71 (1H, m), 8.27 (1H, d, J = 7.9 Hz), 8.64 (1H, d, J = 8.5 Hz), 8.83 (1H, s).

(Step 3) tert-butyl 4-amino-1H-indazole-1-carboxylate Zinc powder (15.0 g) obtained in the above step 2 was added to a suspension of methanol (250 mL) under ice-cooling. After adding 26.1 g) and stirring at the same temperature for 10 minutes, a saturated aqueous ammonium chloride solution (250 mL) was added, and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 4 hours. After filtering the reaction solution through celite, the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (12.4 g) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.72 (9H, s), 4.18 (2H, br s), 6.52 (1H, d, J = 7.3 Hz), 7.27-7.33 (1H, m), 7.54 (1H, d, J = 8.5 Hz), 8.12 (1H, s).

(Step 4) tert-butyl 4-({1-[(benzyloxy) carbonyl] -D-prolyl} amino) -1H-indazole-1-carboxylate 1-[(benzyloxy) carbonyl] -D-proline ( To a solution of 3.00 g, CAS number: 6404-31-5) in N, N-dimethylformamide (60 mL), COMU (5.67 g) and N, N-diisopropylethylamine (2.73 mL) were added. After stirring at room temperature for 15 minutes, the compound (2.81 g) obtained in the above step 3 was added, and the mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform / ethyl acetate, then n-hexane / ethyl acetate) to give the title compound (4.06 g) as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 1.65 (9H, s), 1.85-2.08 (3H, m), 2.23-2.39 (1H, m), 3.44-3.59 (2H, m), 4.52-4.61 ( 1H, m), 4.97-5.14 (2H, m), 7.06-7.39 (5H, m), 7.55 (1H, td, J = 8.2, 2.8 Hz), 7.81 (2H, dd, J = 14.8, 8.2 Hz) , 8.52 (1H, d, J = 32.0 Hz), 10.36 (1H, s). MS (m / z): 465 (M + H) ⁺ .

(Step 5) tert-butyl 4-[({(2R) -1-[(benzyloxy) carbonyl] pyrrolidin-2-yl} methyl) amino] -1H-indazole-1-carboxylate Obtained in the above Step 4. Borane-tetrahydrofuran complex (1 mol / L, tetrahydrofuran solution, 9.5 mL, CAS number: 14044-65-6) was added to a solution of the compound (1.10 g) in tetrahydrofuran (30 mL), and the mixture was stirred at room temperature for 1 hour. And stirred at 60 ° C. for 2 hours. After methanol and water were added to the reaction solution, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to obtain a mixture (0.455 g) containing the title compound as a solid. This compound was used for the next reaction without further purification.
¹ H-NMR (CDCl ₃ ) δ: 1.71 (9H, s), 1.76-2.18 (4H, m), 3.28-3.33 (2H, m), 3.44-3.56 (2H, m), 4.36-4.43 (1H, m), 5.12-5.20 (2H, m), 6.22-6.31 (2H, m), 7.30-7.43 (7H, m), 8.18 (1H, s).

(Step 6) tert-butyl 4-{[(2R) -pyrrolidin-2-ylmethyl] amino} -1H-indazole-1-carboxylate The compound obtained in the above step 5 (455 mg), 10% palladium-carbon (0.15 g) and a mixture of ethanol (15 mL) were stirred at room temperature for 1.5 hours under a hydrogen atmosphere. 1 mol / L hydrochloric acid (1.5 mL) was added to the reaction solution, and the mixture was stirred for 4 hours. After the reaction solution was filtered through celite, the filtrate was basified using a saturated aqueous solution of sodium hydrogen carbonate, and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (286 mg) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.52-2.34 (6H, m), 1.71 (9H, s), 2.99-3.20 (3H, m), 3.32-3.39 (1H, m), 3.52-3.60 (1H, m), 6.31-6.38 (1H, m), 7.27-7.44 (2H, m), 8.21 (1H, s).

Reference Example A-7
3- (1H-indazol-4-ylmethyl) piperidin-4-one

(Step 1) 2-benzyl-4-bromo-2H-indazole A suspension of sodium hydride (purity> 55%, 1.33 g) in N, N-dimethylformamide (50 mL) was added under ice-cooling for 4 hours. -Bromo-1H-indazole (5 g, CAS number: 186407-74-9) was added. After stirring at the same temperature for 15 minutes, benzyl bromide (3.3 mL) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction solution was diluted with ethyl acetate, it was washed three times with a saturated saline solution, and the organic layer was dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (1.4 g) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 5.60 (2H, s), 7.14 (1H, dd, J = 8.5, 7.3 Hz), 7.23 (1H, d, J = 7.3 Hz), 7.27-7.41 (5H, m ), 7.66 (1H, d, J = 8.5 Hz), 7.91 (1H, s).

(Step 2) tert-butyl 4,4-dimethoxy-3-methylidenepiperidine-1-carboxylate potassium tert-butoxide (1.34 g), tetrahydrofuran (30 mL), methyltriphenylphosphonium bromide (4.22 g) ) Was stirred for 30 minutes while heating under reflux. After returning to room temperature, tert-butyl 4,4-dimethoxy-3-oxopiperidine-1-carboxylate (2.00 g, Advanced Synthesis and Catalysis, 352, 2751-2756 (2010)) tetrahydrofuran (2010) was added to the reaction mixture. 20 mL) solution was added dropwise and left at room temperature for 18 hours. After the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (1.88 g) as an oil. .
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.81 (2H, t, J = 5.7 Hz), 3.16 (6H, s), 3.55 (2H, t, J = 5.7 Hz), 3.87 ( 2H, s), 5.12-5.25 (1H, m), 5.33 (1H, d, J = 1.8 Hz).

(Step 3) tert-butyl 3-[(2-benzyl-2H-indazol-4-yl) methyl] -4,4-dimethoxypiperidine-1-carboxylate The compound obtained in the above step 1 (0.600 g) ), The compound obtained in the above step 2 (0.878 g), 9-borabicyclo [3.3.1] nonane (0.50 mol / L, tetrahydrofuran solution, 6.69 mL), potassium carbonate (0. 464 g) and [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (0.0871 g), and the same operation as in Step 3 of Reference Example A-1 was performed. Gave the title compound (0.526 g) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.26 (9H, s), 1.60-1.72 (1H, m), 1.78-1.85 (1H, m), 2.20-2.28 (1H, m), 2.58 -2.68 (1H, m), 2.81-3.00 (3H, m), 3.16 (3H, s), 3.20 (3H, s), 3.63-3.71 (1H, m), 3.82-3.90 (1H, m), 5.62 (2H, s), 6.84-6.88 (1H, m), 7.11-7.17 (1H, m), 7.25-7.36 (5H, m), 7.40-7.44 (1H, m), 8.32 (1H, s).

(Step 4) tert-butyl 3- (1H-indazol-4-ylmethyl) -4,4-dimethoxypiperidine-1-carboxylate 20% palladium hydroxide (0.500 g, CAS number: 12135-22-7) , Ammonium formate (0.747 g, CAS number: 540-69-2), a compound (0.524 g) obtained in the above step 3, and a mixed solvent (30 mL) of methanol / water = 2/1 Was stirred for 2 hours while heating under reflux. After the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed sequentially with water and saturated saline, and the organic layer was dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the title compound (0.406 g) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.30 (9H, s), 1.65-1.77 (1H, m), 1.78-1.89 (1H, m), 2.17-2.28 (1H, m), 2.65 -2.79 (1H, m), 2.82-3.14 (3H, m), 3.19 (3H, s), 3.25 (3H, s), 3.59-3.67 (1H, m), 3.83-3.93 (1H, m), 6.92 -6.98 (1H, m), 7.18-7.39 (2H, m), 8.04 (1H, s), 12.66-12.86 (1H, m).

(Step 5) tert-butyl 3- (1H-indazol-4-ylmethyl) -4-oxopiperidine-1-carboxylate The compound obtained in the above step 4 (0.402 g), tert-butyl alcohol / water = Pyridinium p-toluenesulfonate (0.412 g, CAS number: 24057-28-1) was added to a mixture of 5/1 mixed solvent (12.0 mL) at room temperature, and the mixture was stirred at the same temperature for 4 days. . The reaction solution was diluted with ethyl acetate, washed with water and saturated saline in this order, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.289 g) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.28 (9H, s), 2.35-2.43 (1H, m), 2.49-2.57 (1H, m), 2.71-2.81 (1H, m), 2.84 -2.95 (1H, m), 3.01-3.09 (1H, m), 3.27-3.43 (2H, m), 3.77-3.85 (1H, m), 3.90-4.00 (1H, m), 6.88-6.92 (1H, m m), 7.21-7.27 (1H, m), 7.35-7.40 (1H, m), 8.07 (1H, s), 12.79 (1H, br s) .MS (m / z): 330 (M + H) ⁺ .

(Step 6) 3- (1H-indazol-4-ylmethyl) piperidin-4-one To a solution of the compound (269 mg) obtained in the above step 5 in dichloromethane (6.00 mL) was added trifluoroacetic acid under ice-cooling. (4.00 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a mixture containing the title compound as an oil. This compound was used for the next reaction without further purification.

Reference Example B-1
4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-carboxylic acid

Under a nitrogen atmosphere, a suspension of sodium hydride (purity> 55%, 7.51 g) in N, N-dimethylformamide (150 mL) was cooled on ice, and 4-methoxyphenylacetonitrile (10.5 mL, CAS No. : 104-47-2) and a solution of bis (2-bromoethyl) ether (20.2 g, CAS number: 5414-19-7) in N, N-dimethylformamide (50 mL) were added dropwise over 30 minutes. The mixture was stirred for 1 hour under ice cooling and for 4 hours at room temperature. After cooling again with ice, water was added to the reaction solution, and the mixture was extracted three times with diethyl ether. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave crude 4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-carbonitrile (22.4 g) as an oil. Ethylene glycol (100 mL) and potassium hydroxide (13.01 g) were added to the crude product (22.4 g), and the mixture was stirred under reflux with heating for 8 hours. After allowing to cool to room temperature, water was added to the reaction solution, which was washed twice with diethyl ether. The aqueous layer was acidified by adding 1 mol / L hydrochloric acid, and stirred at room temperature overnight. The precipitated solid was collected by filtration and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (13.6 g) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.93-2.00 (2H, m), 2.47-2.53 (2H, m), 3.58-3.64 (2H, m), 3.80 (3H, s), 3.89-3.94 (2H, m), 6.89 (2H, d, J = 8.5 Hz), 7.33 (2H, d, J = 8.5 Hz).

Reference Example B-2
2- (4-methoxyphenyl) -2,3-dihydro-1H-indene-2-carboxylic acid

(Step 1) Benzyl (4-methoxyphenyl) acetate (4-methoxyphenyl) acetic acid (3.00 g, CAS No .: 104-01-8), N, N-dimethylformamide (40 mL), potassium carbonate (3 .24 g) and benzyl bromide (2.36 mL) were stirred at room temperature overnight. The reaction mixture to which water was added was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (4.44 g) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 3.61 (2H, s), 3.80 (3H, s), 5.12 (2H, s), 6.86 (2H, d, J = 8.5 Hz), 7.20 (2H, d, J = 8.5 Hz), 7.29-7.38 (5H, m).

(Step 2) Benzyl 2- (4-methoxyphenyl) -2,3-dihydro-1H-indene-2-carboxylate N, N-dimethylformamide of sodium hydride (purity> 55%, 0.375 g) ( 15 mL) of the compound (1.00 g) obtained in the above step 1 and 15-crown 5-ether (0.0859 g, CAS No .: 33100-27-5) in ice suspension under cooling with ice. , N-dimethylformamide (15 mL) solution was added and stirred at room temperature for 1 hour. α, α′-Dichloro-o-xylene (0.717 g, CAS number: 612-12-4) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture to which a saturated aqueous ammonium chloride solution was added was extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (0.541 g) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 3.31 (2H, d, J = 15.1 Hz), 3.79 (3H, s), 3.97 (2H, d, J = 15.1 Hz), 5.02 (2H, s), 6.84 ( 2H, d, J = 8.5 Hz), 7.04-7.07 (2H, m), 7.14-7.18 (2H, m), 7.22-7.26 (5H, m), 7.32 (2H, d, J = 8.5 Hz).

(Step 3) 2- (4-methoxyphenyl) -2,3-dihydro-1H-indene-2-carboxylic acid The compound (535 mg) obtained in the above Step 1 and 10% palladium-carbon (250 mg) were added. The title compound (358 mg) was obtained as a solid by performing the same operation as in Step 4B of Reference Example A-1.
¹ H-NMR (CDCl ₃ ) δ: 3.26 (2H, d, J = 15.7 Hz), 3.77 (3H, s), 3.91 (2H, d, J = 15.7 Hz), 6.84 (2H, d, J = 8.5 Hz), 7.13-7.16 (2H, m), 7.19-7.22 (2H, m), 7.32 (2H, d, J = 8.5 Hz).

Reference Example B-3
1- {4- [2- (4-methoxybenzyl) -2H-tetrazol-5-yl] phenyl} cyclohexanecarboxylic acid

(Step 1) 1- (4-Bromophenyl) cyclohexanecarboxylic acid 4-bromobenzyl cyanide (25.3 g, CAS number: 16532-79-9), 1,5-dibromopentane (19.0 mL, CAS No .: 111-24-0), sodium hydride (purity> 55%, 12.2 g), and potassium hydroxide (21.6 g), by performing the same operation as in Reference Example B-1. The title compound (33.1 g) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.22-1.34 (1H, m), 1.47-1.75 (7H, m), 2.40-2.44 (2H, m), 7.32 (2H, d, J = 8.5 Hz), 7.46 (2H, d, J = 8.5 Hz).

(Step 2) Benzyl 1- (4-bromophenyl) cyclohexanecarboxylate Using the compound (5.00 g) obtained in Step 1 above, potassium carbonate (3.68 g), and benzyl bromide (3.15 mL). The title compound (5.31 g) was obtained as a solid by performing the same operation as in Step 1 of Reference Example B-2.
¹ H-NMR (CDCl ₃ ) δ: 1.21-1.31 (1H, m), 1.41-1.51 (2H, m), 1.57-1.74 (5H, m), 2.43-2.50 (2H, m), 5.07 (2H, s), 7.16-7.31 (7H, m), 7.41 (2H, d, J = 9.1 Hz).

(Step 3) Benzyl 1- (4-cyanophenyl) cyclohexanecarboxylate The compound obtained in the above step 2 (1.50 g), zinc cyanide (333 mg, CAS number: 557-21-1), tetrakis ( A mixture of triphenylphosphine) palladium (0) (189 mg, CAS number: 14221-01-3) and N, N-dimethylformamide (15 mL) was stirred at 80 ° C overnight. The reaction mixture to which water and a saturated aqueous sodium hydrogen carbonate solution were added was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (1.15 g) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.23-1.31 (1H, m), 1.44-1.55 (2H, m), 1.61-1.76 (5H, m), 2.46-2.50 (2H, m), 5.09 (2H, s), 7.14-7.19 (2H, m), 7.29-7.30 (3H, m), 7.47 (2H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.5 Hz).

(Step 4) Benzyl 1- [4- (2H-tetrazol-5-yl) phenyl] cyclohexanecarboxylate The compound (1.01 g) obtained in the above Step 3, tetrabutylammonium fluoride trihydrate (2 .49 g, CAS number: 87749-50-6), toluene (11 mL), N, N-dimethylformamide (1.1 mL), trimethylsilyl azide (3.07 mL, CAS number: 4648-54-8) Was stirred at 120 ° C. for 2 hours using a microwave heating synthesizer. The reaction mixture to which a saturated aqueous sodium hydrogen carbonate solution was added was extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained by filtration and concentration under reduced pressure was subjected to high performance liquid chromatography (NOMURA Developersil Combi, acetonitrile / water / 0.1% formic acid). After evaporating the solvent under reduced pressure, the precipitated solid was collected by filtration and dried to give the title compound (0.995 g) as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 1.23-1.47 (3H, m), 1.53-1.67 (3H, m), 1.74-1.82 (2H, m), 2.37-2.44 (2H, m), 5.12 ( 2H, s), 7.21-7.34 (5H, m), 7.59 (2H, d, J = 8.5 Hz), 8.00 (2H, d, J = 8.5 Hz) .MS (m / z): 363 (M + H ) ⁺ .

(Step 5) Benzyl 1- {4- [2- (4-methoxybenzyl) -2H-tetrazol-5-yl] phenyl} cyclohexanecarboxylate The compound obtained in the above Step 4 (995 mg), N, N- A mixture of dimethylformamide (10 mL), potassium carbonate (570 mg), and 4-methoxybenzyl chloride (0.449 mL, CAS number: 824-94-2) was stirred at room temperature overnight. Potassium carbonate (288 mg) and 4-methoxybenzyl chloride (0.224 mL) were added, and the mixture was stirred at 70 ° C for 5 hours. After allowing to cool to room temperature, the reaction mixture to which water was added was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (1.13 g) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.24-1.33 (1H, m), 1.43-1.54 (2H, m), 1.57-1.71 (3H, m), 1.74-1.82 (2H, m), 2.48-2.54 ( 2H, m), 3.79 (3H, s), 5.08 (2H, s), 5.73 (2H, s), 6.89 (2H, d, J = 8.5 Hz), 7.16-7.19 (2H, m), 7.25-7.30 (3H, m), 7.38 (2H, d, J = 8.5 Hz), 7.48 (2H, d, J = 8.5 Hz), 8.05 (2H, d, J = 8.5 Hz).

(Step 6) 1- {4- [2- (4-methoxybenzyl) -2H-tetrazol-5-yl] phenyl} cyclohexanecarboxylic acid The compound (1.13 g) obtained in the above Step 5, tetrahydrofuran (14 mL), methanol (7 mL), and a 1 mol / L aqueous sodium hydroxide solution (7 mL) were stirred at 60 ° C. for 10 hours, and then allowed to stand at room temperature overnight. The mixture was further stirred at 60 ° C. for 7 hours, and left at room temperature overnight. After evaporating the organic solvent under reduced pressure, the residue to which water was added was washed twice with diethyl ether. The aqueous layer made acidic by adding 1 mol / L hydrochloric acid was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.893 g) as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 1.21-1.31 (1H, m), 1.39-1.50 (2H, m), 1.57-1.71 (5H, m), 2.32-2.38 (2H, m), 3.74 ( 3H, s), 5.91 (2H, s), 6.96 (2H, d, J = 8.5 Hz), 7.38 (2H, d, J = 8.5 Hz), 7.56 (2H, d, J = 8.5 Hz), 8.01 ( 2H, d, J = 8.5 Hz), 12.49 (1H, s).

Reference Example B-4
1- [4- (benzyloxy) phenyl] cyclohexanecarboxylic acid

(Step 1) 2- (Trimethylsilyl) ethyl 1- [4- (benzyloxy) phenyl] cyclohexanecarboxylate To a solution of dicyclohexylamine (0.984 mL, CAS number: 101-83-7) in toluene (15 mL) was added: n-Butyllithium (1.6 mol / L, n-hexane solution, 3.09 mL) was added, and the mixture was stirred at room temperature for 5 minutes. A solution of 2- (trimethylsilyl) ethyl cyclohexanecarboxylate (0.955 g, WO2008 / 134690 A1) in toluene (5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. 1-Benzyloxy-4-bromobenzene (1.00 g, CAS number: 6793-92-6) and tris (dibenzylideneacetone) dipalladium (0) (0.104 g, CAS number: 51364) were added to the reaction solution. 51-3) and tri-tert-butylphosphonium tetrafluoroborate (0.0662 g, CAS No .: 131274-22-1) were added, and the mixture was stirred at room temperature overnight. 1 mol / L hydrochloric acid and ethyl acetate were added to the reaction solution, the insolubles were removed by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate), and then to amino silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (1. 00 g) was obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: -0.02 (9H, s), 0.89-0.93 (2H, m), 1.21-1.30 (1H, m), 1.42-1.52 (2H, m), 1.61-1.72 (5H , m), 2.44-2.48 (2H, m), 4.10-4.14 (2H, m), 5.04 (2H, s), 6.92 (2H, d, J = 8.5 Hz), 7.30-7.44 (7H, m).

(Step 2) 1- [4- (benzyloxy) phenyl] cyclohexanecarboxylic acid Compound (511 mg) obtained in the above step 1, tetrahydrofuran (10 mL), tetrabutylammonium fluoride (1 mol / L, tetrahydrofuran solution) , 1.9 mL) was stirred at room temperature for 16 hours and at 70 ° C for 4 hours. After returning to room temperature, the reaction mixture acidified by adding 1 mol / L hydrochloric acid was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was dissolved in water and methanol, and the organic solvent was distilled off under reduced pressure. The resulting solid was collected by filtration and dried to obtain the title compound (301 mg) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.23-1.33 (2H, m), 1.48-1.76 (7H, m), 2.45 (2H, d, J = 12.1 Hz), 5.05 (2H, s), 6.95 (2H , d, J = 8.5 Hz), 7.31-7.44 (7H, m).

Reference Example B-5
1- [4- (benzyloxy) -3-methoxyphenyl] cyclopentanecarboxylic acid

(Step 1) [4- (benzyloxy) -3-methoxyphenyl] acetonitrile (4-hydroxy-3-methoxyphenyl) acetonitrile (3.1 g, CAS number: 4468-59-1), acetone (50 mL) A mixture of benzyl bromide (2.4 mL) and cesium carbonate (6.5 g) was stirred for 2 hours while heating under reflux. After the solvent was distilled off under reduced pressure, the residue to which water was added was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (4.5 g) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 3.68 (2H, s), 3.90 (3H, s), 5.16 (2H, s), 6.76-6.81 (1H, m), 6.83-6.88 (2H, m), 7.26 -7.47 (5H, m).

(Step 2) 1- [4- (benzyloxy) -3-methoxyphenyl] cyclopentanecarbonitrile The compound obtained in the above step 1 (4.5 g), N, N-dimethylformamide (45 mL), 1 Sodium hydride (purity> 55%, 1.9 g) was added to a mixture of 2,4-dibromobutane (2.5 mL, CAS number: 110-52-1) at 0 ° C, and the mixture was heated at the same temperature for 15 minutes. Stirred at room temperature overnight. After adding a saturated aqueous solution of ammonium chloride and water to the reaction mixture, the reaction mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (4.68 g) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.84-2.10 (6H, m), 2.40-2.51 (2H, m), 3.92 (3H, s), 5.16 (2H, s), 6.85 (1H, d, J = 8.5 Hz), 6.90 (1H, dd, J = 8.5, 2.4 Hz), 6.98 (1H, d, J = 2.4 Hz), 7.28-7.45 (5H, m).

(Step 3) 1- [4- (benzyloxy) -3-methoxyphenyl] cyclopentanecarboxylic acid The compound obtained in the above step 2 (4.68 g), ethylene glycol (40 mL), water (15 mL) , Potassium hydroxide (25.6 g) was stirred at 175 ° C. for 64 hours. After returning to room temperature, the reaction solution was diluted with water and washed with diethyl ether. The aqueous layer was acidified with 12 mol / L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with 1 mol / L hydrochloric acid and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was recrystallized from diethyl ether (50 mL) to give the title compound (2.35 g) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.68-1.95 (6H, m), 2.57-2.67 (2H, m), 3.88 (3H, s), 5.13 (2H, s), 6.81 (1H, d, J = 8.5 Hz), 6.87 (1H, dd, J = 8.5, 2.4 Hz), 6.93 (1H, d, J = 2.4 Hz), 7.27-7.45 (5H, m).

Reference Example B-6
1- {5- [1-benzyl-5- (methoxycarbonyl) -4-oxo-1,4-dihydropyridin-3-yl] thiophen-2-yl} cyclohexanecarboxylic acid

(Step 1) 1- (thiophen-2-yl) cyclohexanecarbonitrile thiophen-2-acetonitrile (4.31 mL, CAS number: 20893-30-5), 1,5-dibromopentane (6.0 mL), The title compound (6.89 g) was obtained as an oil by performing the same operation as in Step 2 of Reference Example B-5 using sodium hydride (purity> 55%, 3.90 g).
¹ H-NMR (CDCl ₃ ) δ: 1.22-1.34 (1H, m), 1.74-1.90 (7H, m), 2.28-2.36 (2H, m), 6.98 (1H, dd, J = 5.4, 3.6 Hz) , 7.13 (1H, dd, J = 3.6, 1.2 Hz), 7.25-7.27 (1H, m).

(Step 2) 1- (thiophen-2-yl) cyclohexanecarboxylic acid The compound (6.89 g) obtained in the above step 1 and potassium hydroxide (6.12 g) were used to prepare Reference Example B-5. By performing the same operation as in Step 3, the title compound (7.45 g) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.30-1.37 (1H, m), 1.48-1.69 (5H, m), 1.84-1.91 (2H, m), 2.42-2.49 (2H, m), 6.96-7.01 ( 2H, m), 7.22 (1H, d, J = 5.4 Hz).

(Step 3) tert-butyl 1- (thiophen-2-yl) cyclohexanecarboxylate Thionyl chloride (5.2 mL) was added to a suspension of the compound (7.45 g) obtained in Step 2 above in dichloromethane (175 mL). ) And N, N-dimethylformamide (0.100 mL) were added, and the mixture was stirred at 40 ° C for 3 hours and concentrated under reduced pressure. The operation of adding toluene to the residue and concentrating under reduced pressure was performed twice to obtain a crude acid chloride. To a solution of the crude acid chloride in tetrahydrofuran (175 mL) was added dropwise potassium tert-butoxide (1.0 mol / L, tetrahydrofuran solution, 42 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, a 10% aqueous citric acid solution was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / chloroform) to give the title compound (9.20 g) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.27-1.34 (1H, m), 1.40-1.53 (11H, m), 1.56-1.78 (5H, m), 2.41-2.48 (2H, m), 6.93-6.95 ( 2H, m), 7.16-7.18 (1H, m).

(Step 4) tert-butyl 1- (5-bromothiophen-2-yl) cyclohexanecarboxylate To a solution of the compound (2.67 g) obtained in Step 3 above in tetrahydrofuran (40 mL) was added N-bromosuccinimide ( 1.98 g, CAS number: 128-08-5) was added over 20 minutes, and the mixture was stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / chloroform) to obtain the title compound (3.35 g) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.25-1.34 (1H, m), 1.42-1.52 (11H, m), 1.55-1.73 (5H, m), 2.33-2.41 (2H, m), 6.67 (1H, d, J = 3.6 Hz), 6.87 (1H, d, J = 3.6 Hz).

(Step 5) 4-hydroxy-5-iodopyridine-3-carboxylic acid A mixture of 4-hydroxy-5-iodopyridine-3-carbonitrile (15.3 g, WO2009 / 76602 A1) and concentrated hydrochloric acid (100 mL). Was stirred at room temperature for 18 hours and heated to reflux for 8 hours. After diluting the reaction mixture with water, the resulting solid was collected by filtration to obtain the title compound (14.8 g) as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 8.55-8.61 (2H, m), 13.13 (1H, br s).

(Step 6) Ethyl 4-hydroxy-5-iodopyridine-3-carboxylate A suspension of the compound (10.0 g) obtained in the above step 5 in ethanol (100 mL) was added at 0 ° C to thionyl chloride (8 .64 mL) was added dropwise, and the mixture was stirred at room temperature for 17 hours and heated and refluxed for 9 hours, and then allowed to stand for 2 days. The mixture was stirred for 9 hours while heating and refluxing again. At 0 ° C., ethanol (200 mL) and thionyl chloride (8.64 mL) were added, and the mixture was stirred for 7 hours while heating under reflux. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting solid was collected by filtration to give the title compound (10.9 g) as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 1.23 (3H, t, J = 7.3 Hz), 4.17 (2H, q, J = 7.3 Hz), 8.14-8.34 (2H, m), 12.01 (1H, br s).

(Step 7) Ethyl 1-benzyl-5-iodo-4-oxo-1,4-dihydropyridine-3-carboxylate Compound (10.0 g) obtained in the above Step 6, benzyl bromide (6.08 mL). The same procedure as in Step 1 of Reference Example B-2 was performed using potassium carbonate (9.43 g) to obtain the title compound (11.2 g) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, t, J = 7.3 Hz), 4.35 (2H, q, J = 7.3 Hz), 5.00 (2H, s), 7.21-7.24 (2H, m), 7.42-7.47 (3H, m), 7.85 (1H, d, J = 2.4 Hz), 8.22 (1H, d, J = 2.4 Hz). MS (m / z): 384 (M + H) ⁺ .

(Step 8) 1-benzyl-5-iodo-4-oxo-1,4-dihydropyridine-3-carboxylic acid The compound obtained in the above step 7 (9.41 g), 1 mol / L aqueous sodium hydroxide solution ( 50.0 mL) and methanol (100 mL) were stirred at room temperature for 16 hours. After concentrating the reaction mixture under reduced pressure, water and 1 mol / L hydrochloric acid (52.0 mL) were sequentially added to the obtained residue at room temperature, and the resulting solid was collected by filtration to give the title compound (8.72 g). Obtained as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 5.37 (2H, s), 7.34-7.46 (5H, m), 8.80-8.90 (2H, m).

(Step 9) 1-benzyl-4-oxo-5- (tributylstannyl) -1,4-dihydropyridine-3-carboxylic acid The compound (8.72 g) obtained in the above Step 8, bis (tributyltin) (27.3 mL, CAS number: 819-19-4), tetrahydrofuran (150 mL), and tetrakis (triphenylphosphine) palladium (0) (1.42 g) were mixed at 70 ° C. under a nitrogen atmosphere for 24 hours. Stirred for hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with a mixed solvent of chloroform / methanol = 9/1. The diluted reaction solution was washed sequentially with 1 mol / L hydrochloric acid and saturated saline, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (chloroform / methanol), and the solid formed by adding n-hexane was collected by filtration to give the title compound (7.92 g) as a solid. Obtained.
¹ H-NMR (DMSO-D ₆ ) δ: 0.59 (9H, t, J = 7.2 Hz), 0.74-0.92 (6H, m), 0.97-1.07 (6H, m), 1.13-1.34 (6H, m) , 5.20 (2H, s), 7.11-7.44 (5H, m), 7.66-7.77 (1H, m), 8.55-8.61 (1H, m), 16.31 (1H, s).

(Step 10) 1-benzyl-5- {5- [1- (tert-butoxycarbonyl) cyclohexyl] thiophen-2-yl} -4-oxo-1,4-dihydropyridine-3-carboxylic acid Obtained in Step 4 above. Of the obtained compound (0.502 g), the compound obtained in the above step 9 (1.13 g), toluene (20.0 mL), and tetrakis (triphenylphosphine) palladium (0) (0.173 g). The mixture was stirred at 110 ° C. for 15 hours under a nitrogen atmosphere. The residue obtained by concentrating the reaction mixture under reduced pressure was subjected to silica gel column chromatography (chloroform / methanol) to obtain a mixture containing the title compound. This compound was used for the next reaction without further purification.

(Step 11) Methyl 1-benzyl-5- {5- [1- (tert-butoxycarbonyl) cyclohexyl] thiophen-2-yl} -4-oxo-1,4-dihydropyridine-3-carboxylate In the above step 10, A mixture of the obtained compound (total amount), N, N-dimethylformamide (10.0 mL), potassium carbonate (0.403 g), and iodomethane (0.181 mL) was stirred at 60 ° C. for 5 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to obtain a mixture (0.199 g) containing the title compound as an oil. This compound was used for the next reaction without further purification.

(Step 12) 1- {5- [1-benzyl-5- (methoxycarbonyl) -4-oxo-1,4-dihydropyridin-3-yl] thiophen-2-yl} cyclohexanecarboxylic acid Obtained in the above step 11. To a solution of the compound (199 mg) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) under ice cooling, and the mixture was stirred under ice cooling for 15 minutes and at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, mixed with ethyl acetate and water, and the resulting solid was collected by filtration to obtain the title compound (70 mg). The organic layer of the filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (chloroform / methanol) to give the title compound (41 mg) as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 1.26-1.33 (1H, m), 1.37-1.64 (5H, m), 1.72-1.80 (2H, m), 2.32-2.35 (2H, m), 3.73 ( 3H, s), 5.30 (2H, s), 6.94 (1H, d, J = 3.6 Hz), 7.35-7.42 (5H, m), 7.49 (1H, d, J = 3.6 Hz), 8.47 (1H, d , J = 2.4 Hz), 8.59 (1H, d, J = 2.4 Hz), 12.48 (1H, s). MS (m / z): 452 (M + H) ⁺ .

Reference Example B-7
1- {4-[(benzyloxy) carbonyl] phenyl} cyclohexanecarboxylic acid

(Step 1) tert-butyl 1- (4-bromophenyl) cyclohexanecarboxylate The compound (11.5 g) obtained in Step 1 of Reference Example B-3, thionyl chloride (5.6 mL), potassium tert- The title compound (10.9 g) was obtained as a solid by performing the same operation as in Step 3 of Reference Example B-6 using butoxide (1.0 mol / L, tetrahydrofuran solution, 50 mL).
¹ H-NMR (CDCl ₃ ) δ: 1.19-1.29 (1H, m), 1.36 (9H, s), 1.45-1.68 (7H, m), 2.35-2.41 (2H, m), 7.27 (2H, d, J = 8.5 Hz), 7.43 (2H, d, J = 8.5 Hz).

(Step 2) Phenyl 4- [1- (tert-butoxycarbonyl) cyclohexyl] benzoate Compound (10.9 g) obtained in Step 1 above, palladium (II) acetate (0.361 g), tri-tert- Butylphosphonium tetrafluoroborate (1.86 g, CAS number: 131274-22-1), acetonitrile (50 mL), triethylamine (13.5 mL), phenyl formate (10.5 mL, CAS number: 1864-94) The mixture of -4) was stirred at 80 ° C under nitrogen atmosphere overnight. The reaction mixture to which the aqueous ammonium chloride solution was added was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate), and the solid formed by adding n-hexane was collected by filtration to give the title compound (8.62 g). Was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.24-1.33 (1H, m), 1.38 (9H, s), 1.49-1.58 (2H, m), 1.64-1.73 (5H, m), 2.44-2.47 (2H, m), 7.19-7.29 (3H, m), 7.40-7.45 (2H, m), 7.55 (2H, d, J = 8.5 Hz), 8.15 (2H, d, J = 8.5 Hz).

(Step 3) 4- [1- (tert-butoxycarbonyl) cyclohexyl] benzoic acid Using the compound (8.62 g) obtained in the above step 2 and a 1 mol / L aqueous sodium hydroxide solution (110 mL), The title compound (6.82 g) was obtained as a solid by performing the same operation as in Step 6 of Reference Example B-3.
¹ H-NMR (CDCl ₃ ) δ: 1.21-1.31 (1H, m), 1.37 (9H, s), 1.46-1.58 (2H, m), 1.62-1.72 (5H, m), 2.40-2.47 (2H, m), 7.51 (2H, d, J = 8.5 Hz), 8.06 (2H, d, J = 8.5 Hz). MS (m / z): 303 (MH) ^- .

(Step 4) Benzyl 4- [1- (tert-butoxycarbonyl) cyclohexyl] benzoate Compound (4.01 g) obtained in Step 3 above, potassium carbonate (2.75 g), benzyl bromide (1.87 mL) ), And the same operation as in step 1 of Reference Example B-2 was performed to obtain the title compound (5.11 g) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.21-1.30 (1H, m), 1.35 (9H, s), 1.46-1.57 (2H, m), 1.60-1.72 (5H, m), 2.38-2.45 (2H, m), 5.35 (2H, s), 7.32-7.48 (7H, m), 8.02 (2H, d, J = 8.5 Hz).

(Step 5) 1- {4-[(Benzyloxy) carbonyl] phenyl} cyclohexanecarboxylic acid A solution of the compound (5.10 g) obtained in the above step 4 in a dichloromethane solution (30 mL) was added under ice-cooling with triethanolamine. Fluoroacetic acid (30 mL) was added, and the mixture was stirred at room temperature overnight. After concentrating the reaction mixture under reduced pressure, an operation of adding toluene to the residue and concentrating under reduced pressure was performed twice, and the resulting solid was suspended in n-hexane and then filtered. The obtained solid was subjected to silica gel column chromatography (chloroform / methanol) to give the title compound (3.89 g) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.24-1.33 (1H, m), 1.50-1.80 (7H, m), 2.42-2.49 (2H, m), 5.35 (2H, s), 7.31-7.44 (5H, m), 7.51 (2H, d, J = 8.5 Hz), 8.04 (2H, d, J = 8.5 Hz).

Reference Example C-1
tert-butyl 3-bromo-1H-indazole-1-carboxylate

To a solution of 3-bromoindazole (2.00 g, CAS number: 40598-94-5) in dichloromethane (50 mL), di-tert-butyl dicarbonate (3.32 g), N, N-diisopropylethylamine (3 .48 mL) and 4-dimethylaminopyridine (0.248 g, CAS No. 1122-58-3) were sequentially added, followed by stirring at room temperature for 30 minutes. A 10% aqueous solution of citric acid was added to the reaction solution, and the separated organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / dichloromethane) to quantitatively give the title compound as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.72 (9H, s), 7.36-7.42 (1H, m), 7.57-7.62 (1H, m), 7.63-7.67 (1H, m), 8.14-8.19 (1H, m) .MS (m / z): 197,199 (M + H-Boc) ⁺ .

Reference Example C-2
tert-butyl 4-bromo-1H-pyrazolo [3,4-b] pyridine-1-carboxylate

4-Bromo-1H-pyrazolo [3,4-b] pyridine (300 mg, CAS number: 85659-49-9), di-tert-butyl dicarbonate (364 mg), N, N-diisopropylethylamine (0. 285 mL) and 4-dimethylaminopyridine (18.5 mg) to give the title compound (459 mg) as a solid by performing the same operation as in Reference Example C-1.
¹ H-NMR (CDCl ₃ ) δ: 1.74 (9H, s), 7.49 (1H, d, J = 4.9 Hz), 8.19 (1H, s), 8.56 (1H, d, J = 4.9 Hz) .MS ( m / z): 198,200 (M + H-Boc) ⁺ .

Reference Example C-3
tert-butyl 4-chloro-1H-pyrazolo [4,3-c] pyridine-1-carboxylate

4-Chloro-1H-pyrazolo [4,3-c] pyridine (300 mg, CAS number: 871836-51-0), di-tert-butyl dicarbonate (512 mg), N, N-diisopropylethylamine (0. 401 mL), 4-dimethylaminopyridine (23.9 mg), and tetrahydrofuran (8 mL) in place of dichloromethane to perform the same operation as in Reference Example C-1 to give the title compound (494 mg). Was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.74 (9H, s), 7.99 (1H, d, J = 5.5 Hz), 8.30 (1H, s), 8.38 (1H, d, J = 5.5 Hz).

Reference Example C-4
tert-butyl 4-bromo-6-fluoro-1H-indazole-1-carboxylate

4-bromo-6-fluoro-1H-indazole (1.00 g, CAS number: 885520-35-4), di-tert-butyl dicarbonate (1.23 g), triethylamine in place of N, N-diisopropylethylamine (0.967 mL), 4-dimethylaminopyridine (54.9 mg), and tetrahydrofuran (25 mL) in place of dichloromethane to perform the same operation as in Reference Example C-1 to give the title compound ( 1.22 g) were obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.73 (9H, s), 7.27-7.30 (1H, m), 7.85-7.88 (1H, m), 8.14 (1H, s) .MS (m / z): 215,217 (M + H-Boc) ⁺ .

Reference Example C-5
tert-butyl 4-bromo-7-methyl-1H-indazole-1-carboxylate

4-Bromo-7-methyl-1H-indazole (400 mg, CAS No .: 11595911-74-6), di-tert-butyl dicarbonate (498 mg), triethylamine (0.1 mg) instead of N, N-diisopropylethylamine. 394 mL), 4-dimethylaminopyridine (24.7 mg), and tetrahydrofuran (8 mL) instead of dichloromethane to give the title compound (553 mg). Was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.73 (9H, s), 2.58 (3H, s), 6.93-6.94 (1H, m), 7.15-7.18 (1H, m), 8.53 (1H, s) .MS (m / z): 211,213 (M + H-Boc) ⁺ .

Reference Example C-6
tert-butyl 4-hydroxy-1H-indazole-1-carboxylate

1H-indazol-4-ol hydrochloride (0.733 g, CAS number: 81382-45-8), tetrahydrofuran (15 mL), N, N-dimethylformamide (15 mL), triethylamine (0.596 mL), A mixture of di-tert-butyl carbonate (0.985 g) and 4-dimethylaminopyridine (0.0525 g) was stirred at room temperature for 18 hours. After a 1 mol / L aqueous sodium hydroxide solution (15 mL) was added to the reaction solution, the mixture was further stirred for 1.5 hours. The reaction solution was washed twice with diethyl ether, and ice was added to the aqueous layer. The aqueous layer was adjusted to about pH 3-5 using 1 mol / L hydrochloric acid, and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (0.653 g) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.71 (9H, s), 6.39 (1H, s), 6.65-6.69 (1H, m), 7.34-7.39 (1H, m), 7.70-7.75 (1H, m) , 8.29 (1H, s). MS (m / z): 135 (M + H-Boc) ⁺ .

Reference Example D-1
[1- (4-methoxyphenyl) cyclohexyl] (6-methylidene-1,4-oxazepan-4-yl) methanone

(Step 1) 6-methylidene-1,4-oxazepane hydrochloride The compound (5.00 g) obtained in Step 1 of Reference Example A-1 and hydrogen chloride (4 mol / L, 1,4-dioxane solution, (50 mL) was stirred at room temperature for 2 hours. The residue obtained by concentrating the reaction solution under reduced pressure was diluted with methanol, then concentrated and dried again under reduced pressure to obtain the title compound (3.51 g) as a solid.
MS (m / z): 114 (M + H-HCl) ⁺ .

(Step 2) [1- (4-methoxyphenyl) cyclohexyl] (6-methylidene-1,4-oxazepan-4-yl) methanone The compound obtained in the above step 1 (3.51 g), 1- (4 -Methoxyphenyl) cyclohexane-1-carboxylic acid (5.00 g, CAS number: 7469-83-2), dichloromethane (100 mL), N, N-diisopropylethylamine (12.8 mL) was added to an ice-cooled mixture. HATU (8.11 g) was added thereto, and the mixture was stirred at room temperature for 19 hours. The reaction solution was diluted with dichloromethane, washed sequentially with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution, and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (dichloromethane / ethyl acetate) to obtain the title compound (6.60 g) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.24-1.31 (1H, m), 1.56-1.64 (7H, m), 2.20-2.25 (2H, m), 3.32-3.38 (4H, m) , 3.72-3.73 (3H, m), 3.88-3.93 (4H, m), 4.78-4.81 (1H, m), 4.85-4.88 (1H, m), 6.87-6.90 (2H, m), 7.12-7.17 ( 2H, m) .MS (m / z): 330 (M + H) ⁺ .

Reference Example D-2
[1- (4-methoxyphenyl) cyclohexyl] (3-methylidene-1,5-oxazocan-5-yl) methanone

(Step 1) tert-butyl 3-methylidene-1,5-oxazocan-5-carboxylate sodium hydride (purity> 55%, 0.959 g), 3-chloro-2-chloromethyl-1-propene (0 .946 mL) and 3- (tert-butoxycarbonylamino) -1-propanol (1.75 g, CAS number: 58885-58-8), and the same operation as in step 1 of Reference example A-1. This gave the title compound (0.506 g) as an oil.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.40 (9H, s), 1.68 (2H, s), 3.30 (2H, s), 3.52 (2H, t, J = 5.7 Hz), 3.86 ( 2H, s), 4.00 (2H, s), 5.09-5.20 (2H, br m) .MS (m / z): 128 (M-Boc) ⁺ .

(Step 2) [1- (4-methoxyphenyl) cyclohexyl] (3-methylidene-1,5-oxazocan-5-yl) methanone The compound obtained in the above step 1 (500 mg), hydrogen chloride (4 mol / L, 1,4-dioxane solution, 10 mL) was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The obtained residue, 1- (4-methoxyphenyl) cyclohexane-1-carboxylic acid (0.572 g), HATU (0.920 g), N, N-dimethylformamide (10 mL), N, N-diisopropyl A mixture of ethylamine (1.15 mL) was stirred at room temperature overnight. The reaction mixture to which 1 mol / L hydrochloric acid was added was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution, and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to amino silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (658 mg) as an oil.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.22-1.31 (1H, m), 1.53-1.67 (9H, m), 2.24-2.27 (2H, m), 3.23 (2H, t, J = 5.1 Hz), 3.44 (2H, t, J = 5.1 Hz), 3.63 (2H, s), 3.71-3.75 (5H, m), 5.03 (2H, d, J = 9.7 Hz), 6.89 (2H, d, J = 8.5 Hz), 7.17 (2H, d, J = 8.5 Hz). MS (m / z): 344 (M + H) ⁺ .

Reference Example D-3
[1- (4-methoxyphenyl) cyclohexyl] (2-methyl-6-methylidene-1,4-oxazepan-4-yl) methanone

(Step 1) tert-butyl 2-methyl-6-methylidene-1,4-oxazepan-4-carboxylate 3-chloro-2-chloromethyl-1-propene (4.28 g), N, N-dimethylformamide (50 mL) and a mixture of sodium hydride (purity> 55%, 2.99 g) and tert-butyl N- (2-hydroxypropyl) carbamate (5.00 g, CAS number: 95656) under ice-cooling. After dropwise adding a solution of 86-3) in tetrahydrofuran (20 mL), the mixture was stirred at room temperature for 2.5 hours. Acetic acid (4.08 mL) was added to the reaction solution, water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) three times to give the title compound (2.61 g) as an oil.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.06 (3H, d, J = 6.0 Hz), 1.40 (9H, s), 2.69-2.76 (1H, m), 3.53-3.59 (1H, m ), 3.69 (1H, d, J = 15.7 Hz), 3.80 (1H, d, J = 14.5 Hz), 3.90 (1H, d, J = 14.5 Hz), 4.26-4.36 (2H, m), 4.92 (2H , d, J = 9.1 Hz). MS (m / z): 128 (M + H-Boc) ⁺ .

(Step 2) 2-Methyl-6-methylidene-1,4-oxazepane hydrochloride Compound (614 mg) obtained in the above step 1, dichloromethane (4.0 mL), hydrogen chloride (4 mol / L, 1, 4-Dioxane solution (4.0 mL) was stirred at room temperature for 15１５ hours. The reaction solution was concentrated under reduced pressure to give the title compound quantitatively as an oil.
¹ H-NMR (DMSO-D ₆ ) δ: 1.13 (3H, d, J = 6.0 Hz), 2.70-2.82 (1H, m), 3.18-3.27 (1H, m), 3.60-3.69 (1H, m) , 3.75-3.92 (2H, m), 4.24 (1H, d, J = 14.5 Hz), 4.38 (1H, d, J = 14.5 Hz), 5.21 (1H, s), 5.32 (1H, s), 8.95- 10.12 (2H, m).

(Step 3) [1- (4-methoxyphenyl) cyclohexyl] (2-methyl-6-methylidene-1,4-oxazepan-4-yl) methanone 1- (4-methoxyphenyl) cyclohexane-1-carboxylic acid ( To a solution of 0.696 g) in dichloromethane (10 mL) were added N, N-dimethylformamide (0.010 mL) and thionyl chloride (0.215 mL) at room temperature, and the mixture was stirred at 45 ° C for 1 hour. After returning the reaction solution to room temperature, the solvent was distilled off under reduced pressure to obtain a crude acid chloride. A mixture of the compound obtained in the above step 2 (0.442 g), dichloromethane (10 mL), N, N-diisopropylethylamine (1.18 mL), and 4-dimethylaminopyridine (0.0165 g) was added to a mixture at room temperature. A solution of the above-mentioned acid chloride in dichloromethane (10 mL) was added, and the mixture was stirred at the same temperature for 19 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the organic solvent was distilled off under reduced pressure. After the obtained residue was extracted with ethyl acetate, the organic layer was washed successively with water and saturated saline and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (0.726 g) as an oil.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 0.88 (3H, d, J = 4.8 Hz), 1.26 (1H, br s), 1.55-1.68 (7H, m), 2.18-2.25 (2H, m), 2.48-2.55 (1H, m), 3.03-3.11 (1H, m), 3.46 (1H, d, J = 15.7 Hz), 3.67-3.72 (4H, m), 3.94 (1H, d, J = 13.9 Hz), 4.08 (1H, d, J = 13.9 Hz), 4.38 (1H, d, J = 15.1 Hz), 4.77 (1H, s), 4.84 (1H, s), 6.90 (2H, d, J = 7.9 Hz), 7.15 (2H, d, J = 7.9 Hz). MS (m / z): 344 (M + H) ⁺ .

Reference Example D-4
[1- (4-methoxyphenyl) cyclohexyl] (3-methylideneazepan-1-yl) methanone

(Step 1) tert-butyl 3-methylideneazepan-1-carboxylate potassium tert-butoxide (1.26 g), methyltriphenylphosphonium iodide (4.55 g), tert-butyl 3-oxoazepan-1 -The same operation as in Step 1 of Reference Example A-3 was performed using carboxylate (2.00 g, CAS No .: 870842-23-2) to give the title compound (1.85 g) as an oil. Obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.45-1.47 (9H, m), 1.54-1.69 (4H, m), 2.17-2.23 (2H, m), 3.24-3.31 (2H, m), 3.99-4.06 ( 2H, m), 4.80-4.87 (2H, m).

(Step 2) 3-methylideneazepan hydrochloride Using the compound obtained in the above step 1 (1.83 g) and hydrogen chloride (4 mol / L, 1,4-dioxane solution, 25 mL), By performing the same operation as in Step 1 of Example D-1, the title compound was quantitatively obtained as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 1.58-1.65 (2H, m), 1.75-1.81 (2H, m), 2.34-2.38 (2H, m), 2.98-3.03 (2H, m), 3.67- 3.69 (2H, m), 5.07-5.14 (2H, m), 9.34 (2H, br s) .MS (m / z): 112 (M + H-HCl) ⁺ .

(Step 3) [1- (4-methoxyphenyl) cyclohexyl] (3-methylideneazepan-1-yl) methanone The compound obtained in the above step 2 (1.24 g), 1- (4-methoxyphenyl) ) Using cyclohexane-1-carboxylic acid (1.81 g), N, N-diisopropylethylamine (4.6 mL) and HATU (2.92 g), the same operation as in Step 2 of Reference Example D-1 To give the title compound (2.32 g) as an oil.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.22-1.34 (1H, m), 1.40-1.49 (4H, m), 1.53-1.69 (7H, m), 1.90-1.95 (2H, m) , 2.20-2.31 (2H, m), 3.18-3.26 (2H, m), 3.73 (3H, s), 3.76-3.80 (2H, m), 4.63-4.74 (2H, m), 6.86-6.93 (2H, m m), 7.11-7.18 (2H, m) .MS (m / z): 328 (M + H) ⁺ .

Reference Example E-1
(6-Amino-1,4-oxazepan-4-yl) [4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] methanone

(Step 1) tert-butyl 6-{[(benzyloxy) carbonyl] amino} -1,4-oxazepan-4-carboxylate tert-butyl 6-amino-1,4-oxazepan-4-carboxylate hydrochloride ( To a mixture of 1.00 g, CAS number: 14149958-25-0), tetrahydrofuran (8 mL), water (8 mL), and sodium hydrogencarbonate (0.665 g) was added benzyl chloroformate (0.619 g) under ice-cooling. mL) was added dropwise over 5 minutes, and the mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 40 minutes. After the reaction solution was extracted with ethyl acetate, the organic layer was washed sequentially with a 10% aqueous citric acid solution and saturated saline, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, a mixture (1.58 g) containing the title compound was obtained as an oil. This compound was used for the next step without further purification.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.40 (9H, s), 3.24-3.31 (2H, m), 3.51-3.55 (2H, m), 3.61-3.69 (4H, m), 3.79 -3.82 (1H, m), 5.03 (2H, s), 6.71 (1H, br s), 7.28-7.34 (5H, m). MS (m / z): 251 (M + H-Boc) ⁺ .

(Step 2) Benzyl 1,4-oxazepan-6-ylcarbamate hydrochloride The compound obtained in the above step 1 (1.58 g), 1,4-dioxane (10 mL) instead of dichloromethane, and hydrogen chloride (4 The same operation as in Step 2 of Reference Example D-3 was performed using moL / L, 1,4-dioxane solution, 10 mL) to obtain a mixture (1.32 g) containing the title compound as a solid. Was. This compound was used for the next step without further purification.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 3.16-3.25 (3H, m), 3.28-3.35 (1H, m), 3.58-3.66 (1H, m), 3.83-3.92 (3H, m) , 4.06-4.13 (1H, m), 5.05 (2H, s), 7.22 (1H, br s), 7.27-7.39 (5H, m), 9.46 (1H, br s) .MS (m / z): 251 (M + H) ⁺ .

(Step 3) Benzyl (4-{[4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] carbonyl} -1,4-oxazepan-6-yl) carbamate Compound obtained in Step 2 above (0.968 g), the compound obtained in Reference Example B-1 (0.600 g), dichloromethane (12 mL), N, N-diisopropylethylamine (2.17 mL), HATU (1.16 g) The title compound (0.922 g) was obtained as a solid by performing the same operation as in Step 2 of Reference Example D-1 using
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.83-1.95 (2H, m), 2.18-2.27 (2H, m), 3.06-3.16 (3H, m), 3.20-3.27 (1H, m) , 3.32-3.38 (1H, m), 3.49-3.76 (11H, m), 4.97-5.07 (2H, m), 6.74 (1H, br s), 6.89-6.93 (2H, m), 7.16-7.20 (2H , m), 7.27-7.37 (5H, m) .MS (m / z): 469 (M + H) ⁺ .

(Step 4) (6-amino-1,4-oxazepan-4-yl) [4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] methanone The compound obtained in the above Step 3 (815 mg) ), Ethanol (20 mL), and 10% palladium-carbon (300 mg) were stirred at room temperature under a hydrogen atmosphere for 4.5 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure to a volume of about 20 mL to 30 mL. The resulting solution, a mixture of 10% palladium-carbon (466 mg), was stirred again at room temperature under a hydrogen atmosphere for 30 minutes. After filtering the reaction solution, the filtrate was concentrated under reduced pressure. The obtained residue was diluted with tetrahydrofuran, the insolubles were filtered, and the filtrate was concentrated under reduced pressure to give the title compound (545 mg) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.85-1.98 (2H, m), 2.16-2.25 (2H, m), 3.00-3.88 (18H, m), 6.91-6.95 (2H, m) , 7.18-7.23 (2H, m). MS (m / z): 335 (M + H) ⁺ .

Reference Example E-2
(6-Hydroxy-1,4-oxazepan-4-yl) [4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] methanone

(Step 1) 1,4-oxazepan-6-ol hydrochloride tert-butyl 6-hydroxy-1,4-oxazepan-4-carboxylate (380 mg, CAS number: 12727258-40-3), hydrogen chloride (4 The same operation as in Step 1 of Reference Example D-1 was performed using moL / L, 1,4-dioxane solution (10 mL) to quantitatively obtain the title compound as a solid.
MS (m / z): 118 (M + H-HCl) ⁺ .

(Step 2) (6-Hydroxy-1,4-oxazepan-4-yl) [4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] methanone The compound obtained in Reference Example B-1 ( 330 mg), the compound obtained in the above step 1 (260 mg), N, N-diisopropylethylamine (1.20 mL) and HATU (637 mg), in the same manner as in Step 2 of Reference Example D-1. By performing the operation, the title compound (448 mg) was obtained as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.85-1.95 (2H, m), 2.22 (2H, t, J = 13.7 Hz), 2.89-2.94 (1H, m), 3.07-3.13 (2H , m), 3.32-3.45 (3H, m), 3.51-3.80 (10H, m), 6.92 (2H, d, J = 7.0 Hz), 7.18 (2H, d, J = 7.0 Hz) .MS (m / z): 336 (M + H) ⁺ .

Reference Example E-3
[6- (Hydroxymethyl) -1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone

A mixture of the compound (542 mg) obtained in Step 2 of Reference Example D-1 and 9-borabicyclo [3.3.1] nonane (0.50 mol / L, tetrahydrofuran solution, 6.6 mL) was heated. The mixture was stirred for 2 hours while refluxing. Under ice-cooling, methanol (0.2 mL), 5 mol / L aqueous sodium hydroxide solution (0.6 mL) and aqueous hydrogen peroxide (30%, 0.6 mL) were sequentially added to the reaction solution, and the mixture was added for 45 minutes. Stirred. The reaction was diluted with water and extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to quantitatively give the title compound as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.25-1.30 (1H, m), 1.52-1.81 (8H, m), 2.22-2.27 (2H, m), 2.85-2.93 (1H, m) , 3.08-3.17 (3H, m), 3.22-3.33 (3H, m), 3.45-3.52 (2H, m), 3.57-3.64 (1H, m), 3.73 (3H, s), 4.11-4.18 (1H, m), 6.89 (2H, d, J = 8.5 Hz), 7.15 (2H, d, J = 8.5 Hz). MS (m / z): 348 (M + H) ⁺ .

Example 1
[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] [4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] methanone

(Step 1) tert-butyl 4-[(4-{[4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] carbonyl} -1,4-oxazepan-6-yl) methyl] -1H -Indazole-1-carboxylate The compound (0.198 g) obtained in Reference Example B-1, HATU (0.368 g) was added to the compound (total amount) obtained in Step 4B of Reference Example A-1. N, N-dimethylformamide (7 mL) and N, N-diisopropylethylamine (0.225 mL) were added, and the mixture was stirred at room temperature overnight. After adding a saturated aqueous solution of ammonium chloride to the reaction solution, the reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel chromatography (n-hexane / ethyl acetate), and then to amino silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (0 .224 g) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.67 (9H, s), 1.72-1.81 (2H, m), 1.96-2.05 (2H, m), 2.17 (1H, d, J = 13.9 Hz ), 2.59-2.66 (1H, m), 2.70-2.75 (1H, m), 2.85-2.91 (1H, m), 3.11-3.18 (1H, m), 3.28-3.46 (4H, m), 3.55-3.72 (9H, m), 6.82 (2H, d, J = 7.3 Hz), 6.99-7.07 (3H, m), 7.47-7.51 (1H, m), 7.96 (1H, d, J = 8.5 Hz), 8.33 ( 1H, s). MS (m / z): 550 (M + H) ⁺ .

(Step 2) [6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] [4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] methanone Step 1 above Hydrogen chloride (4 mol / L, 1,4-dioxane solution, 5 mL) was added to a solution of the compound (217 mg) obtained in (2) in dichloromethane (0.5 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, made basic with saturated sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was suspended in ethyl acetate. The resulting solid was collected by filtration and dried to give the title compound (141 mg).
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.67-1.80 (2H, m), 1.97-2.06 (2H, m), 2.16-2.20 (1H, m), 2.54-2.69 (2H, m) , 2.83-2.90 (1H, m), 3.13-3.19 (1H, m), 3.26-3.65 (10H, m), 3.73 (3H, s), 6.77 (1H, d, J = 6.7 Hz), 6.84 (2H , d, J = 8.5 Hz), 7.00 (2H, d, J = 8.5 Hz), 7.24 (1H, t, J = 7.9 Hz), 7.38 (1H, d, J = 7.9 Hz), 7.98 (1H, s ), 12.79 (1H, s). MS (m / z): 450 (M + H) ⁺ .

Example 2
1- [6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] -2- (4-methoxyphenyl) ethanone

(Step 1) 2- (4-methoxyphenyl) -1- {6-[(1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazol-4-yl) methyl] -1,4-oxazepane -4-yl @ ethanone The compound obtained in Step 2 of Reference Example A-2 (101 mg), dichloromethane (2.0 mL), 4-methoxyphenylacetic acid (51 mg, CAS number: 104-01-8) , EDCI (80.3 mg), triethylamine (0.106 mL), and 4-dimethylaminopyridine (5.0 mg) were stirred at room temperature for 1 hour. After diluting the reaction solution with ethyl acetate, it was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (112 mg) as an oil.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: -0.11 (9H, s), 0.79 (2H, t, J = 7.9 Hz), 2.27-2.32 (1H, m), 2.82-2.85 (2H, br m), 3.22-3.92 (15H, m), 5.70 (2H, br s), 6.72-6.89 (3H, m), 6.96-6.99 (1H, br m), 7.12-7.14 (1H, br m), 7.32-7.34 (1H, br m), 7.51 (1H, br s), 8.15 (1H, br s). MS (m / z): 510 (M + H) ⁺ .

(Step 2) 1- [6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] -2- (4-methoxyphenyl) ethanone The compound obtained in the above step 1 (112 mg) ) In dichloromethane (3.0 mL) was added trifluoroacetic acid (1.0 mL) at room temperature, and the mixture was stirred at the same temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, the obtained residue was diluted with dichloromethane and concentrated again under reduced pressure. An operation of diluting with dichloromethane and concentrating again under reduced pressure was performed several times. A mixture of the obtained residue, methanol (2.0 mL) and aqueous ammonia (28%, 2.0 mL) was stirred at room temperature for 2 hours. After water was added to the reaction solution, the reaction mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (chloroform / methanol), and then to silica gel column chromatography (ethyl acetate / methanol) to give the title compound (33.6 mg) as a solid. Obtained.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 2.25-2.33 (1H, m), 2.79-2.84 (2H, m), 2.97-3.03 (3H, m), 3.16-3.27 (2H, m) , 3.40-3.47 (1H, m), 3.54-3.68 (4H, m), 3.71 (3H, s), 6.75-6.90 (4H, m), 7.07-7.17 (1H, m), 7.23-7.24 (1H, m), 7.35-7.38 (1H, m), 8.08 (1H, br s), 12.78 (1H, br s) .MS (m / z): 380 (M + H) ⁺ .

Example 3
[3- (1H-indazol-4-ylmethyl) azepan-1-yl] [2- (4-methoxyphenyl) spiro [3.3] heptane-2-yl] methanone

(Step 1) tert-butyl 4-[(1-{[2- (4-methoxyphenyl) spiro [3.3] heptane-2-yl] carbonyl} azepan-3-yl) methyl] -1H-indazole- 1-carboxylate The compound (40 mg) obtained in Step 4 of Reference Example A-5, 2- (4-methoxyphenyl) spiro [3.3] heptane-2-carboxylic acid (36 mg, CAS No .: 1498455) -82-5), HATU (60 mg), N, N-dimethylformamide (0.8 mL) and N, N-diisopropylethylamine (0.031 mL) were used in the same manner as in Step 1 of Example 1. The operation gave the title compound (69 mg) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 0.67-0.97 (2H, m), 0.98-1.78 (15H, m), 1.79-1.98 (4H, m), 2.04-2.95 (7H, m), 2.99-3.27 ( 2H, m), 3.50-3.99 (5H, m), 6.70-6.88 (2H, m), 6.95-6.99 (1H, m), 7.11-7.22 (2H, m), 7.39-7.46 (1H, m), 7.96-8.07 (1H, m), 8.23-8.25 (1H, m) .MS (m / z): 558 (M + H) ⁺ .

(Step 2) [3- (1H-indazol-4-ylmethyl) azepan-1-yl] [2- (4-methoxyphenyl) spiro [3.3] heptane-2-yl] methanone Obtained in the above step 1. A mixture of the compound (69 mg), dichloromethane (2 mL) and trifluoroacetic acid (0.38 mL) was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, made basic with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (51 mg) as a solid.
¹ H-NMR (DMSO-D ₆ , 150 ° C) δ: 1.00-1.62 (5H, m), 1.66-1.77 (2H, m), 1.78-1.99 (5H, m), 2.17-2.33 (2H, m) , 2.59-2.82 (6H, m), 3.00-3.12 (1H, m), 3.31-3.55 (2H, m), 3.72 (3H, s), 6.75-6.82 (3H, m), 6.99-7.06 (2H, m), 7.18-7.25 (1H, m), 7.33-7.39 (1H, m), 7.98 (1H, s), 12.36-12.74 (1H, m) .MS (m / z): 458 (M + H) ⁺ .

  The following compounds were synthesized by performing a combination of the same operations as in any of the steps of Examples 1 to 3 or Step 4 of Reference Example A-6.

Example 11
[6- (1H-indazol-4-ylmethyl) -1,4-diazepan-1-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone

(Step 1) tert-butyl 4-{[1- (tert-butoxycarbonyl) -4-{[1- (4-methoxyphenyl) cyclohexyl] carbonyl} -1,4-diazepan-6-yl] methyl}- 1H-indazole-1-carboxylate 1- (4-methoxyphenyl) cyclohexane-1-carboxylic acid (331 mg), N, N-dimethylformamide (10 mL), obtained in step 6 of Reference Example A-4 A mixture of the compound (468 mg), HATU (537 mg), and N, N-diisopropylethylamine (0.284 mL) was stirred at room temperature for 60 hours and at 50 ° C. for 3 hours. 4-Dimethylaminopyridine (12 mg) was added to the reaction solution, and the mixture was stirred at the same temperature for 2.5 hours. After diluting the reaction solution with ethyl acetate, it was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (201 mg) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.29 (9H, br s), 1.39-1.52 (7H, m), 1.59-1.68 (10H, m), 1.83-1.92 (2H, m), 2.12-2.17 (1H, m), 2.59-2.66 (2H, m), 2.71-2.77 (1H, m), 2.84-2.95 (3H, m), 3.38-3.42 (1H, m), 3.54-3.66 (2H , m), 3.71 (3H, s), 3.90-3.98 (1H, m), 6.70 (2H, d, J = 7.9 Hz), 6.81 (2H, d, J = 7.3 Hz), 7.05 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.98 (1H, d, J = 8.5 Hz), 8.24 (1H, s). MS (m / z): 647 (M + H) ⁺ .

(Step 2) [6- (1H-indazol-4-ylmethyl) -1,4-diazepan-1-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone The compound obtained in the above step 1 (201 mg) ) In dichloromethane (1.0 mL) was added with hydrogen chloride (4 mol / L, 1,4-dioxane solution, 3.0 mL), and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, made basic with a saturated aqueous solution of sodium hydrogen carbonate, and then extracted with a mixed solvent of chloroform / methanol = 9/1. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to amino silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (43.9 mg) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.19-1.28 (1H, m), 1.42-1.56 (7H, m), 1.63-1.72 (1H, m), 1.83 (1H, br s), 1.99-2.04 (1H, m), 2.08-2.12 (1H, m), 2.19-2.22 (1H, m), 2.38 (1H, dd, J = 13.9, 7.3 Hz), 2.55-2.69 (4H, m), 2.78-2.84 (1H, m), 3.43-3.50 (1H, m), 3.54-3.60 (1H, m), 3.72 (3H, s), 6.77-6.83 (3H, m), 7.01 (2H, d, J = 9.1 Hz), 7.22 (1H, t, J = 8.5 Hz), 7.35 (1H, d, J = 8.5 Hz), 7.99 (1H, s), 12.75 (1H, br s) .MS (m / z) : 447 (M + H) ⁺ .

Example 12
[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] {1- [4- (2H-tetrazol-5-yl) phenyl] cyclohexyl} methanone

(Step 1) tert-butyl 4-({4-[(1- {4- [2- (4-methoxybenzyl) -2H-tetrazol-5-yl] phenyl} cyclohexyl) carbonyl] -1,4-oxazepane -6-yl @ methyl) -1H-indazole-1-carboxylate The compound obtained in Step 6 of Reference Example B-3 (326 mg), the compound obtained in Step 4A of Reference Example A-1 (250 mg) ), HATU (344 mg) and N, N-diisopropylethylamine (0.2 mL), and the title compound (377 mg) was obtained as an oil by performing the same operation as in Step 1 of Example 1. Was.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.16-1.34 (1H, m), 1.47-1.72 (16H, m), 1.91-2.28 (3H, m), 2.54-2.78 (2H, m) , 2.81-2.94 (1H, m), 3.10-3.19 (1H, m), 3.23-3.69 (6H, m), 3.75 (3H, s), 5.86 (2H, s), 6.89-7.01 (3H, m) , 7.20-7.41 (5H, m), 7.86-7.96 (3H, m), 8.32 (1H, s) .MS (m / z): 706 (M + H) ⁺ .

(Step 2) [6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] {1- [4- (2H-tetrazol-5-yl) phenyl] cyclohexyl} methanone Step 1 above (370 mg), anisole (0.57 mL, CAS number: 100-66-3), and dichloromethane (8 mL) were added to a mixture of trifluoroacetic acid (4 mL), and the mixture was added at room temperature for 12 hours. The mixture was stirred for 10 hours while heating under reflux. After cooling to room temperature, the residue obtained by concentrating the reaction mixture was subjected to silica gel column chromatography (chloroform / methanol). The obtained solid was suspended in diethyl ether and collected by filtration to obtain the title compound (110 mg) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.18-1.34 (1H, m), 1.40-1.78 (7H, m), 1.97-2.31 (3H, m), 2.52-2.74 (2H, m) , 2.77-3.73 (8H, m), 6.67-6.77 (1H, m), 7.11-7.23 (3H, m), 7.32-7.40 (1H, m), 7.87-8.05 (3H, m) .MS (m / z): 484 (MH) ^- .

Example 13
[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclopentyl] methanone

(Step 1) tert-butyl 4-[(4-{[1- (4-methoxyphenyl) cyclopentyl] carbonyl} -1,4-oxazepan-6-yl) methyl] -1H-indazole-1-carboxylate 1 -(4-methoxyphenyl) cyclopentanecarboxylic acid (1.73 g) and the compound obtained in Step 4A of Reference Example A-1 (2.00 g), HATU (3.44 g), N, N- The same operation as in step 1 of Example 1 was performed using diisopropylethylamine (2.10 mL) to obtain the title compound (2.65 g) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.55-1.57 (4H, m), 1.67-1.71 (10H, m), 1.82-1.85 (1H, m), 1.97 (1H, br s), 2.18-2.29 (2H, m), 2.61-2.77 (2H, m), 2.91 (1H, br s), 3.13-3.19 (1H, m), 3.28-3.71 (9H, m), 6.78 (2H, d, J = 8.5 Hz), 6.95 (2H, d, J = 7.9 Hz), 7.06 (1H, d, J = 5.4 Hz), 7.48 (1H, td, J = 7.9, 2.6 Hz), 7.95 (1H, d, J = 8.5 Hz), 8.32 (1H, s). MS (m / z): 534 (M + H) ⁺ .

(Step 2) [6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclopentyl] methanone The compound obtained in the above step 1 (2. A mixture of 65 g) and hydrogen chloride (4 mol / L, 1,4-dioxane solution, 50 mL) was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, made basic with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (chloroform / methanol) to obtain the title compound (2.11 g) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.50-1.60 (4H, m), 1.72-1.86 (2H, m), 2.04-2.20 (2H, m), 2.25-2.33 (1H, m) , 2.60-2.70 (2H, m), 2.93-2.87 (1H, m), 3.14-3.20 (1H, m), 3.27-3.45 (4H, m), 3.54-3.68 (2H, m), 3.72 (3H, s), 6,76-6.82 (3H, m), 6.98 (2H, d, J = 7.9 Hz), 7.22 (1H, t, J = 7.6 Hz), 7.37 (1H, d, J = 8.5 Hz), 7.97 (1H, s), 12.77 (1H, s) .MS (m / z): 434 (M + H) ⁺ .

By optically resolving the obtained compound (600 mg) under the following conditions, (13a, first peak, 281 mg) was obtained as a solid, and (13b, second peak, 282 mg) was obtained as a solid.
Separation condition column: Daicel CHIRALPAK IA 20 × 250 mm
Elution solvent: n-hexane / ethanol = 70/30
Flow rate: 20 mL / min
Temperature: 40 ° C

13a (first peak)
Optical purity: 99.8% ee or more
[α] _D ²⁰ -38.861 ° (c = 1.004, MeOH)

13b (second peak)
Optical purity: 99.3% ee
[α] _D ²⁰ + 37.941 ° (c = 1.009, MeOH)

Example 14
[1- (4-Hydroxyphenyl) cyclohexyl] [3- (1H-indazol-4-ylmethyl) azepan-1-yl] methanone

(Step 1) tert-butyl 4-{[1-({1- [4- (benzyloxy) phenyl] cyclohexyl} carbonyl) azepan-3-yl] methyl} -1H-indazole-1-carboxylate Reference Example B -Compound (259 mg) obtained in step 2 of N-4, N, N-dimethylformamide (0.010 mL), thionyl chloride (0.070 mL), compound obtained in step 4 of Reference Example A-5 (250 mg), N, N-diisopropylethylamine (0.198 mL) and 4-dimethylaminopyridine (9.2 mg) by performing the same operation as in Step 3 of Reference Example D-3. The title compound (386 mg) was obtained as an oil.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.06-1.13 (2H, m), 1.19-1.56 (12H, m), 1.65 (9H, s), 1.81-1.90 (1H, m), 2.06 -2.11 (1H, m), 2.17-2.21 (1H, m), 2.62-2.73 (3H, m), 2.95-3.00 (1H, m), 3.42-3.55 (2H, m), 5.04 (2H, s) , 6.86-6.89 (2H, m), 6.94-6.98 (2H, m), 7.06-7.08 (1H, m), 7.28-7.32 (1H, m), 7.34-7.37 (2H, m), 7.40-7.43 ( 2H, m), 7.46-7.50 (1H, m), 7.94-7.96 (1H, m), 8.36 (1H, s).

(Step 2) tert-butyl 4-[(1-{[1- (4-hydroxyphenyl) cyclohexyl] carbonyl} azepan-3-yl) methyl] -1H-indazole-1-carboxylate Obtained in Step 1 above. Compound (286 mg), 10% palladium-carbon (140 mg), using silica gel column chromatography instead of amino silica gel column chromatography, performing the same operation as in step 4A of Reference Example A-1. The title compound (221 mg) was obtained as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.05-1.11 (2H, m), 1.16 -1.62 (12H, m), 1.67 (9H, s), 1.86-1.94 (1H, m), 2.10 (1H, d, J = 12.8 Hz), 2.19 (1H, d, J = 13.4 Hz), 2.64-2.76 (3H, m), 2.98-3.04 (1H, m), 3.36-3.44 (1H, m), 3.57 (1H, d, J = 12.1 Hz), 6.67 (2H, d, J = 7.9 Hz), 6.91 (2H, d, J = 7.9 Hz), 7.07 (1H, d, J = 6.7 Hz), 7.47 ( 1H, t, J = 7.9 Hz), 7.93 (1H, d, J = 8.5 Hz), 8.35 (1H, s), 8.86 (1H, s) .MS (m / z): 532 (M + H) ⁺ .

(Step 3) [1- (4-Hydroxyphenyl) cyclohexyl] [3- (1H-indazol-4-ylmethyl) azepan-1-yl] methanone The compound obtained in the above Step 2 (100 mg), hydrogen chloride ( The same operation as in step 2 of Example 1 was performed using 4 mol / L, 1,4-dioxane solution, 4.0 mL) to obtain the title compound (57.1 mg) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.04-1.12 (2H, m), 1.19-1.25 (1H, m), 1.34-1.58 (10H, m), 1.63-1.71 (1H, m) , 1.94-2.01 (1H, m), 2.06-2.10 (1H, m), 2.18 (1H, d, J = 12.7 Hz), 2.59-2.71 (3H, m), 2.98-3.04 (1H, m), 3.38 -3.43 (1H, m), 3.55-3.60 (1H, m), 6.67 (2H, d, J = 8.5 Hz), 6.78 (1H, d, J = 6.7 Hz), 6.89 (2H, d, J = 7.9 Hz), 7.22 (1H, t, J = 7.9 Hz), 7.35 (1H, d, J = 8.5 Hz), 8.02 (1H, s), 8.96 (1H, br s), 12.79 (1H, br s). MS (m / z): 432 (M + H) ⁺ .

Example 15
[1- (3,4-Dimethoxyphenyl) cyclopentyl] [3- (1H-indazol-4-ylmethyl) azepan-1-yl] methanone

(Step 1) tert-butyl 4-{[1-({1- [4- (benzyloxy) -3-methoxyphenyl] cyclopentyl} carbonyl) azepan-3-yl] methyl} -1H-indazole-1-carboxy Rate A mixture of the compound (0.773 g) obtained in Step 3 of Reference Example B-5, dichloroethane (15 mL), and oxalyl chloride (0.206 mL) was stirred at 70 ° C. for 2 hours. Oxalyl chloride (0.206 mL) was added to the reaction solution, and the mixture was stirred at 70 ° C for 2 hours, and then concentrated under reduced pressure. The operation of adding dichloroethane to the residue and concentrating under reduced pressure was performed twice to obtain a crude acid chloride. A dichloroethane (7.5 mL) solution of the compound (600 mg) obtained in Step 4 of Reference Example A-5 was added to a dichloroethane (7.5 mL) solution of the crude acid chloride, and pyridine (0.734 mL). ) And 4-dimethylaminopyridine (0.0267 g) were added, and the mixture was stirred at 70 ° C for 3 hours, and allowed to stand at room temperature overnight. After concentration, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate), and then to amino silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (0. 769 g) were obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 0.82-1.22 (3H, m), 1.31-2.00 (9H, m), 1.73 (9H, s), 2.03-2.54 (4H, m), 2.55-4.12 (5H, m), 3.74-3.85 (3H, m), 5.08-5.16 (2H, m), 6.45-8.34 (3H, m), 6.67-6.85 (3H, m), 7.24-7.50 (6H, m) .MS ( m / z): 538 (M + H-Boc) ⁺ .

(Step 2) tert-butyl 4-[(1-{[1- (4-hydroxy-3-methoxyphenyl) cyclopentyl] carbonyl} azepan-3-yl) methyl] -1H-indazole-1-carboxylate The above step The title compound (700 mg) was obtained by performing the same operation as in Step 4B of Reference Example A-1 using the compound (0.765 g) obtained in Step 1 and 10% palladium-carbon (200 mg). Obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 0.82-1.20 (2H, m), 1.33-4.16 (23H, m), 1.73 (9H, s), 6.47-8.34 (6H, m), 7.37-7.49 (1H, m) .MS (m / z): 448 (M + H-Boc) ⁺ .

(Step 3) tert-butyl 4-[(1-{[1- (3,4-dimethoxyphenyl) cyclopentyl] carbonyl} azepan-3-yl) methyl] -1H-indazole-1-carboxylate In the above step 2, Iodomethane (0.075 mL) was added to a mixture of the obtained compound (220 mg), acetone (8 mL), and potassium carbonate (722 mg), and the mixture was stirred at 55 ° C for 2 hours. Iodomethane (0.175 mL) was added, and the mixture was stirred at 55 ° C for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was subjected to amino silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (199 mg) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 0.80-4.19 (20H, m), 1.73 (9H, s), 3.72-3.92 (6H, m), 6.47-8.36 (4H, m), 6.66-6.89 (3H, m), 7.38-7.49 (1H, m) .MS (m / z): 462 (M + H-Boc) ⁺ .

(Step 4) [1- (3,4-Dimethoxyphenyl) cyclopentyl] [3- (1H-indazol-4-ylmethyl) azepan-1-yl] methanone The compound obtained in the above Step 3 (199 mg), Hydrogen (4 mol / L, 1,4-dioxane solution, 5 mL), silica gel column chromatography was used in place of amino silica gel column chromatography, and the same operation as in step 2 of Example 11 was performed to give the title. The compound (130 mg) was obtained as a solid.
¹ H-NMR (DMSO-D ₆ , 150 ° C) δ: 1.00-3.50 (21H, m), 3.64-3.70 (3H, m), 3.70-3.76 (3H, m), 6.57-6.71 (2H, m) , 6.71-6.86 (2H, m), 7.16-7.24 (1H, m), 7.29-7.38 (1H, m), 7.95-8.02 (1H, m), 12.54-12.79 (1H, m) .MS (m / z): 462 (M + H) ⁺ .

Example 16
1-benzyl-5- [5- (1-{[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] carbonyl} cyclohexyl) thiophen-2-yl] -4-oxo -1,4-dihydropyridine-3-carboxylic acid

(Step 1) tert-butyl 4-({4-[(1- {5- [1-benzyl-5- (methoxycarbonyl) -4-oxo-1,4-dihydropyridin-3-yl] thiophen-2-] Il {cyclohexyl) carbonyl] -1,4-oxazepan-6-yl {methyl) -1H-indazole-1-carboxylate Compound (98 mg) obtained in Step 12 of Reference Example B-6, Reference Example A- Using the compound (72 mg) obtained in Step 4A of Step 1, HATU (99 mg), and N, N-diisopropylethylamine (0.06 mL), the same operation as in Step 1 of Example 1 was performed. The title compound (88 mg) was obtained as an oil.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.13-1.35 (2H, m), 1.40-1.82 (14H, m), 2.02-2.38 (3H, m), 2.57-2.81 (2H, m) , 2.96-3.54 (7H, m), 3.65-3.78 (5H, m), 5.29 (2H, s), 5.67 (1H, s), 6.60-6.70 (1H, m), 7.02-7.09 (1H, m) , 7.29-7.48 (6H, m), 7.86-7.94 (1H, m), 8.29-8.48 (3H, m) .MS (m / z): 765 (M + H) ⁺ .

(Step 2) Methyl 1-benzyl-5- [5- (1-{[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] carbonyl} cyclohexyl) thiophen-2-yl ] -4-oxo-1,4-dihydropyridine-3-carboxylate The same operation as in step 2 of Example 3 using the compound (85 mg) obtained in the above step 1 and trifluoroacetic acid (1 mL). To give the title compound (57 mg) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.22-1.38 (1H, m), 1.41-1.73 (7H, m), 2.09-2.21 (2H, m), 2.23-2.33 (1H, m) , 2.56-2.75 (2H, m), 2.93-3.08 (1H, m), 3.17-3.27 (1H, m), 3.29-3.54 (4H, m), 3.66-3.78 (5H, m), 5.28 (2H, s), 6.62 (1H, s), 6.77 (1H, d, J = 6.7 Hz), 7.16 (1H, t, J = 7.6 Hz), 7.29-7.43 (7H, m), 8.00 (1H, s), 8.31-8.36 (1H, m), 8.40 (1H, s), 12.80 (1H, br s) .MS (m / z): 665 (M + H) ⁺ .

(Step 3) 1-benzyl-5- [5- (1-{[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] carbonyl} cyclohexyl) thiophen-2-yl] -4-oxo-1,4-dihydropyridine-3-carboxylic acid The compound obtained in the above step 2 (50 mg), tetrahydrofuran (2 mL), methanol (0.5 mL), 1 mol / L aqueous sodium hydroxide solution (0.22 mL) was stirred at room temperature for 1 hour. The organic solvent was distilled off under reduced pressure, and the reaction solution was acidified using 1 mol / L hydrochloric acid, and the resulting solid was collected by filtration to obtain the title compound (37 mg) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.16-1.32 (1H, m), 1.39-1.71 (7H, m), 2.06-2.34 (3H, m), 2.55-2.75 (2H, m) , 2.89-3.26 (2H, m), 3.31-3.55 (4H, m), 3.65-3.78 (2H, m), 5.33 (2H, s), 6.59 (1H, br s), 6.76 (1H, d, J = 6.7 Hz), 7.14 (1H, t, J = 7.6 Hz), 7.29-7.47 (7H, m), 8.00 (1H, s), 8.35 (1H, br s), 8.49 (1H, br s) .MS (m / z): 649 (MH) ^- .

Example 17
N-hydroxy-4- (1-{[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] carbonyl} cyclohexyl) benzamide

(Step 1) tert-butyl 4-({4-[(1- {4-[(benzyloxy) carbonyl] phenyl} cyclohexyl) carbonyl] -1,4-oxazepan-6-yl} methyl) -1H-indazole -1-carboxylate The compound obtained in Step 5 of Reference Example B-7 (1.84 g), dichloromethane (25 mL), thionyl chloride (0.985 mL), N, N-dimethylformamide (0.035 mL) was stirred at 40 ° C. for 2 hours. After returning the reaction solution to room temperature, the solvent was distilled off under reduced pressure to obtain a crude acid chloride. To a mixture of the compound (1.50 g) obtained in Step 4A of Reference Example A-1, dichloromethane (25 mL), and N, N-diisopropylethylamine (1.58 mL), the crude acid was added under ice-cooling. A solution of chloride in dichloromethane (25 mL) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution to which 1 mol / L hydrochloric acid was added was extracted with dichloromethane, and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to amino silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (2.29 g) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.25 (1H, s), 1.54 (6H, s), 1.67 (10H, s), 1.93-2.10 (2H, m), 2.19-2.21 (1H , m), 2.55-2.63 (1H, m), 2.68-2.76 (1H, m), 2.79-2.89 (1H, m), 3.08-3.15 (1H, m), 3.27-3.51 (5H, m), 3.62 (1H, br s), 5.35 (2H, s), 6.98-7.02 (1H, m), 7.19-7.23 (2H, m), 7.33-7.46 (6H, m), 7.85-7.87 (2H, m), 7.93-7.95 (1H, m), 8.33 (1H, s) .MS (m / z): 552 (M + H-Boc) ⁺ .

(Step 2) 4- {1-[(6-{[1- (tert-butoxycarbonyl) -1H-indazol-4-yl] methyl} -1,4-oxazepan-4-yl) carbonyl] cyclohexyl} benzoate Acid Using the compound (2.28 g) obtained in the above Step 1 and 10% palladium-carbon (1.01 g), the same operation as in Step 4B of Reference Example A-1 was performed to give the title compound (2.07 g) was obtained as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.22 (1H, s), 1.46-1.68 (16H, m), 2.00-2.10 (2H, m), 2.16-2.24 (1H, m), 2.55 -2.90 (3H, m), 3.00-3.15 (1H, m), 3.28-3.64 (6H, m), 7.01-7.06 (1H, m), 7.15-7.20 (2H, m), 7.45-7.50 (1H, m m), 7.80-7.85 (2H, m), 7.95-7.97 (1H, m), 8.37 (1H, s), 12.50 (1H, br s) .MS (m / z): 462 (M + H-Boc ) ⁺ .

(Step 3) tert-butyl 4-{[4-({1- [4- (hydroxycarbamoyl) phenyl] cyclohexyl} carbonyl) -1,4-oxazepan-6-yl] methyl} -1H-indazole-1- Carboxylate The compound obtained in the above step 2 (400 mg), N, N-dimethylformamide (10 mL), EDCI (215 mg), 1-hydroxybenzotriazole (115 mg, CAS number: 2592-95-2) , N, N-diisopropylethylamine (0.620 mL) was stirred at room temperature for 2 hours, then hydroxylamine hydrochloride (150 mg, CAS No .: 5470-11-1) was added, and the mixture was stirred at room temperature for 5 半 hours. . The reaction mixture to which 1 mol / L hydrochloric acid was added was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline in this order, and then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to high-performance liquid chromatography (NOMURA Developersil Combi, acetonitrile / water / 0.1% formic acid). After evaporating the organic solvent under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the title compound (255 mg) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.25 (1H, s), 1.52-1.67 (16H, m), 2.01-2.23 (3H, m), 2.58-2.77 (2H, m), 2.83 -2.92 (1H, m), 3.01-3.15 (1H, m), 3.25-3.59 (6H, m), 7.01-7.06 (1H, m), 7.14-7.19 (2H, m), 7.49 (1H, t, J = 7.9 Hz), 7.69 (2H, d, J = 7.9 Hz), 7.95 (1H, d, J = 8.5 Hz), 8.39 (1H, s), 8.71 (1H, s), 10.95 (1H, s) MS (m / z): 577 (M + H) ⁺ .

(Step 4) N-hydroxy-4- (1-{[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] carbonyl} cyclohexyl) benzamide Compound obtained in Step 3 above (250 mg) and trifluoroacetic acid (4 mL), and the same operation as in step 2 of Example 3 was performed to obtain the title compound (133 mg) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.17-1.28 (1H, m), 1.40-1.74 (7H, m), 1.97-2.22 (3H, m), 2.52-2.60 (1H, m) , 2.64-2.70 (1H, m), 2.77-2.86 (1H, m), 3.02-3.16 (1H, m), 3.28-3.57 (6H, m), 6.72-6.76 (1H, m), 7.12-7.14 ( 2H, m), 7.21-7.26 (1H, m), 7.37-7.40 (1H, m), 7.68 (2H, d, J = 7.9 Hz), 8.01 (1H, s), 8.71 (1H, s), 10.95 (1H, s), 12.83 (1H, s). MS (m / z): 477 (M + H) ⁺ .

Example 18
[6- (1H-indazol-3-ylmethyl) -1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone

(Step 1) tert-butyl 3-[(4-{[1- (4-methoxyphenyl) cyclohexyl] carbonyl} -1,4-oxazepan-6-yl) methyl] -1H-indazole-1-carboxylate Reference Compound (150 mg) obtained in Step 2 of Example D-1, 9-borabicyclo [3.3.1] nonane (0.50 mol / L, tetrahydrofuran solution, 1.82 mL), Reference Example C-1 (135 mg), N, N-dimethylformamide (2 mL), water (0.2 mL), potassium carbonate (81.8 mg), [1,1′-bis (diphenylphosphino) Ferrocene] palladium (II) dichloride dichloromethane complex (37.2 mg) was used to perform the same operation as in Step 3 of Reference Example A-1 to give the title compound (150 mg). It was obtained as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.21-1.30 (1H, m), 1.37-1.70 (7H, m), 1.68 (9H, s), 2.10-2.29 (3H, m), 2.60 -2.77 (2H, m), 2.82-2.90 (1H, m), 3.08-3.16 (1H, m), 3.28-3.47 (3H, m), 3.52-3.58 (1H, m), 3.61-3.73 (5H, m), 6.72-6.78 (2H, m), 6.96-7.02 (2H, m), 7.32-7.38 (1H, m), 7.55-7.61 (1H, m), 7.69-7.74 (1H, m), 8.05- 8.09 (1H, m) .MS (m / z): 548 (M + H) ⁺ .

(Step 2) [6- (1H-indazol-3-ylmethyl) -1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone The compound obtained in the above step 1 (140 mg) ) And trifluoroacetic acid (1 mL), and the same operation as in step 2 of Example 3 was performed to obtain the title compound (63 mg) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.19-1.29 (1H, m), 1.42-1.68 (7H, m), 2.09-2.15 (1H, m), 2.16-2.24 (2H, m) , 2.59-2.71 (2H, m), 2.80-2.89 (1H, m), 3.09-3.17 (1H, m), 3.29-3.45 (3H, m), 3.50-3.54 (1H, m), 3.58-3.68 ( 2H, m), 3.70 (3H, s), 6.78-6.82 (2H, m), 6.99-7.03 (2H, m), 7.04-7.08 (1H, m), 7.29-7.33 (1H, m), 7.46 ( 1H, d, J = 8.5 Hz), 7.58 (1H, d, J = 8.5 Hz), 12.41 (1H, br s). MS (m / z): 448 (M + H) ⁺ .

  The following compounds were synthesized by combining and carrying out the same operations as in each step of Example 18 or Step 2 of Example 1.

Example 25
2-acetamido-N- (4-{[4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] carbonyl} -1,4-oxazepan-6-yl) -1,3-thiazole-4 -Carboxamide

The compound obtained in Step 4 of Reference Example E-1 (55 mg), 2-acetamido-1,3-thiazole-4-carboxylic acid (28 mg, Heterocycles, 45, 1299-1308 (1997)), N, The same operation as in Step 2 of Reference Example D-1 was performed using N-diisopropylethylamine (0.057 mL) and HATU (69 mg) to obtain the title compound (47 mg) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.87-1.94 (2H, m), 2.15-2.16 (3H, m), 2.19-2.28 (2H, m), 3.18-3.38 (4H, m) , 3.41-3.47 (1H, m), 3.55-3.77 (10H, m), 4.01-4.05 (1H, m), 6.90-6.94 (2H, m), 7.17-7.21 (2H, m), 7.54-7.56 ( 1H, m), 7.69-7.70 (1H, m), 11.88 (1H, s) .MS (m / z): 503 (M + H) ⁺ .

Example 26
[6- (1H-indazol-4-ylamino) -1,4-oxazepan-4-yl] [4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] methanone

(Step 1) tert-butyl 4-[(4-{[4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] carbonyl} -1,4-oxazepan-6-yl) amino] -1H -Indazole-1-carboxylate The compound obtained in Step 4 of Reference Example E-1 (100 mg), tert-butyl 4-bromo-1H-indazole-1-carboxylate (88.9 mg), cesium carbonate ( 195 mg), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (34.6 mg, CAS No .: 161265-03-8), tris (dibenzylideneacetone) dipalladium (0) (27 0.4 mg, CAS number: 51364-51-3) and 1,4-dioxane (2 mL) were mixed using a microwave heating synthesizer. 2 hours at 00 ℃, and the mixture was stirred for 2 hours at 130 ℃. The reaction solution was filtered through celite, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (dichloromethane / methanol), followed by amino silica gel column chromatography (n-hexane / ethyl acetate) to give the title. The compound (50 mg) was obtained as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.63 (9H, s), 1.88-1.98 (2H, m), 2.23-2.27 (2H, m), 3.09-3.16 (3H, m), 3.40 -3.46 (1H, m), 3.55-3.74 (11H, m), 4.02-4.05 (1H, m), 5.96-6.00 (1H, m), 6.28-6.32 (1H, m), 6.90-6.93 (2H, m), 7.21-7.27 (4H, m), 8.42 (1H, s) .MS (m / z): 451 (M + H-Boc) ⁺ .

(Step 2) [6- (1H-indazol-4-ylamino) -1,4-oxazepan-4-yl] [4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] methanone Step 1 above The title compound (20 mg) was obtained as a solid by performing the same operation as in Step 2 of Example 3 using the compound (48 mg) obtained in and a trifluoroacetic acid (0.33 mL).
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.86-1.97 (2H, m), 2.23-2.28 (2H, m), 3.12-3.21 (3H, m), 3.37-3.43 (1H, m) , 3.50-3.76 (11H, m), 3.98-4.05 (1H, m), 5.54-5.58 (1H, m), 5.99-6.02 (1H, m), 6.69-6.71 (1H, m), 6.91-6.95 ( 2H, m), 7.02-7.06 (1H, m), 7.20-7.24 (2H, m), 8.06 (1H, s), 12.43 (1H, br s) .MS (m / z): 451 (M + H ) ⁺ .

Example 27
[6- (1H-indazol-4-yloxy) -1,4-oxazepan-4-yl] [4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] methanone

(Step 1) tert-butyl 4-[(4-{[4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] carbonyl} -1,4-oxazepan-6-yl) oxy] -1H -Indazole-1-carboxylate The compound obtained in Step 2 of Reference Example E-2 (100 mg), the compound obtained in Reference Example C-6 (69.8 mg), triphenylphosphine (196 mg), Diisopropyl azodicarboxylate (0.147 mL, CAS No .: 2446-83-5) was added dropwise to a mixture of toluene (2 mL) under ice cooling, and the mixture was stirred at the same temperature for 5 minutes and at 60 ° C for 5 hours. After magnesium chloride (142 mg, CAS number: 7786-30-3) was added to the reaction solution, the mixture was stirred at 60 ° C for 1 hour. After cooling to room temperature, the reaction solution was diluted with toluene, and insolubles were removed by filtration. The residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (n-hexane / ethyl acetate), and then reversed-phase preparative HPLC (Unipoint, Gilson, 0.1% formic acid aqueous solution-0.1% formic acid solution) (Acetonitrile solution). The fraction containing the title compound was diluted with a saturated aqueous solution of sodium hydrogen carbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (11 mg) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.65 (9H, s), 1.83-1.99 (2H, m), 2.18-2.27 (2H, m), 3.16-3.25 (1H, m), 3.38 -3.45 (1H, m), 3.49-3.76 (11H, m), 3.78-3.84 (1H, m), 4.06-4.13 (1H, m), 4.54-4.61 (1H, m), 6.77-6.81 (1H, m m), 6.89-6.93 (2H, m), 7.18-7.22 (2H, m), 7.45-7.50 (1H, m), 7.64-7.67 (1H, m), 8.21 (1H, s) .MS (m / z): 452 (M + H-Boc) ⁺ .

(Step 2) [6- (1H-indazol-4-yloxy) -1,4-oxazepan-4-yl] [4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] methanone Step 1 above Using the compound obtained in the above (11 mg) and trifluoroacetic acid (0.3 mL), the same operation as in Step 2 of Example 3 was performed to obtain the title compound (6.33 mg) as a solid. Was.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.85-1.96 (2H, m), 2.20-2.27 (2H, m), 3.17-3.24 (1H, m), 3.33-3.38 (1H, m) , 3.52-3.74 (11H, m), 3.79-3.84 (1H, m), 4.10-4.16 (1H, m), 4.50-4.55 (1H, m), 6.46-6.48 (1H, m), 6.90-6.92 ( 2H, m), 7.08-7.11 (1H, m), 7.18-7.22 (3H, m), 7.92 (1H, s), 12.75 (1H, br s) .MS (m / z): 452 (M + H ) ⁺ .

Example 28
[1- (4-methoxyphenyl) cyclohexyl] {6-[(1H-pyrazol-4-yloxy) methyl] -1,4-oxazepan-4-yl} methanone

(Step 1) tert-butyl 4-[(4-{[1- (4-methoxyphenyl) cyclohexyl] carbonyl} -1,4-oxazepan-6-yl) methoxy] -1H-pyrazole-1-carboxylate Reference Compound obtained in Example E-3 (130 mg), tert-butyl 4-hydroxy-1H-pyrazole-1-carboxylate (69.0 mg, US 2016/95858 A1), toluene (4 mL), tri-n To a mixture of -butylphosphine (0.140 mL, CAS number: 998-40-3) was added 1,1 '-(azodicarbonyl) dipiperidine (142 mg, CAS number: 10465-81-3) under ice-cooling. Was added and stirred at room temperature overnight. The reaction solution diluted with toluene was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (127 mg) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.25-1.31 (1H, m), 1.54-1.73 (16H, m), 2.04-2.11 (1H, m), 2.22-2.27 (2H, m) , 3.00-3.06 (1H, m), 3.12-3.18 (1H, m), 3.21-3.26 (1H, m), 3.34-3.43 (2H, m), 3.50-3.55 (2H, m), 3.63-3.73 ( 6H, m), 6.87-6.89 (2H, m), 7.15-7.18 (2H, m), 7.56 (1H, s), 7.74 (1H, s) .MS (m / z): 414 (M + H- Boc) ⁺ .

(Step 2) [1- (4-methoxyphenyl) cyclohexyl] {6-[(1H-pyrazol-4-yloxy) methyl] -1,4-oxazepan-4-yl} methanone The compound obtained in the above step 1 (124 mg) and trifluoroacetic acid (1 mL), and the same operation as in step 2 of Example 3 was performed to obtain the title compound (67.9 mg) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.25-1.30 (1H, m), 1.53-1.73 (7H, m), 2.05-2.11 (1H, m), 2.23-2.26 (2H, m) , 2.96-3.02 (1H, m), 3.12-3.26 (2H, m), 3.35-3.43 (2H, m), 3.51-3.57 (4H, m), 3.68-3.72 (4H, m), 6.89 (2H, m d, J = 8.5 Hz), 7.16 (2H, d, J = 8.5 Hz), 7.22 (2H, s) .MS (m / z): 414 (M + H) ⁺ .

Example 29
6- (1H-indazol-4-ylmethyl) -N- (4-methoxyphenyl) -N-methyl-1,4-oxazepan-4-carboxamide

(Step 1) tert-butyl 4-({4-[(4-methoxyphenyl) (methyl) carbamoyl] -1,4-oxazepan-6-yl} methyl) -1H-indazole-1-carboxylate 4-methoxy To a solution of -N-methylaniline (93 mg, CAS number: 5961-59-1) in 1,2-dichloroethane (5.0 mL) under ice cooling, triethylamine (0.126 mL) and triphosgene (67 mg). After stirring at room temperature for 1.5 hours, a solution of the compound (150 mg) obtained in Step 4A of Reference Example A-1 in 1,2-dichloroethane (5.0 mL) was added, and the mixture was heated at 70 ° C. for 1 hour. Stirred. After returning to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution. The reaction mixture was extracted with dichloromethane, and the organic layer was washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (152 mg) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.74 (9H, s), 2.05-2.11 (1H, m), 2.72-2.84 (2H, m), 2.93 (1H, dd, J = 14.5, 9.1 Hz), 3.02 -3.10 (4H, m), 3.42-3.56 (4H, m), 3.57-3.67 (2H, m), 3.78 (3H, s), 6.77 (2H, s), 6.92 (2H, d, J = 8.5 Hz ), 7.03 (1H, d, J = 7.9 Hz), 7.42 (1H, t, J = 7.9 Hz), 8.03 (1H, d, J = 7.9 Hz), 8.14 (1H, s) .MS (m / z ): 495 (M + H) ⁺ .

(Step 2) 6- (1H-indazol-4-ylmethyl) -N- (4-methoxyphenyl) -N-methyl-1,4-oxazepan-4-carboxamide The compound obtained in the above Step 1 (152 mg) Using hydrogen chloride (4 mol / L, 1,4-dioxane solution, 2.0 mL) in the same manner as in Step 2 of Example 1, the title compound (70.0 mg) was solid. As obtained.
¹ H-NMR (CDCl ₃ ) δ: 2.09-2.18 (1H, m), 2.73-2.84 (2H, m), 2.95 (1H, dd, J = 14.2, 9.4 Hz), 3.06-3.11 (4H, m) , 3.47-3.57 (4H, m), 3.58-3.68 (2H, m), 3.78 (3H, s), 6.78 (2H, d, J = 9.1 Hz), 6.88 (1H, d, J = 8.5 Hz), 6.92 (2H, d, J = 9.1 Hz), 7.26-7.30 (1H, m), 7.35 (1H, d, J = 8.5 Hz), 8.02 (1H, s), 10.15 (1H, s) .MS (m / z): 395 (M + H) ⁺ .

Example 30
3-[(4-{[1- (4-methoxyphenyl) cyclohexyl] carbonyl} -1,4-oxazepan-6-yl) methyl] benzamide

(Step 1)-(4-Methoxyphenyl) cyclohexyl] carbonyl {-1,4-oxazepan-6-yl) methyl] ethyl benzoate The compound obtained in Step 2 of Reference Example D-1 (0.400 g) , 9-borabicyclo [3.3.1] nonane (0.50 mol / L, tetrahydrofuran solution, 4.86 mL), ethyl 3-iodobenzoate (0.202 mL, CAS number: 58313-23-8) , N, N-dimethylformamide (5 mL), water (0.5 mL), potassium carbonate (0.218 g) and [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex The title compound (0.180 g) was obtained as a solid by performing the same operation as in Step 3 of Reference Example A-1 using (0.0992 g).
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.21-1.30 (1H, m), 1.34 (3H, t, J = 7.3 Hz), 1.46-1.71 (7H, m), 1.85-1.93 (1H , m), 2.07-2.15 (1H, m), 2.17-2.23 (1H, m), 2.28-2.36 (1H, m), 2.40-2.47 (1H, m), 2.77-2.85 (1H, m), 3.09 -3.16 (1H, m), 3.21-3.67 (6H, m), 3.72 (3H, s), 4.34 (2H, q, J = 7.3 Hz), 6.82-6.87 (2H, m), 7.03-7.07 (2H , m), 7.32-7.36 (1H, m), 7.40-7.44 (1H, m), 7.67 (1H, s), 7.77-7.83 (1H, m) .MS (m / z): 480 (M + H ) ⁺ .

(Step 2) 3-[(4-{[1- (4-methoxyphenyl) cyclohexyl] carbonyl} -1,4-oxazepan-6-yl) methyl] benzoic acid The compound obtained in the above step 1 (0. 176 g), a mixture of tetrahydrofuran (1 mL), a 5 mol / L aqueous sodium hydroxide solution (0.5 mL), and ethanol (1 mL) were stirred overnight. The reaction was diluted with water and washed twice with diethyl ether. The aqueous layer was acidified with 1 mol / L hydrochloric acid, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give the title compound (0.169 g) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.21-1.30 (1H, m), 1.45-1.68 (7H, m), 1.85-1.93 (1H, m), 2.07-2.14 (1H, m) , 2.16-2.23 (1H, m), 2.27-2.35 (1H, m), 2.39-2.44 (1H, m), 2.75-2.83 (1H, m), 3.08-3.17 (1H, m), 3.21-3.47 ( 4H, m), 3.49-3.67 (2H, m), 3.73 (3H, s), 6.82-6.87 (2H, m), 7.02-7.07 (2H, m), 7.28-7.32 (1H, m), 7.36- 7.40 (1H, m), 7.65 (1H, s), 7.75-7.80 (1H, m) .MS (m / z): 452 (M + H) ⁺ .

(Step 3) 3-[(4-{[1- (4-methoxyphenyl) cyclohexyl] carbonyl} -1,4-oxazepan-6-yl) methyl] benzamide The compound obtained in the above step 2 (53.0 mg), N, N-dimethylformamide (1 mL), ammonia (7 mol / L, methanol solution, 0.168 mL), 1-hydroxybenzotriazole (24 mg) and EDCI (34 mg) at room temperature. Stirred overnight. The reaction solution was diluted with ethyl acetate, washed sequentially with water, a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, and then dried over anhydrous sodium sulfate. After filtration, the concentrated residue was subjected to silica gel column chromatography (methanol / dichloromethane). The residue obtained by evaporating the solvent under reduced pressure was washed with slurry with diisopropyl ether to obtain the title compound (35.4 mg) as a solid.
¹ H-NMR (DMSO-D ₆ , 100 ° C) δ: 1.19-1.31 (1H, m), 1.44-1.71 (7H, m), 1.89-1.98 (1H, m), 2.07-2.14 (1H, m) , 2.17-2.24 (1H, m), 2.27-2.34 (1H, m), 2.37-2.43 (1H, m), 2.75-2.83 (1H, m), 3.08-3.16 (1H, m), 3.23-3.47 ( 4H, m), 3.51-3.67 (2H, m), 3.73 (3H, s), 6.84-6.88 (2H, m), 7.02-7.07 (2H, m), 7.18-7.36 (2H, m), 7.60 ( 1H, s), 7.68-7.71 (1H, m) .MS (m / z): 451 (M + H) ⁺ .

(Formulation example)
Formulation Example 1 (injection)
1.5% by weight of the example compound is stirred in 10% by volume of propylene glycol, then adjusted to a constant volume with water for injection, and then sterilized to give an injection.

Formulation Example 2 (hard capsule)
A mixture of 100 mg of the powdered example compound, 128.7 mg of lactose, 70 mg of cellulose, and 1.3 mg of magnesium stearate was passed through a 60-mesh sieve, and the resulting powder was mixed with 250 mg of No. 3 gelatin. Put in a capsule to make a capsule.

Formulation Example 3 (tablet)
100 mg of the powdered example compound, 124 mg of lactose, 25 mg of cellulose and 1 mg of magnesium stearate are mixed, and the mixture is compressed with a tablet machine to give one tablet of 250 mg. The tablets can be sugar-coated as needed.

(Test example)
The pharmacological activity of the compound of the present invention was confirmed by the following test.

[Test Example] Evaluation of EP300 and CREBBP histone acetyltransferase inhibitory activities 10 μL of a reaction solution (50 mM Tris-containing) containing the compounds of Examples 1, 4, 6, 11, 13b, 15, 19, 20, and 22 at different concentrations. HCl (pH 8.0), 0.1 mM EDTA, 1 mM dithiothreitol, 0.01% Tween-20, 0.01% Bovine serum albumin, 330 nM trichostatin A, 2 μM Acetyl-CoA (Sigma-Aldrich, # A2056), 100 nM Histone H4 (1-25) -GSGSK (Biotin) (Anaspec, # 65242-1), 1% dimethyl sulfoxide, 10-0.0006 μM compounds, 50 ng / mL EP300 or 125 ng / mL CREBBP) in each well of a 384-well plate And cultured at 28 ° C. for 1 hour. Thereafter, 5 μL of 30 μM Lys-CoA (Daiichi Sankyo Co., Ltd.) dissolved in LANCE detection buffer (Perkin Elmer, # CR97-100) was added to each well, and further 2 nM Eu-anti pan-Ac ( 5 μL of a LANCE detection buffer containing Perkin Elmer (# TRF0412) and 50 nM Sta-Ulight (Perkin Elmer, # TRF0102) was added to each well, followed by culturing at room temperature overnight. ULight signal was measured with EnVision (PerkinElmer, model 2104-0020). The enzyme inhibition rate of the example compound at each concentration was measured based on the measured ULight signal, and the obtained data was analyzed with medical statistical analysis software GraphPad Prism (GraphPad Software, Inc.) to calculate an IC ₅₀ value. . EP300 and CREBBP were produced and purified by Daiichi Sankyo RD Novale Co., Ltd.

  Table 5 shows the results of the test examples.

  The compound represented by the general formula (1) or a pharmacologically acceptable salt thereof of the present invention has excellent EP300 / CREBP histone acetyltransferase inhibitory activity and is therefore useful as a therapeutic agent for tumors. Specifically, the compound represented by the general formula (1) of the present invention or a pharmacologically acceptable salt thereof may be used as a tumor, preferably a prostate cancer, a liver cancer, a lung cancer, a breast cancer, a colon cancer, Stomach cancer, blood cancer, pancreatic cancer, esophageal cancer, bladder cancer, gastrointestinal stromal tumor, NUT midline carcinoma, or ovarian cancer, more preferably prostate cancer, lung cancer, blood cancer, esophagus It is useful as a therapeutic agent for NUT midline carcinoma.

Claims (21)

A compound represented by the following general formula (1) or a pharmacologically acceptable salt thereof.
[Where,
Ring Q ¹ is, have from 1 to 3 substituents independently selected substituents independently selected from the following group A 1 to 3 optionally having phenyl group or the following group A, A nitrogen atom, an oxygen atom, and a 5- or 6-membered aromatic heterocyclic group having 1 or 2 hetero atoms in a ring independently selected from the group consisting of a sulfur atom;
The ring Q ² may have one or two substituents independently selected from the following group B. In addition to the nitrogen atom shown in the general formula (1), a nitrogen atom, an oxygen atom, and a sulfur A 5- to 8-membered heterocycloalkyl ring which may have one heteroatom in the ring independently selected from the group consisting of atoms,
Ring Q ³ has a phenyl group which may have 1 to 3 substituents independently selected from the following group C, and has 1 to 3 substituents independently selected from the following group C A 5- or 6-membered aromatic heterocyclic group having 1 or 2 heteroatoms in the ring independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; An 8- to 10-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom which may have 1 to 3 substituents selected A bicyclic aromatic heterocyclic group of
L _{is, - (CH 2) m -} , or indicates one of the following formulas (2A) to (2C),
(Where
* It is attached to the ring ^{Q 2,}
** is bonded to ring Q ³ ,
m represents an integer of 1 to 3,
n represents an integer of 0 to 2,
p represents an integer of 0 to 2,
R ¹ represents a hydrogen atom or a C _1-6 alkyl group,
R ² represents a hydrogen atom or a methyl group. )
X is, ^-CR 3 ^{R 4} - or -NR ⁵ - indicates,
R ³ and R ⁴ each independently represent a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,
Or
R ³ and R ⁴ together with the carbon atom to which R ³ and R ⁴ are bonded may have 3 to 3 members which may have 1 to 3 substituent (s) independently selected from the following group D A 7-membered cycloalkyl ring, a tetrahydropyran ring optionally having 1 to 3 substituents independently selected from Group D below, or 1 to 3 substituents independently selected from Group D below Forming an indane ring which may have
R ⁵ represents a hydrogen atom or a C _1-6 alkyl group. ]
Group A: halogen atom, hydroxy group, carboxy group, C _1-6 alkyl group, hydroxy C _1-6 alkyl group, C _1-6 alkoxy group, halogeno C _1-6 alkoxy group, C _2-7 alkanoyl group, C _2-7 alkanoylamino group, phenyl group, carbamoyl group, (C _3-7 cycloalkyl) sulfonylcarbamoyl group, hydroxycarbamoyl group, tetrazolyl group, 1-benzyl-carboxy-4-oxo-3-pyridinyl group B: halogen Atom, C _1-6 alkyl group, oxo group Group C: halogen atom, cyano group, amino group, C _1-6 alkyl group, C _1-6 alkoxy group, hydroxy C _1-6 alkyl group, C _1-6 alkyl Amino group, C _1-6 alkoxy C _1-6 alkyl group, hydroxy group, halogeno C _1-6 alkyl group, C _2-7 Lucanoylamino group, halogeno C _1-6 alkoxy group, C _1-6 alkylsulfonylamino group, carbamoyl group D group: halogen atom, C _1-6 alkyl group When the ring Q ² is a pyrrolidine ring, piperidine ring, azepan ring, oxazepan ring, diazepan ring, or oxazocan ring (the pyrrolidine ring, piperidine ring, azepan ring, oxazepan ring, diazepan ring, or oxazocan ring is an oxo group or C ₁ Or a pharmacologically acceptable salt thereof according to claim 1, wherein the compound may have one _-6 alkyl group). Ring Q ² indicates one of the following formulas (3A) to (3G), a compound or a pharmacologically acceptable salt thereof according to claim 1.
[Where,
* Is attached to the carbon atom of the carbonyl group,
** is linked to L,
R ⁶ represents a hydrogen atom or a methyl group. ] 4. The method according to claim 1, wherein L represents —CH ₂ —, —NH—, —N (CH ₃ ) —, an oxygen atom, or one of the following formulas (4A) to (4C). 5. Or a pharmacologically acceptable salt thereof.
[Where,
* It is attached to the ring ^{Q 2,}
** it is attached to the ring ^{Q 3.} ] The compound according to any one of claims 1 to 4, wherein the ring Q ¹ represents ^one of the following formulas (5A) to (5C), or a pharmaceutically acceptable salt thereof.
[Where,
* Indicates a bond,
R ⁷ , R ⁸ , and R ⁹ each independently represent a hydrogen atom, a halogen atom, a hydroxy group, a C _1-6 alkoxy group, a hydroxycarbamoyl group, or a tetrazolyl group;
R ¹⁰ represents a hydrogen atom or a C _1-6 alkoxy group,
R ¹¹ represents a hydrogen atom or a 1-benzyl-carboxy-4-oxo-3-pyridinyl group. ] Ring Q ¹ is 4-hydroxyphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-hydroxycarbamoyl, 3,4-dimethoxyphenyl, 3-pyridinyl, 4- (tetrazol-5-yl) The compound according to any one of claims 1 to 4, which is a phenyl group or a 5- (1-benzyl-5-carboxy-4-oxo-3-pyridinyl) -2-thienyl group, or a pharmaceutically acceptable compound thereof. Salt. Ring Q ³ is a phenyl group (the phenyl group may have one carbamoyl group), a thiazolyl group (the thiazolyl group may have one C _2-7 alkanoylamino group) ) Or a pyrazolyl group, or a pharmacologically acceptable salt thereof, according to any one of claims 1 to 6. Ring ^{Q 3} is 3-carbamoyl phenyl group, 2-acetamide-4-yl group, or a 1H- pyrazol-4-yl group, a compound or a pharmacologically according to any one of claims 1 to 6 Above acceptable salts. Ring Q ³ indicates the following formula (6A) or (6B), a compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 6.
[Where,
* Indicates a bond,
Z represents a nitrogen atom or CR ¹³ ;
R ¹² represents a hydrogen atom or a halogen atom,
R ¹³ represents a hydrogen atom or a C _1-6 alkyl group. ] Ring Q ³ indicates one of the following formulas (7A) to (7F), a compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 6.
[In the formula, * represents a bond. ] X is, -CH ₂ - or -N (CH ₃₎ - a compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 10. X is, ^-CR 3 ^{R 4} - a and,
R ³ and R ⁴ together with the carbon atom to which R ³ and R ⁴ are attached form a cyclopentane ring, a cyclohexane ring, a tetrahydropyran ring, a [3.3] heptane ring, or an indane ring A compound according to any one of claims 1 to 10 or a pharmacologically acceptable salt thereof. X is, ^-CR 3 ^{R 4} - a and,
R ³ and R ⁴ together with the carbon atom to which R ³ and R ⁴ are attached, a cyclopentane ring, form a cyclohexane ring or 4-tetrahydropyran ring, any one of claims 1 to 10 Item 4. The compound according to item 1 or a pharmacologically acceptable salt thereof. Ring Q ¹ is 4-hydroxyphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-hydroxycarbamoylphenyl, 3,4-dimethoxyphenyl, 3-pyridinyl, 4- (tetrazol-5-yl ) Represents either a phenyl group or a 5- (1-benzyl-5-carboxy-4-oxo-3-pyridinyl) -2-thienyl group;
Ring Q ² represents any of formulas (3A) to (3G) below;
[Where,
* Is attached to the carbon atom of the carbonyl group,
** is linked to L,
R ⁶ represents a hydrogen atom or a methyl group. ]
Ring ^{Q 3} is 3-carbamoyl phenyl group, 2-acetamide-4-yl group, 1H-pyrazol-4-yl group, or indicates one of the following formulas (7A) to (7F),;
[In the formula, * represents a bond. ]
L _{is, -CH 2 -, - NH -} , - N (CH 3) -, indicates one of an oxygen atom or the following formula, (4A) to (4C);
[Where,
* It is attached to the ring ^{Q 2,}
** it is attached to the ring ^{Q 3.} ]
X is, ^-CR 3 ^{R 4} - a and,
R ³ and R ⁴ together with the carbon atom to which R ³ and R ⁴ are attached form a cyclopentane ring, a cyclohexane ring, or a 4-tetrahydropyran ring;
A compound according to claim 1 or a pharmacologically acceptable salt thereof. Any compound selected from the following group or a pharmacologically acceptable salt thereof.
[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] [4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] methanone,
1- [6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] -2- (4-methoxyphenyl) ethanone,
[3- (1H-indazol-4-ylmethyl) azepan-1-yl] [2- (4-methoxyphenyl) spiro [3.3] heptane-2-yl] methanone,
[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone,
[3- (1H-indazol-4-ylmethyl) piperidin-1-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone,
[1- (4-chlorophenyl) cyclohexyl] [6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] methanone,
[3- (1H-indazol-4-ylmethyl) azepan-1-yl] [2- (4-methoxyphenyl) -2,3-dihydro-1H-inden-2-yl] methanone,
3- (1H-indazol-4-ylmethyl) -1-{[1- (4-methoxyphenyl) cyclohexyl] carbonyl} piperidin-4-one,
{(2R) -2-[(1H-indazol-4-ylamino) methyl] pyrrolidin-1-yl} [1- (4-methoxyphenyl) cyclopentyl] methanone,
[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] [1- (pyridin-3-yl) cyclohexyl] methanone,
[6- (1H-indazol-4-ylmethyl) -1,4-diazepan-1-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone,
[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] {1- [4- (2H-tetrazol-5-yl) phenyl] cyclohexyl} methanone,
[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclopentyl] methanone,
(+)-[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclopentyl] methanone,
[1- (4-hydroxyphenyl) cyclohexyl] [3- (1H-indazol-4-ylmethyl) azepan-1-yl] methanone,
[1- (3,4-dimethoxyphenyl) cyclopentyl] [3- (1H-indazol-4-ylmethyl) azepan-1-yl] methanone,
1-benzyl-5- [5- (1-{[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] carbonyl} cyclohexyl) thiophen-2-yl] -4-oxo -1,4-dihydropyridine-3-carboxylic acid,
N-hydroxy-4- (1-{[6- (1H-indazol-4-ylmethyl) -1,4-oxazepan-4-yl] carbonyl} cyclohexyl) benzamide;
[6- (1H-indazol-3-ylmethyl) -1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone,
[1- (4-methoxyphenyl) cyclohexyl] [6- (1H-pyrazolo [3,4-b] pyridin-4-ylmethyl) -1,4-oxazepan-4-yl] methanone,
[1- (4-methoxyphenyl) cyclohexyl] [6- (1H-pyrazolo [4,3-c] pyridin-4-ylmethyl) -1,4-oxazepan-4-yl] methanone,
[3- (1H-indazol-4-ylmethyl) -1,5-oxazocan-5-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone,
{6-[(6-fluoro-1H-indazol-4-yl) methyl] -1,4-oxazepan-4-yl} [1- (4-methoxyphenyl) cyclohexyl] methanone,
[6- (1H-indazol-4-ylmethyl) -2-methyl-1,4-oxazepan-4-yl] [1- (4-methoxyphenyl) cyclohexyl] methanone,
[1- (4-methoxyphenyl) cyclohexyl] {3-[(7-methyl-1H-indazol-4-yl) methyl] azepan-1-yl} methanone,
2-acetamido-N- (4-{[4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] carbonyl} -1,4-oxazepan-6-yl) -1,3-thiazole-4 -Carboxamide,
[6- (1H-indazol-4-ylamino) -1,4-oxazepan-4-yl] [4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] methanone,
[6- (1H-indazol-4-yloxy) -1,4-oxazepan-4-yl] [4- (4-methoxyphenyl) tetrahydro-2H-pyran-4-yl] methanone,
[1- (4-methoxyphenyl) cyclohexyl] {6-[(1H-pyrazol-4-yloxy) methyl] -1,4-oxazepan-4-yl} methanone,
6- (1H-indazol-4-ylmethyl) -N- (4-methoxyphenyl) -N-methyl-1,4-oxazepan-4-carboxamide;
3-[(4-{[1- (4-methoxyphenyl) cyclohexyl] carbonyl} -1,4-oxazepan-6-yl) methyl] benzamide   A pharmaceutical composition comprising the compound according to any one of claims 1 to 15 or a pharmacologically acceptable salt thereof as an active ingredient.   An EP300 and / or CREBBP inhibitor comprising the compound according to any one of claims 1 to 15 or a pharmacologically acceptable salt thereof as an active ingredient.   An antitumor agent comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof as an active ingredient.   If the tumor is prostate, liver, lung, breast, colorectal, stomach, blood, pancreas, esophagus, bladder, gastrointestinal stromal tumor, NUT midline carcinoma, or ovary 19. The antitumor agent according to claim 18, which is an antitumor agent.   A method for treating a tumor, comprising administering the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.   If the tumor is prostate, liver, lung, breast, colorectal, stomach, blood, pancreas, esophagus, bladder, gastrointestinal stromal tumor, NUT midline carcinoma, or ovary 21. The treatment method according to claim 20, wherein