JP2016056133A - Pyrazolone derivative having cyclic side chain - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound that has excellent inhibitory action on ATPase activity of TIP48/TIP49 complex and is therefore useful for the treatment of tumor, or a pharmacologically acceptable salt thereof.SOLUTION: The present invention provides a compound having a structure represented by general formula (I), its pharmacologically acceptable salt, or a pharmaceutical composition comprising the compound (where R, R, R, R, R, R, R, W, and Z are as defined in the specifications).SELECTED DRAWING: None

Description

  The present invention relates to a compound having a specific chemical structure having an inhibitory effect on ATPase activity of an excellent TIP48 / TIP49 complex or a pharmacologically acceptable salt thereof.

  TIP48 (referred to as CGI-46, ECP51, INO80J, REPTIN, RUVBL2, RUVB-LIKE2, RVB2, TIH2, or TIP49B) and TIP49 (ECP54, INO80H, NMP238, PONTIN, Pontin52, RUVBL1, KUV1, HUVV1, HUV1H Or referred to as TIP49A) is a Walker-type superfamily ATPase that is classified into AAA + (adenosine triphosphatase associated with diverse cellular activities) ATPase family, and forms a ring-shaped multimer and forms various chromatin. Protein group, telomerase or chi Forming a Burin such complexes, regulation of gene expression by the transcription factor, DNA damage repair, is involved in the control of various cellular molecular mechanisms such as telomerase activity (Non-patent Documents 1 and 2).

For example, c-Myc, an oncogene that promotes canceration of cells, is known as a factor that interacts with the TIP48 / TIP49 complex. c-Myc is a transcription factor that induces the expression of genes involved in cell cycle and cell apoptosis in response to various stresses. c-Myc is thought to promote canceration of cells due to an abnormality in its transcriptional regulatory function. In fact, translocation or mutation of c-Myc gene has been observed in human lymphomas. One of the factors involved in the ability of c-Myc to promote canceration is the ATPase activity of the TIP48 / TIP49 complex. It has been reported that inhibition of ATPase activity of TIP48 / TIP49 complex suppresses the ability of c-Myc to promote canceration (Non-patent Document 3). In addition, β-catenin, ATF-2, E2F family and the like have been reported as transcription factor groups involved in canceration of cells that interact with the TIP48 / TIP49 complex (Non-patent Document 2).
TIP48 / TIP49 has been reported to be more highly expressed in tumor tissues such as liver cancer, colon cancer, lymphoma, etc. than normal tissues, suggesting an association with TIP48 / TIP49 canceration. (Non-Patent Documents 4 to 6).

  Focusing on the function of such a TIP48 / TIP49 complex, substances that inhibit the ATPase activity of the TIP48 / TIP49 complex have been considered to be candidates for antitumor agents. For example, low molecular weight compounds that inhibit the ATPase activity of TIP49 have been reported (Non-patent Documents 7 and 8).

Sci. Signal. , 2013, 12, mr1 Biochim. Biophys. Acta. 2011, 1815, 147-157 Mol. Cell, 2000, 5, 321-330 Hepatology, 2009, 50, 1871-1883. Oncol. Rep. , 2012, 28, 1619-1624 Jpn. J. et al. Cancer Res. 2002, 93, 894-901 Biochem. J. et al. , 2012, 443, 549-559 Bioorganic & Medicinal Chemistry Letters, 2014, 24, 2512-516

  The present invention provides a novel low molecular weight compound having a potent TIP48 / TIP49 complex ATPase activity inhibitory action and showing an antitumor effect.

The present invention relates to the following (1) to (14).
(1) General formula (I)

[Where:
R ¹ is a hydrogen atom, a C ₁ -C ₆ alkyl group that may have 1 to 3 substituents independently selected from the following group A, and a substituent 1 independently selected from the following group A. A C _{2 to} C ₆ alkenyl group which may have 1 to 3 or a C _{2 to} C ₆ alkynyl group which may have 1 to 3 substituents independently selected from the following group A;
Z is a single bond, or _C 1 -C ₃ represents an alkylene group,
R ² may have 1 to 3 heteroatoms in the ring independently selected from the group consisting of a C _{3 to} C ₆ cycloalkyl group, a phenyl group, a nitrogen atom, an oxygen atom, and a sulfur atom. 5-membered ring which may have 1 to 3 heteroatoms independently selected from the group consisting of 3-membered to 7-membered aliphatic heterocyclic groups or nitrogen, oxygen and sulfur atoms Or a 6-membered aromatic heterocyclic group,
The C _{3 to} C ₆ cycloalkyl group and the phenyl group may have 1 to 5 substituents independently selected from the following group B, and the 3- to 7-membered aliphatic heterocyclic ring And the 5-membered or 6-membered aromatic heterocyclic group may have 1 to 3 substituents independently selected from the following group B,
R ³ represents a hydrogen atom, a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkoxy group,
R ⁴ and R ⁵ are each independently a hydrogen atom, a hydroxyl group, a halogen atom, a C ₁ -C ₆ alkyl group optionally having 1 to 3 halogen atoms, a C ₁ -C ₆ alkoxy group, or C Represents a _{1 to} C ₆ alkylcarbonyloxy group, or
R ⁴ and R ⁵ are a combination of R ⁴ and R ⁵ together with a 3- to 6-membered cycloalkyl ring, or
A 5-membered or 6-membered aliphatic heterocyclic ring which may have 1 to 3 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom may be formed ,
W is the following W ^{1 to} W ³

Indicates one of
R ⁶ may have a phenyl group optionally having 1 to 5 substituents independently selected from the following group E, and may have 1 to 3 substituents independently selected from the following group E 5 to 6 member which may have 1 to 3 hetero atoms independently selected from the group consisting of a good C _{3 to} C ₇ cycloalkyl group or a nitrogen atom, an oxygen atom and a sulfur atom An aromatic heterocyclic group of
The 5-membered or 6-membered aromatic heterocyclic ring may have 1 to 4 substituents independently selected from the following group E,
R ⁷ represents a hetero atom independently selected from the group consisting of a phenyl group, a nitrogen atom, an oxygen atom, and a sulfur atom, which may have 1 to 5 substituents independently selected from the following group F: 1 to 3 heteroatoms independently selected from the group consisting of a 5- or 6-membered aromatic heterocyclic group, nitrogen atom, oxygen atom and sulfur atom which may have 1 to 3 in the ring Or an 8- to 10-membered bicyclic aromatic heterocyclic group optionally having 3 or 3 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in the ring An aliphatic heterocyclic group in which a part of the 8- to 10-membered bicyclic ring optionally having 1 to 3 is unsaturated,
The 5-membered or 6-membered aromatic heterocyclic group, the 8-membered to 10-membered bicyclic aromatic heterocyclic group, and an aliphatic heterocyclic group in which a part of the bicyclic ring is unsaturated May have 1 to 4 substituents independently selected from Group F below. ]
Or a pharmacologically acceptable salt thereof.
Group A: _hydroxyl, C 1 -C ₆ alkoxy group, amino _group, C 1 -C ₆ alkylamino group, di _C 1 -C ₆ alkylamino group, a nitrogen atom, an oxygen atom, and more independently the group consisting of sulfur atoms 5-membered or 6-membered aliphatic heterocyclic group B which may have 1 to 3 heteroatoms in the ring: halogen atom, hydroxyl group, —NR ^2a R ^2b , —CONR ^2c R ^2d , 1 to 3 C ₁ -C ₆ alkyl groups optionally having 1 to 3 substituents independently selected from the following group C, ₁ to 3 substituents independently selected from the following group D C ₁ -C ₆ alkoxy group, optionally having 1 to 3 substituents independently selected from group D below C ₁ -C ₆ alkoxycarbonyl group, independently selected from group C below C _1- which may have 1 to 3 substituents C ₆ alkylcarbonyl groups R ^2a and R ^2b each independently have a hydrogen atom, a C ₁ -C ₆ alkyl group optionally having 1 to 3 substituents independently selected from the following group C, C ₁ -C ₆ alkylcarbonyl group optionally having 1 to 3 substituents independently selected from Group C, or 1 to 3 substituents independently selected from Group D below It shows good _C 1 -C ₆ alkoxycarbonyl group optionally,
R ^2c and R ^2d each independently represent a hydrogen atom or a C ₁ -C ₆ alkyl group.
Group C: halogen atom, hydroxyl group, phenyl group Group D: may have 1 to 3 heteroatoms in the ring independently selected from the group consisting of halogen atom, phenyl group, oxygen atom and sulfur atom 5 Membered or 6-membered aromatic heterocyclic group E group: halogen atom, C ₁ -C ₆ alkyl group optionally substituted by 1 to 3 halogen atoms, C ₁ -C ₆ alkoxy group F group: halogen atom , _hydroxyl, C 1 -C ₆ alkyl group, 1 to 3 of which may be substituted with a halogen atom _C 1 -C ₆ alkoxy _group, C 1 -C ₆ alkoxy _C 1 -C ₆ alkyl _{group, C} 3 ~ C ₆ cycloalkoxy group, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy group
(2) In the formula (I),
The compound according to (1) or a pharmacologically acceptable salt thereof, wherein R ¹ represents a C ₁ -C ₆ alkyl group.
(3) In the formula (I),
Z represents a single bond or a methylene group;
R ² may have 1 or 2 heteroatoms independently selected from the group consisting of a C _{3 to} C ₆ cycloalkyl group, a phenyl group, a nitrogen atom and an oxygen atom in the ring. Member aliphatic heterocyclic group, or pyridyl group,
The C ₃ -C ₆ cycloalkyl group, the 4-membered to 6-membered aliphatic heterocyclic group, and the pyridyl group may have one substituent selected independently from the following G group ( The compound according to 1) or (2) or a pharmacologically acceptable salt thereof.
Group G: halogen atom, a hydroxyl group, one _C 1 may be substituted with a hydroxyl -C ₆ alkyl _group, C 1 -C ₆ alkoxy group, amino _group, C 1 -C ₆ group, di _C 1 ~ C ₆ amino group (4) In the formula (I),
W is W ¹ or W ² below

Or a pharmacologically acceptable salt thereof according to any one of (1) to (3).
(5) In the formula (I),
R ⁶ represents a phenyl group or a pyridyl group optionally substituted with a methyl group,
The compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof.
(6) In the formula (I),
R ⁷ represents the following formula (II) or (III)

(Where
R ⁷¹ represents a halogen atom,
R ⁷² represents a hydrogen atom, a halogen atom, or a C ₁ -C ₆ alkoxy group,
R ⁷³ represents a C ₁ -C ₆ alkoxy group, or a C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy group,
R ⁷⁴ represents a C ₁ -C ₆ alkyl group,
V represents a nitrogen atom or CH)
The compound according to any one of claims 1 to 5, or a pharmacologically acceptable salt thereof.
(7) General formula (IV)

[Where:
R ⁸ represents a phenyl group, a pyridyl group, a cyclopropyl group, a cyclopentyl group, a cyclobutyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a tetrahydrofuryl group, a tetrahydropyryl group, a dioxanyl group, or a morpholinyl group,
The phenyl group may be substituted with one substituent selected from the group consisting of an amino group and a dimethylamino group,
The pyridyl group may be substituted with one methyl group,
The cyclopropyl group, the cyclopentyl group, and the cyclobutyl group may have one or two substituents independently selected from the group consisting of a hydroxyl group, a methyl group, a methoxy group, and a dimethylamino group,
The azetidinyl group, the pyrrolidinyl group, the piperidinyl group, the tetrahydrofuryl group, the tetrahydropyryl group, the dioxanyl group, and the morpholinyl group may be substituted with one C ₁ -C ₃ alkyl group ,
R ⁹ represents a halogen atom,
R ¹⁰ represents a hydrogen atom or a halogen atom,
R ¹¹ represents an ethoxy group or a methoxymethoxy group,
T represents a single bond or a methylene group;
U represents a nitrogen atom or CH. ]
Or a pharmacologically acceptable salt thereof.
(8) Any one compound selected from the following group or a pharmacologically acceptable salt thereof.
5-chloro-N- (2,2-dimethyl-4-{[1-methyl-5- (1-methylazetidin-3-yl) -3-oxo-2-phenylpyrazol-4-yl] amino} -4-oxobutyl) -2-ethoxybenzamide,
5-chloro-2-ethoxy-4-fluoro-N- (4-{[5- (3-hydroxycyclobutyl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino} -2 , 2-dimethyl-4-oxobutyl) benzamide,
5-chloro-2-ethoxy-N- (4-{[5- (3-methoxycyclobutyl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino} -2,2-dimethyl -4-oxobutyl) benzamide,
5-chloro-N- (2,2-dimethyl-4-{[1-methyl-5- (1-methylpyrrolidin-3-yl) -3-oxo-2-phenylpyrazol-4-yl] amino}- 4-oxobutyl) -2-ethoxypyridine-3-carboxamide,
5-Chloro-N- (2,2-dimethyl-4-{[1-methyl-5-((3S) -1-methylpyrrolidin-3-yl) -3-oxo-2-phenylpyrazol-4-yl Amino} -4-oxobutyl) -2-ethoxybenzamide,
5-Chloro-N- (2,2-dimethyl-4-{[1-methyl-5-((3R) -1-methylpyrrolidin-3-yl) -3-oxo-2-phenylpyrazol-4-yl] Amino} -4-oxobutyl) -2-ethoxybenzamide,
5-chloro-N- (2,2-dimethyl-4-{[1-methyl-5- (1-methyl-3-piperidyl) -3-oxo-2-phenylpyrazol-4-yl] amino} -4 -Oxobutyl) -2-ethoxybenzamide,
5-chloro-N- (2,2-dimethyl-4-{[1-methyl-5- (4-methylmorpholin-2-yl) -3-oxo-2-phenylpyrazol-4-yl] amino}- 4-oxobutyl) -2-ethoxybenzamide,
5-chloro-N- {2,2-dimethyl-4-[(1-methyl-3-oxo-2-phenyl-5-tetrahydrofuran-3-yl-pyrazol-4-yl) amino] -4-oxobutyl} 2-ethoxybenzamide,
5-chloro-N- {2,2-dimethyl-4-[(1-methyl-3-oxo-2-phenyl-5-tetrahydrofuran-3-ylpyrazol-4-yl) amino] -4-oxobutyl}- 2- (methoxymethoxy) benzamide,
5-Chloro-N- {2,2-dimethyl-4-[(1-methyl-3-oxo-2-phenyl-5-tetrahydropyran-3-yl-pyrazol-4-yl) amino] -4-oxobutyl } -2-Ethoxybenzamide,
5-Chloro-N- {2,2-dimethyl-4-[(1-methyl-3-oxo-2-phenyl-5-tetrahydropyran-4-yl-pyrazol-4-yl) amino] -4-oxobutyl } -2-Ethoxybenzamide,
5-chloro-N- (4-{[5- (1,4-dioxan-2-yl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino} -2,2-dimethyl -4-oxobutyl) -2-ethoxybenzamide,
N- (4-{[5- (4-aminophenyl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino} -2,2-dimethyl-4-oxobutyl) -5-chloro 2-ethoxybenzamide,
5-chloro-N- (2,2-dimethyl-4-{[1-methyl-3-oxo-2-phenyl-5- (3-pyridyl) pyrazol-4-yl] amino} -4-oxobutyl)- 2- (methoxymethoxy) benzamide,
5-chloro-N- {4-[(5-{[1- (dimethylamino) cyclopropyl] methyl} -1-methyl-3-oxo-2-phenylpyrazol-4-yl) amino] -2,2 -Dimethyl-4-oxobutyl} -2-ethoxy-4-fluorobenzamide,
5-chloro-N- {4-[(5-{[1- (dimethylamino) cyclopropyl] methyl} -1-methyl-3-oxo-2-phenylpyrazol-4-yl) amino] -2,2 -Dimethyl-4-oxobutyl} -2-ethoxybenzamide,
5-chloro-N- {4-[(5-{[1- (dimethylamino) cyclopropyl] methyl} -1-methyl-3-oxo-2-phenylpyrazol-4-yl) amino] -2,2 -Dimethyl-4-oxobutyl} -2-ethoxypyridine-3-carboxamide (9) The compound according to any one of (1) to (8) or a pharmacologically acceptable salt thereof is contained as an active ingredient. Pharmaceutical composition.
(10) An ATPase activity inhibitor of a TIP48 / TIP49 complex comprising the compound according to any one of (1) to (8) or a pharmacologically acceptable salt thereof as an active ingredient.
(11) An antitumor agent comprising the compound according to any one of (1) to (8) or a pharmacologically acceptable salt thereof as an active ingredient.
(12) The tumor is bladder cancer, breast cancer, brain tumor, colon cancer, ovarian cancer, stomach cancer, head and neck cancer, kidney cancer, leukemia, multiple myeloma, lymphoma, liver cancer, lung cancer, pancreatic cancer, prostate cancer, skin cancer Or an antitumor agent according to (11), which is a bone soft tissue tumor.
(13) A therapeutic agent for a tumor in which the expression level of TIP48 / TIP49 complex is increased, comprising the compound according to any one of (1) to (8) or a pharmacologically acceptable salt thereof as an active ingredient .
(14) Treatment can be carried out by inhibiting the ATPase activity of the TIP48 / TIP49 complex comprising the compound according to any one of (1) to (8) or a pharmacologically acceptable salt thereof as an active ingredient. A possible therapeutic agent for tumors.

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

In the present invention, the “C ₁ -C ₆ alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, A hexyl group, an isohexyl group, a 4-methylpentyl group, etc. are mentioned.

In the present invention, the “C ₁ -C ₃ alkyl group” means a linear or branched alkyl group having 1 to 3 carbon atoms. A methyl group, an ethyl group, a propyl group, or an isopropyl group;

In the present invention, the “C ₃ -C ₆ cycloalkyl group” is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

In the present invention, the “C ₃ -C ₇ cycloalkyl group” is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or a cycloheptyl group.

In the present invention, the “C ₁ -C ₆ alkoxy group” means a C ₁ -C ₆ alkoxy group formed from the above C ₁ -C ₆ alkyl group. For example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentoxy group, isopentoxy group, 2-methylbutoxy group, hexyloxy, or iso A hexyloxy group etc. are mentioned.

In the present invention, _"C 3 -C ₆ cycloalkoxy group" means a _C 3 -C ₆ cycloalkoxy group formed by _C 3 -C ₆ cycloalkyl group as described above. Examples thereof include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, and a cyclohexyloxy group.

In the present invention, “C ₁ -C ₆ alkylamino group” means a group in which one of the above C ₁ -C ₆ alkyl groups is substituted with an amino group. For example, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group, pentylamino group, isopentylamino group, 2-methyl Examples thereof include a butylamino group, a neopentylamino group, a 1-ethylpropylamino group, a hexylamino group, and an isohexylamino group.

In the present invention, the “di-C ₁ -C ₆ alkylamino group” means a group in which two identical or different C ₁ -C ₆ alkyl groups are substituted with an amino group. For example, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, dipentylamino group, dineopentylamino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-isopropyl-N-methylamino group, N-butyl-N-methylamino group, N-isobutyl-N-methylamino group, N-ethyl-N-propylamino group, N-ethyl-N-isopropylamino group, N-butyl-N-ethylamino group, N-ethyl-N-isopentylamino group and the like can be mentioned.

In the present invention, “C ₁ -C ₆ alkylcarbonyl group” means a group in which one of the above C ₁ -C ₆ alkyl groups is substituted with a carbonyl group. Examples thereof include an acetyl group, an ethylcarbonyl group, a propylcarbonyl group, and an isopropylcarbonyl group.

In the present invention, the “C ₁ -C ₆ alkoxycarbonyl group” means a group in which one of the above C ₁ -C ₆ alkoxy groups is substituted with a carbonyl group. Examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, and a tert-butoxycarbonyl group.

In the present invention, “C ₁ -C ₆ alkylcarbonyloxy group” means a group in which one of the above C ₁ -C ₆ alkylcarbonyl groups is bonded to an oxy group. Examples thereof include a methylcarbonyloxy group, an ethylcarbonyloxy group, a propylcarbonyloxy group, and an isopropylcarbonyloxy group.

In the present invention, the “C ₂ -C ₆ alkenyl group” means a linear or branched alkenyl group having 2 to 6 carbon atoms. For example, vinyl group, allyl group, 1-propenyl group, isopropenyl group, 2-methyl-1-propenyl group, 2-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, Examples include 1-pentenyl group, 1-hexenyl group, 1,3-hexadienyl group, 1,5-hexadienyl group, and the like.

In the present invention, the “C ₂ -C ₆ alkynyl group” means a linear or branched alkynyl group having 2 to 6 carbon atoms. For example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-ethynyl-2-propynyl group, 1-methyl-2-propynyl group, 1- A pentynyl group, 1-hexynyl group, 1,3-hexadiinyl group, 1,5-hexadiinyl group, and the like can be given.

In the present invention, “C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group” means a group in which one C ₁ -C ₆ alkoxy group is substituted with the C ₁ -C ₆ alkyl group. Examples thereof include a methoxymethyl group, an ethoxymethyl group, a propoxymethyl group, an isopropoxymethyl group, a methoxyethyl group, an ethoxyethyl group, a propoxyethyl group, and an isopropoxyethyl group.

In the present invention, _"C 1 -C ₆ alkoxy _C 1 -C ₆ alkoxy group", one of the _C 1 -C ₆ alkoxy group means a group substituted in the _C 1 -C ₆ alkoxy group. Examples thereof include a methoxymethoxy group, an ethoxymethoxy group, a propoxymethoxy group, an isopropoxymethoxy group, a methoxyethoxy group, an ethoxyethoxy group, a propoxyethoxy group, and an isopropoxyethoxy group.

  In the present invention, the “aromatic heterocyclic group” means a group derived from a monocyclic aromatic compound containing a hetero atom as a ring constituent atom. For example, furyl, thienyl, pyrrolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazoyl, imidazolyl, oxadiazoyl, thiadiazoyl, triazinyl, pyrazoyl, pyridyl, pyrazyl, pyrimidinyl, or pyridazinyl Etc.

  In the present invention, the “aliphatic heterocyclic group” means a group derived from a monocyclic aliphatic cyclic compound containing a hetero atom as a ring constituent atom. For example, oxiranyl group, aziridinyl group, tyranyl group, oxetanyl group, azetidyl group, thietanyl group, tetrahydrofuranyl group, pyrrolidinyl group, tetrahydrothiophenyl group, tetrahydropyranyl group, piperazinyl group, tetrahydrothiopyranyl group, morpholino group, morpholinyl Group, piperidinyl group and the like.

  In the present invention, the “bicyclic aromatic heterocyclic group” means a group derived from a condensed aromatic cyclic compound containing a hetero atom as a constituent atom of the ring. For example, indolyl group, isoindolyl group, benzofuryl group, benzothienyl group, benzoimidazolyl group, benzoxazolyl group, benzothiazolyl group, benzo [b] pyridyl group, imidazopyridyl group, benzo [c] pyridyl group, and the like can be given.

  In the present invention, the “aliphatic heterocyclic group in which a part of the bicyclic ring is unsaturated” means a condensed aliphatic group having an unsaturated bond in a part of the ring and containing a hetero atom in the ring constituent atom. This means a group derived from a cyclic compound. For example, indolyl group, 2,3-dihydrobenzofuryl group, 2,3-dihydrobenzothienyl group, 1,3-benzodioxolyl group, benzopyranyl group, 1,2,3,4-tetrahydroquinolyl group, 3 , 4-dihydro-2H-1,4-benzoxazyl group, 2,3-dihydro-1,4-benzodioxy group, 4H-1,4-benzoxazyl group, and the like.

In the present invention, the “C ₁ -C ₃ alkylene group” is a divalent substituent obtained by removing one hydrogen atom from the above C ₁ -C ₃ alkyl group, and is a straight chain having 1 to 3 carbon atoms or A branched alkylene group is meant. Examples include a methylene group, an ethylene group, a propane-1,3-diyl group, a methylmethylene group, a dimethylmethylene group, or a 1-methylethylene group.

  In the present invention, the “tumor” is not limited to a malignant tumor and includes all kinds of tumors, for example, a carcinoma, sarcoma, benign tumor and the like. In particular, a malignant tumor may be expressed as “cancer”.

  In the present invention, “enhanced expression of TIP48 / TIP49 complex” means that TIP48 gene or TIP49 gene mRNA expression level and protein expression level increase gene transcriptional activity, promote translation, suppress protein degradation, It means that it has increased due to improvements in stabilization.

  In the present invention, “ATPase activity of TIP48 / TIP49 complex” refers to an enzyme activity that catalyzes the hydrolysis of ATP in the presence of TIP48 protein and TIP49 protein.

Next, each suitable substituent of general formula (I) is demonstrated.
R ¹ is preferably a methyl group.
Z is preferably a single bond or a methylene group.
R ² is preferably any of the following R ^{2A to} R ^2W .

R ³ is preferably a hydrogen atom or a fluorine atom.
R ⁴ and R ⁵ are preferably both methyl groups.
W is preferably either W ¹ or W ² below.

More preferably a ^{W 1.}

R ⁶ is preferably a phenyl group, a 2-pyridyl group, or a 6-methyl-2-pyridyl group. More preferably, it is a phenyl group.
R ⁷ is preferably any of the following R ^{7A to} R ^7J .

More preferably, it is any one of R ^7C , R ^7D , R ^7E , R ^7G , or R ^7I .

As a combination of each suitable substituent of general formula (I),
R ¹ is a methyl group,
Z is a single bond or a methylene group,
R ² is any one of R ^{2A to} R ^2W ,
R ³ is a hydrogen atom,
R ⁴ and R ⁵ are both methyl groups,
R ⁶ is a phenyl group,
R ⁷ is any of R ^7C , R ^7D , R ^7E , R ^7G , or R ^7I .

  The compound represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt as desired. A pharmacologically acceptable salt refers to a salt that has no significant toxicity and can be used as a medicament. When the compound represented by the general formula (I) of the present invention has a basic group, it can be converted into a salt by reacting with an acid.

Examples of the salt based on the basic group include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; C ₁ -C ₆ alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, etc. Organic acid salts such as aryl sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, adipate, maleate; And amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate.

  The compound represented by the general formula (I) of the present invention or a salt thereof may be left in the atmosphere or recrystallized to take in water molecules and become a hydrate. Such hydrates are also encompassed by the salts of the present invention.

  The compound represented by the general formula (I) of the present invention or a salt thereof may be allowed to stand in a solvent or recrystallize to absorb a certain solvent and become a solvate. Such solvates are also encompassed by the salts of the present invention.

  The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof includes all isomers (diastereoisomers, optical isomers, geometric isomers, rotational isomers, etc.). .

  In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in an arbitrary ratio.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Examples of atomic isotopes include deuterium ( ² H), tritium ( ³ H), iodine-125 ( ¹²⁵ I), carbon-14 ( ¹⁴ C), and the like. The compound may also be radiolabeled with a radioisotope such as, for example, tritium ( ³ H), iodine-125 ( ¹²⁵ I), or carbon-14 ( ¹⁴ C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.

  The ATPase activity of the TIP48 / TIP49 complex can be measured using the ATPase assay described in Test Examples 1 and 2 below. For example, the ATPase activity of the TIP48 / TIP49 complex is determined by recombinant human TIP48 and TIP49 proteins (hereinafter referred to as rTIP48 and rTIP49) in the presence or absence of a test compound, as described in the following test examples. And ATP can be detected by measuring the amount of ADP hydrolyzed by the ATPase activity of the TIP48 / TIP49 complex using ADP-Glo. Alternatively, the ATPase activity of the TIP48 / TIP49 complex is described, for example, in J. Org. Mol. Biol. 366, 172-179 (2007) may be performed.

The cell growth inhibitory activity of the compound of the present invention can be examined using a growth inhibition test method commonly used by those skilled in the art. Cell growth inhibitory activity can be carried out, for example, by comparing the degree of cell growth in the presence or absence of a test compound, as described in Test Example 3 below. The degree of proliferation can be examined, for example, using a test system that measures live cells. Examples of the method for measuring living cells include [ ³ H] -thymidine incorporation test, BrdU method, MTT assay, and the like.

  Moreover, the antitumor activity in vivo can be investigated using the antitumor test method normally used by those skilled in the art. For example, after transplanting various tumor cells into mice, rats, etc., and confirming the engraftment of the transplanted cells, the compound of the present invention is administered orally, intravenously, etc. The in vivo antitumor activity of the present invention can be confirmed by comparing the tumor growth in and the compound administration group.

  The compound of the present invention is a tumor such as bladder cancer, breast cancer, brain tumor, colon cancer, ovarian cancer, gastric cancer, head and neck cancer, kidney cancer, leukemia, multiple myeloma, lymphoma, liver cancer, lung cancer, pancreatic cancer, prostate It can be used for the treatment of cancer, skin cancer, or bone and soft tissue tumors.

Since it has been suggested that the TIP48 / TIP49 complex is involved in cancer growth, survival, etc., the compound of the present invention can be used for tumors in which TIP48 / TIP49 expression is enhanced. preferable. Known tumors with enhanced expression of TIP48 / TIP49 include liver cancer, colon cancer, lymphoma, and the like.
Whether TIP48 / TIP49 expression is increased is determined by determining whether TIP48 / TIP49 in a test tissue of a patient (for example, collected by blood sampling, biopsy, etc.) is Southern blot, Northern blot, Western blot, ELISA, DNA chip, FISH Assays, tissue immunostaining, and other known gene analysis methods (for example, PCR, LCR (Ligase chain reaction), SDA (Strand displacement an amplification), NASBA (Nucleic acid sequence-based amplification, ICAN (Issimilar) amplification), LAMP method (Loop-mediated isoth) Analysis using rnal amplification), etc.} and the like can be confirmed by using a pathological techniques such known methods.
The compound of the present invention may be used in combination with other antitumor agents. For example, alkylating agents, antimetabolites, antitumor antibiotics, antitumor plant components, BRM (biological response regulator), hormones, vitamins, antitumor antibodies, molecular targeted drugs, other antitumor agents Etc.

  More specifically, examples of the alkylating agent include an alkylating agent such as nitrogen mustard, nitrogen mustard N-oxide or chlorambutyl, an aziridine alkylating agent such as carbocone or thiotepa, dibromomannitol or dibromodarsi Examples thereof include epoxide-based alkylating agents such as Toll, carmustine, lomustine, semustine, nimustine hydrochloride, nitrosourea-based alkylating agents such as streptozocin, chlorozotocin or ranimustine, busulfan, improsulfan tosylate or dacarbazine.

  Examples of various antimetabolites include, for example, purine antimetabolites such as 6-mercaptopurine, 6-thioguanine or thioinosine, and pyrimidine metabolism antagonists such as fluorouracil, tegafur, tegafur uracil, carmofur, doxyfluridine, broxuridine, cytarabine or enocytabine And antifolate inhibitors such as methotrexate or trimethrexate.

  Antitumor antibiotics include, for example, mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4′-epidoxorubicin or epirubicin and other anthracycline antibiotic antitumor agents, chromomycin A 3 or actinomycin D.

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

  Examples of BRM include tumor necrosis factor or indomethacin.

  Examples of the hormone include hydrocortisone, dexamethasone, methylprednisolone, prednisolone, plasterone, betamethasone, triamcinolone, oxymetholone, nandrolone, metenolone, phosfestol, ethinylestradiol, chlormadinone, or medroxyprogesterone.

  Examples of vitamins 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, sorafenib and the like.

  Examples of the other antitumor agents include cisplatin, carboplatin, oxaliplatin, tamoxifen, camptothecin, ifosfamide, cyclophosphamide, melphalan, L-asparaginase, acecraton, schizophyllan, picibanil, procarbazine, pipobroman, neocartinostatin, Examples include hydroxyurea, ubenimex, and krestin.

  Next, typical production methods for the compound represented by formula (I) will be described. The compound of the present invention can be produced by various production methods, and the production methods shown below are merely examples, and the present invention should not be construed as being limited thereto. The compound represented by the general formula (I) and its production intermediate can be produced by utilizing various known reactions described below. In this case, the functional group may be protected with a suitable protecting group at the stage of the raw material or intermediate. Examples of such a functional group include a hydroxyl group, a carboxy group, an amino group, and the like. The types of protecting groups and the conditions for introducing and removing these protecting groups are, for example, Protective Groups in Organic Synthesis (T. W. Green and PMGM Wuts, John Wiley & Sons, Inc., New York, 2006) can be referred to.

Production method general formula (I)

[R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , W, and Z are as defined above. ]
In the present invention, R ² in the general formula (I) can be protected with a suitable protecting group. Therefore, the compound represented by the general formula (I) and the compound in which R ² in the general formula (I) is protected by an appropriate protecting group are collectively represented as the general formula (Ia).
Formula (Ia)

[R ²⁰ represents a substituent in which R ² or R ² is protected with an appropriate protecting group. ]
As a main synthesis procedure, a method of constructing W between the site (B) and the site (C) represented by the general formula (Ia) and binding the complex to the site (A), or the site (A) And the site (B) are first amide-bonded, and then W is constructed between the site (C), etc., but is not particularly limited.

[Production Method 1]
First, the synthesis of the aminopyrazolone derivative (9) constituting the site (A) will be described.

[Wherein, R ¹ _, R ⁶ , R ²⁰ and Z are as defined above. R ³⁰ is a protecting group for a carboxy group, and in this case, a lower alkyl group such as methyl or ethyl is preferable. ]

Synthesis of Compound (3) When a commercially available product corresponding to Compound (3) exists, it can be used. Commercial products corresponding to the compound (3) can be purchased from, for example, Tokyo Chemical Industry Co., Ltd. When there is no commercially available product, it can be obtained by activating a commercially available carboxylic acid or an appropriately synthesized carboxylic acid (2) and reacting it in the presence of malonic acid monoester and magnesium chloride. Examples of the method for activating the carboxylic acid include a method using 1,1′-carbonyldiimidazole and a method via an acid chloride. In the reaction, a base can be added as necessary, and examples of the base include triethylamine. Examples of the solvent used for the reaction include tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, toluene, and a mixed solvent thereof, and are not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
In the case where an unprotected amino group, a hydroxyl group, or a heterocyclic ring having a proton on the nitrogen atom constituting the ring exists in R ² of the compound (2), a protecting group is introduced to these groups or atoms. From the above, the compound (3) can be obtained by subjecting to the above conditions. The conditions for introducing the protecting group vary depending on the protecting group. For example, when the protecting group is a tert-butoxycarbonyl group or a trifluoroacetyl group, the reaction is introduced by reacting the corresponding acid anhydride with an amino group in the presence or absence of a base. can do. When a base is used, triethylamine, pyridine and the like can be mentioned. Examples of the solvent used in the reaction include tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, methylene chloride, toluene and the like, or a mixed solvent thereof, and is not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C. When the protecting group is a benzoyl group, a tosyl group or the like, it can be introduced by reacting the corresponding acid chloride with an amino group in the presence of a base. When a base is used, triethylamine, pyridine and the like can be mentioned. Examples of the solvent used in the reaction include tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, methylene chloride, toluene and the like, or a mixed solvent thereof, and is not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.

Synthesis of Compound (4) Compound (3) can be obtained by reacting compound (3) with an appropriate hydrazine derivative in the presence or absence of a base. An appropriate hydrazine derivative can be purchased from, for example, Tokyo Chemical Industry Co., Ltd. Examples of the solvent used for the reaction include, but are not limited to, ethanol, tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, toluene, acetic acid, and the like, or a mixed solvent thereof. When a base is used, examples of the base used include potassium carbonate and potassium tert-butoxide. The reaction temperature is usually in the range from −78 ° C. to 180 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 150 ° C.

Synthesis of Compound (5) It can be obtained by reacting Compound (4) with an alkyl halide, dimethyl sulfate, alkyl trifluoromethanesulfonate, or the like. Examples of the solvent used in the reaction include tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, methylene chloride, toluene and the like, or a mixed solvent thereof, and is not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 180 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 150 ° C.
Compound (5) can be obtained by reacting compound (4) with the corresponding alcohol in the presence of phosphine and azodicarboxylic acid ester or azodicarboxylic acid amide. Examples of the phosphine used include triphenylphosphine and tri-n-butylphosphine. Examples of the azodicarboxylic acid ester or azodicarboxylic acid amide used include diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1 ′-(azodicarbonyl) dipiperidine, and the like. Examples of the solvent used in the reaction include tetrahydrofuran, dioxane, toluene, and a mixed solvent thereof, and are not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
Compound (5) can also be obtained by reacting compound (6) with an appropriate aryl halide in the presence of a copper catalyst, a ligand and a base. Compound (6) can be synthesized, for example, by the method shown in WO2007 / 10015, or can be purchased from Enamine. Examples of the copper catalyst used include copper iodide. Examples of the ligand include trans-N, N′-dimethylcyclohexane-1,2-diamine, and examples of the base include potassium carbonate and sodium carbonate. Examples of the solvent used in the reaction include tetrahydrofuran, dioxane, N, N-dimethylformamide, toluene, and a mixed solvent thereof, and are not particularly limited. The reaction temperature is usually in the range from about room temperature to 200 ° C. or the boiling point of the solvent, but preferably in the range from about room temperature to 180 ° C.

Synthesis of Compound (7) The compound (5) can be obtained by reacting with a nitrating agent such as nitric acid or nitrate. Examples of the solvent used in the reaction include sulfuric acid, trifluoroacetic acid, acetic acid, and the like, or a mixed solvent thereof, and is not particularly limited. When nitric acid is used, nitric acid can be substituted for the solvent. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, and preferably in the range from −20 ° C. to 100 ° C. If there is labile protecting group to acidic conditions in R ^2, replacement stable protecting groups initially acidic conditions at this time, it is also possible to perform the nitration in the manner described above.

Synthesis of Compound (9) from Compound (7) Obtained by reducing compound (7) by dissolving it in a solvent or suspending it, adding a reduction catalyst such as palladium carbon and reacting in a hydrogen atmosphere. Can do. Examples of the solvent used in the reaction include methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, acetic acid, and the like, or a mixed solvent thereof, and is not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
In the case where the compound (9) is a racemic compound having an asymmetric carbon, it is possible to perform optical resolution using a chiral column by liquid chromatography under an appropriate condition at this point, or at a later stage. It is also possible.

Synthesis of Compound (8) Compound (5) can be obtained by reacting with sodium nitrite under acidic conditions or by reacting with alkyl nitrite in an organic solvent. Examples of the alkyl nitrite used include tert-butyl nitrite and isoamyl nitrite. When using sodium nitrite, the solvent used for the reaction includes hydrochloric acid, acetic acid, sulfuric acid and the like, or a mixed solvent thereof such as water and alcohol, and is not particularly limited. When alkyl nitrite is used, ethanol, tetrahydrofuran, dioxane, acetonitrile, methylene chloride, toluene and the like, or a mixed solvent thereof can be used, and is not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, and preferably in the range from −20 ° C. to 100 ° C. If there is labile protecting group to acidic conditions in R ^2, replacement stable protecting groups initially acidic conditions at this time, it is also possible to carry out the nitrosation in the manner described above.

Synthesis of Compound (9) from Compound (8) Compound (8) can be obtained by coexisting with a metal under acidic conditions. Examples of the metal used include tin and zinc. Examples of the solvent used in the reaction include hydrochloric acid, a mixed solvent of ethanol and water, or acetic acid, and are not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
Compound (9) can also be obtained by reduction by adding a reduction catalyst such as palladium carbon in a state where compound (8) is dissolved or suspended in a solvent and reacting in a hydrogen atmosphere. Examples of the solvent used in the reaction include methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, acetic acid, and the like, or a mixed solvent thereof, but is not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
In the case where the compound (9) is a racemic compound having an asymmetric carbon, it is possible to perform optical resolution using a chiral column by liquid chromatography under an appropriate condition at this point, or at a later stage. It is also possible.

Synthesis of Compound (10) It can be obtained by reacting Compound (4) with benzyl chloroformate in the presence of calcium hydroxide. Examples of the solvent used in the reaction include tetrahydrofuran, dioxane, toluene, and a mixed solvent thereof, and are not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 150 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.

Synthesis of Compound (11) Compound (11) can be obtained by appropriately selecting and using the reaction conditions described in the production method from Compound (4) to Compound (5) for Compound (10).

Synthesis of Compound (12) In a state where compound (11) is dissolved or suspended in a solvent, a reduction catalyst such as palladium carbon is added and reacted in a hydrogen atmosphere to perform deprotection. Examples of the solvent used in the reaction include methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide and the like, or a mixed solvent thereof, and is not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.

Synthesis of Compound (9) from Compound (12) It can be obtained by reacting compound (12) with diphenylphosphoric acid azide under basic conditions. Examples of the base used include triethylamine, N, N-diisopropylethylamine and the like. Examples of the solvent used in the reaction include tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, water, and a mixed solvent thereof, and are not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 150 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 150 ° C.
In the case where the compound (9) is a racemic compound having an asymmetric carbon, it is possible to perform optical resolution using a chiral column by liquid chromatography under an appropriate condition at this point, or at a later stage. It is also possible.

[Production Method 2]
Compound (7) and R ² of R ²⁰ is protected R ² or functional groups, and when bound to a Z is an alkylene group with a nitrogen atom constituting the ring, suitable leaving on Z The compound (13) containing a group can be converted to the compound (7) by reacting with R ²⁰ having a proton on the nitrogen atom constituting the ring. Compound (7) to compound (9) can be synthesized in the same manner as in Production Method 1.

[Wherein, X represents a leaving group such as halogen or a methanesulfonyloxy group. R ¹ and R ⁶ are as defined above. R ²⁰ represents the case ^{R 2} or ^{R 2} which functional groups are protected. Z in this case represents other than a single bond. ]

Synthesis of Compound (7) It can be obtained by reacting compound (13) with an appropriate R ²⁰ having a proton on the nitrogen atom constituting the ring in the presence of a base. Compound (13) can be synthesized according to the synthesis method from Compound (2) to Compound (7) described in Production Method 1-1 using a carboxylic acid derivative corresponding to Compound (13) as a starting material. Examples of the base used for the reaction include sodium hydride, triethylamine, potassium carbonate and the like. Examples of the solvent used in the reaction include tetrahydrofuran, acetonitrile, N, N-dimethylformamide, methylene chloride, toluene, and a mixed solvent thereof, and are not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.
Next, the synthesis of the carboxylic acid derivative (14) constituting the sites (B) and (C) will be described.

[Production Method 3]
First, a method for producing the compound (14a) in which W is W ¹ in the general formula (14) will be described.

[Wherein R ³ , R ⁴ , R ⁵ and R ⁷ have the same meanings as described above. R ³⁵ means a protecting group for a carboxy group. ]
Examples of the protecting group for the carboxyl group include a methyl group, an ethyl group, a tert-butyl group, and a benzyl group.

Synthesis of Compound (16) It can be obtained by reacting compound (15) and nitromethane in the presence of a base. As the compound (15), for example, a compound purchased from Tokyo Chemical Industry Co., Ltd. or a compound synthesized from commercially available compounds can be used. Examples of the base to be used include 1,8-diazabicyclo (5,4,0) -7-undecene. Examples of the solvent used for the reaction include tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, and the like, or a mixed solvent thereof, and is not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 150 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.

Synthesis of Compound (17) Compound (16) can be obtained by coexisting with ammonium chloride in the presence of iron powder. Examples of the solvent used in the reaction include ethanol, tetrahydrofuran, dioxane, acetic acid, water, and the like, or a mixed solvent thereof, and an organic solvent that can be mixed with water in an arbitrary ratio is preferable. The reaction temperature is usually in the range from −78 ° C. to 150 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
In addition, compound (17) can be obtained by reducing compound (16) in a state where compound (16) is dissolved or suspended in a solvent by adding a reduction catalyst such as palladium carbon and applying a reaction under a hydrogen atmosphere pressure. it can. Examples of the solvent used in the reaction include methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, acetic acid, and the like, or a mixed solvent thereof, and is not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
When the compound (17) needs to be purified, for example, a method in which the amino group is protected with an arbitrary protecting group, purified by silica gel column chromatography, and then deprotected is exemplified.

Synthesis of Compound (19) It can be obtained by reacting Compound (17) and Compound (18) in the presence of a condensing agent. As the compound (18), for example, a compound purchased from Tokyo Chemical Industry Co., Ltd. or an appropriate compound synthesized from a commercially available compound can be used. As the condensing agent to be used, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N ′,-tetramethylronium hexafluorophosphate (HATU), 4- (4,6- And dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholine (DMT-MM), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (WSC), and the like. Examples thereof include ethanol, tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, methylene chloride, toluene and the like, or a mixed solvent thereof, and is not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
Compound (19) can also be obtained by reacting compound (17) with a compound obtained by converting the carboxyl group of compound (18) to an acid chloride in the presence of a base. Examples of the base used include triethylamine and pyridine. Examples of the solvent used in the reaction include tetrahydrofuran, acetonitrile, methylene chloride, toluene and the like, or a mixed solvent thereof, and is not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C. Examples of the reagent for converting a carboxyl group into an acid chloride include thionyl chloride and oxalyl chloride. Examples of the solvent used in the reaction include tetrahydrofuran, N, N-dimethylformamide, methylene chloride, toluene and the like, or a mixed solvent thereof, and is not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C. Examples of the reducing agent from acid chloride to alcohol include lithium borohydride. Examples of the solvent used in the reaction include ether, tetrahydrofuran, dioxane and the like, or a mixed solvent thereof, and are not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from −78 ° C. to 50 ° C.

Is a leaving step of the synthesis the protecting group ^{R 35} of Compound (14a).
Although the deprotection reaction conditions differ depending on the type of R ³⁵ , it may be hydrolyzed. When R ³⁵ is a methyl group, an ethyl group, a benzyl group or the like, the compound (19) is converted into sodium hydroxide, potassium hydroxide, It can be obtained by treating with a base such as lithium hydroxide or potassium tert-butoxide, hydrochloric acid, p-toluenesulfonic acid or the like. Here, examples of the solvent used for the reaction include methanol, ethanol, water, tetrahydrofuran, dioxane, and the like, or a mixed solvent thereof, and an organic solvent that can be mixed with water at an arbitrary ratio is preferable. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
When R ³⁵ is a tert-butyl group or the like, it is desirable to treat the compound (19) with trifluoroacetic acid or hydrochloric acid. Examples of the solvent used in the reaction include methylene chloride, chloroform, and a mixed solvent thereof, and are not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from −20 ° C. to around 100 ° C.
When R ³⁵ is a benzyl group or the like, the compound (19) can be obtained by deprotection by adding a reducing catalyst such as palladium carbon and reacting in a hydrogen atmosphere in a state where the compound (19) is dissolved or suspended in a solvent. . Examples of the solvent used in the reaction include methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide and the like, or a mixed solvent thereof, and is not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.

[Production Method 4]
Next, in the general formula (14), W is described Formula ^W compounds represented by ² (14b) of the production method.

[Wherein R ³ , R ⁴ , R ⁵ and R ⁷ have the same meanings as described above. R ³⁵ means a protecting group for a carboxyl group. ]
Examples of the protecting group for the carboxyl group include a methyl group, an ethyl group, a tert-butyl group, and a benzyl group.

Synthesis of Compound (22) Compound (22) can be prepared by reacting compound (20) and compound (21) in the presence of a condensing agent, or by converting the carboxyl group of compound (21) and compound (20) to acid chloride. It can be obtained by reacting the converted compound in the presence of a base. Compound (20) may be purchased from ENAMINE or the like or may be appropriately synthesized. Compound (21) can be purchased from Tokyo Kasei Kogyo Co., Ltd. or the like or synthesized appropriately. The reaction conditions can be appropriately selected from the reaction conditions for the same kind of reactions described in the method for producing compound (19).

Is a leaving step of the synthesis the protecting group ^{R 35} of the compound from the compound (22) (14b).
Compound (14b) can be obtained by appropriately selecting and using the reaction conditions described in the above production method of compound (14a) for compound (22).

Synthesis of Compound (14b) from Compound (23) Compound (14b) can be obtained by reacting a commercially available product such as Compound (23) or an appropriately synthesized acid anhydride with Compound (21) in the presence of a base. Can be obtained. Examples of the base used include triethylamine. Examples of the solvent used in the reaction include tetrahydrofuran, dioxane, methylene chloride, chloroform, N, N-dimethylformamide, and a mixed solvent thereof, and are not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.

[Production Method 5]
Next, a method for producing the compound (14c) in which W is represented by the general formula W ³ in the general formula (14) will be described.

[Wherein R ³ , R ⁴ , R ⁵ and R ⁷ have the same meanings as described above. R ³⁵ means a protecting group for a carboxyl group. ]
Examples of the protecting group for the carboxyl group include a methyl group, an ethyl group, a tert-butyl group, and a benzyl group.

Synthesis of Compound (25) It can be obtained by reacting Compound (17) with Isocyanate (24). Compound (24) can be purchased from Sigma-Aldrich, or can be synthesized from commercially available compounds as appropriate. Examples of the solvent used in the reaction include tetrahydrofuran, dioxane, methylene chloride, chloroform, and a mixed solvent thereof, and are not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.

Is a leaving step of the synthesis the protecting group ^{R 35} of Compound (14c).
Compound (14c) can be obtained by appropriately selecting and using the reaction conditions described in the above production method of compound (14a) for compound (25).

[Production Method 6]
Next, the synthesis of the compound represented by the general formula (Ia) using the compound (9) and the compound (14) will be described.

[Wherein, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ²⁰ , Z and W are as defined above] ]

Synthesis of Compound (Ia) Compound (9) and compound (14) can be obtained by reacting in the presence of a condensing agent. As the condensing agent to be used, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N ′,-tetramethylronium hexafluorophosphate (HATU), 4- (4,6- Examples include dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholine (DMT-MM), and examples of the solvent include ethanol, tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, A methylene chloride, toluene, etc., or these mixed solvents are mentioned, It does not specifically limit. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C.
The compound of general formula (Ia) is condensed with compound (9) and moiety (B) under the above conditions, and then condensed with moiety (C) by appropriately selecting appropriate conditions from production methods 3 to 5. Can also be obtained.

[Production Method 7]
When R ^{20 of the} compound represented by the general formula (Ia) synthesized by the above production method contains a nitrogen atom or an oxygen atom protected by a protecting group, this is deprotected by the following method, and the compound (I).

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Z and W are as defined above] R ²⁰ in this case represents R ² containing a nitrogen or oxygen atom protected by a protecting group. ]

  The deprotection conditions vary depending on the protecting group, but when the protecting group is a carbamate such as a tert-butoxycarbonyl group, it can be deprotected by treatment with hydrochloric acid or trifluoroacetic acid. Examples of the solvent used here include dioxane, ethyl acetate, methylene chloride, and a mixed solvent thereof, and are not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C. Further, when the protecting group is, for example, a trifluoroacetyl group, it can be deprotected by treatment with a base such as sodium hydroxide or potassium hydroxide. Examples of the solvent used here include methanol, ethanol, water, tetrahydrofuran, dioxane, and the like, or a mixed solvent thereof. An organic solvent that can be mixed with water at an arbitrary ratio is preferable. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C. When the protecting group is an aralkyl group such as a benzyl group, it can be deprotected by catalytic hydrogen reduction in the presence of a palladium catalyst or by treatment with a strong acid such as trifluoroacetic acid. Examples of the solvent used for the catalytic hydrogen reduction reaction include methanol, ethanol and the like. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C. Examples of the solvent used in the case of a strong acid treatment include methylene chloride and no solvent. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 100 ° C. When the protecting group is a silyl-based protecting group such as a trimethylsilylethoxymethyl group, it can be deprotected by treatment with hydrochloric acid or the like or treatment with fluoride ions. Examples of the solvent used in the reaction include ethanol, tetrahydrofuran, dioxane, water and the like, or a mixed solvent thereof, and are not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.

When R ^{2 of the} compound represented by the general formula (I) contains a nitrogen atom or an oxygen atom that is deprotected by the above production method or the like, it can be alkylated or the like. Examples of the conditions for alkylation include conditions for reacting with alkyl halide or alkyl trifluoromethanesulfonate in the presence of a base. Examples of the base used include triethylamine, N, N-diisopropylethylamine, and potassium carbonate. Examples of the solvent to be used include tetrahydrofuran, dioxane, N, N-dimethylformamide, methylene chloride and the like, or a mixed solvent thereof, and is not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C. Further, when the functional group to be modified is an amino group or a heterocyclic nitrogen atom, it can be alkylated by reacting with an aldehyde or a ketone in the presence of a reducing agent. Examples of the reducing agent to be used include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride and the like. Examples of the solvent to be used include methanol, ethanol, water, tetrahydrofuran, dioxane, N, N-dimethylformamide, methylene chloride, acetic acid, and a mixed solvent thereof, and are not particularly limited. The reaction temperature is usually in the range from −78 ° C. to 100 ° C. or the boiling point of the solvent, preferably in the range from 0 ° C. to 100 ° C.

  In the present invention, as the stereoisomer of the compound represented by the general formula (I), an optically active raw material compound is used, or a compound is synthesized using an asymmetric synthesis or asymmetric induction method, or is synthesized. The obtained compound can be obtained by isolation using a conventional optical resolution method or separation method, if desired.

  In the present invention, the compound represented by the general formula (I) includes those labeled with an atomic isotope or a radioisotope. For example, a raw material labeled with an isotope instead of the raw material in the above production method It can manufacture by using.

  When the compound represented by the general formula (I) of the present invention has a basic group, it can be converted into a salt by reacting with an acid.

Examples of the salt based on the basic group include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; C ₁ -C ₆ alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, etc. Organic acid salts such as aryl sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, adipate, maleate; And amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate.

  When the compound represented by the general formula (I) of the present invention or a salt thereof can be made into a hydrate by taking in water molecules by leaving it in the atmosphere or by recrystallization. There is.

  The compound represented by the general formula (I) of the present invention or a salt thereof absorbs a certain solvent by being left in a solvent or recrystallized in a solvent, You may be able to.

  The solvate is not particularly limited as long as it is pharmacologically acceptable, and examples thereof include hydrates and ethanol solvates.

  The compound of the present invention or a pharmacologically acceptable salt thereof can be administered in various forms. Examples of the administration form include oral administration by tablets, capsules, granules, emulsions, pills, powders, syrups (solutions), etc., or injections (intravenous, intramuscular, subcutaneous or intraperitoneal administration), Examples include parenteral administration such as instillation and suppository (rectal administration). These various preparations are usually used in the pharmaceutical preparation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, etc. as main ingredients in accordance with conventional methods. It can be formulated with the resulting adjuvant.

  When used as a tablet, as a carrier, for example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid; water, ethanol, propanol, simple syrup, glucose Solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc .; dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid Disintegrators such as esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose; disintegrators such as sucrose, stearin, cocoa butter, hydrogenated oil; quaternary ammonium salts, sodium lauryl sulfate Moisturizers such as glycerin and starch; Adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; Uses a lubricant such as purified talc, stearate, boric acid powder and polyethylene glycol be able to. Moreover, it can be set as the tablet which gave the normal coating as needed, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, and a multilayer tablet.

  When used as pills, as carriers, for example, excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin, talc; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol; laminaran, Disintegrants such as agar can be used.

  When used as a suppository, a carrier conventionally known in this field can be widely used as a carrier, and examples thereof include polyethylene glycol, cocoa butter, higher alcohol, esters of higher alcohol, gelatin, semi-synthetic glyceride and the like.

  When used as an injection, it can be used as a solution, emulsion or suspension. These solutions, emulsions or suspensions are preferably sterilized and isotonic with blood. The solvent used in the production of these solutions, emulsions or suspensions is not particularly limited as long as it can be used as a medical diluent. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isoforms are used. Examples include stearyl alcohol and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of sodium chloride, glucose or glycerin may be included in the preparation to prepare an isotonic solution, and a normal solubilizing agent, buffer, soothing agent, etc. may be included. You may go out.

  Moreover, a coloring agent, a preservative, a fragrance | flavor, a flavoring agent, a sweetening agent, etc. can also be included in said formulation as needed, and also other pharmaceuticals can be included.

  The amount of the active ingredient compound contained in the preparation is not particularly limited and is appropriately selected within a wide range, but is usually 0.5 to 70% by weight, preferably 1 to 30% by weight in the total composition.

  The amount used varies depending on the symptoms, age, etc. of the patient (warm-blooded animal, particularly human), but in the case of oral administration, the upper limit is 2000 mg (preferably 100 mg) per day, and the lower limit is 0.1 mg ( Preferably 1 mg, more preferably 10 mg) is administered to adults 1 to 6 times per day depending on the symptoms.

  EXAMPLES Hereinafter, although a reference example, an Example, and a test example are given and this invention is demonstrated further in detail, the scope of the present invention is not limited to these.

Elution in the column chromatography of Reference Examples and Examples was performed under observation by TLC (Thin Layer Chromatography). In TLC observation, Merck silica gel 60F ₂₅₄ or silica gel 60NH ₂ F ₂₅₄ S or Fuji Silysia Chemical NHTLC plate was used as the TLC plate, and the solvent used as the elution solvent in column chromatography was used as the developing solvent. As a detection method, a UV detector was adopted. As silica gel for the column, silica gel SK-85 (230-400 mesh) manufactured by Merck Ltd. or Fuji Silysia Chemical Chromatorex NH (200-350 mesh) was used. In addition to ordinary column chromatography, Shoko Science's automatic purifier (Purif-α2 or Purif-espoir2), Yamazen's automatic purifier (YFLC-5404-FC) or Biotage's automatic purifier (HORIZON) , SP1 or Isolera) were used as appropriate. The elution solvent used was the solvent specified in each Reference Example and Example. The ratio of the eluting solvent described in the section of separation and purification by chromatography indicates a volume ratio unless otherwise specified. The abbreviations used in Reference Examples and Examples have the following significance.
mg: milligram, g: gram, μL: microliter, mL: milliliter, L: liter, MHz: megahertz.

In the following examples, nuclear magnetic resonance (hereinafter, ¹ H-NMR: 400 MHz or 500 MHz) spectra are described with chemical shift values as δ values (ppm) using tetramethylsilane as a standard substance. The measurement solvent is shown in parentheses. The splitting pattern is indicated by s for a single line, d for a double line, t for a triple line, q for a quadruple line, m for a multiple line, and br for broad. The symbol “MS” means “mass spectrometry”. The ionization method is shown in parentheses.

(Intermediate 1a) 4-[(5-chloro-2-ethoxybenzoyl) amino] -3,3-dimethylbutanoic acid

(Step 1) Ethyl 3,3-dimethyl-4-nitrobutanoate 245 mL (226 g, 1.76 mol) of ethyl 3,3-dimethylacrylate was dissolved in 1.8 L of acetonitrile, and 645 mL (903 g, 14.8 mol) of nitromethane and 394 mL (402 g, 2.64 mol) of 1,8-diazabicyclo (5,4,0) -7-undecene was added and stirred at 60 ° C. for 5 days. The reaction solution was brought to room temperature, the solvent was distilled off under reduced pressure, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the resulting crude product was purified using silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 100/0 to 70/30) to give 280 g of the title compound ( Yield 84.1%) was obtained as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 4.54 (2H, s), 4.16 (2H, q, J = 7.2 Hz), 2.45 (2H, s), 1.28 (3H, t, J = 7.2 Hz), 1.17 ( 6H, s).

(Step 2) Ethyl 3,3-dimethyl-4-aminobutanoate hydrochloride 178 g (0.941 mmol) of ethyl 3,3-dimethyl-4-nitrobutanoate synthesized in Step 1 was dissolved in 712 mL of ethanol, and 5% palladium on carbon. 83.0 g of catalyst (M type) and 712 mL of acetic acid were added, and the mixture was stirred at 70 ° C. for 5 hours in a 0.5 MPa hydrogen atmosphere. The reaction solution was brought to room temperature and filtered, and then the filtrate was concentrated. Two more lots of the same reaction were performed, and the resulting crude amino product was dissolved in 4.10 L of toluene, 926 g (4.24 mol) of di-tert-butyl dicarbonate was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into a water / ethyl acetate mixture, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. After filtration, the crude Boc product obtained by concentrating the filtrate was dissolved in 2.82 L of ethyl acetate, 2.82 L of 4N hydrochloric acid-ethyl acetate was added, and the mixture was stirred at room temperature for 24 hours. After concentrating the reaction solution, the residue was suspended in diisopropyl ether, collected by filtration, washed with diisopropyl ether and dried to give 290 g (yield 52.7%) of the title compound as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 8.16 (3H, s), 4.07 (2H, q, J = 7.2 Hz), 2.79 (2H, s), 2.37 (2H, s), 1.19 (3H, t , J = 7.2 Hz), 1.02 (6H, s).

(Step 3) Ethyl 5-chloro-2-ethoxybenzoate 50.0 g (290 mmol) of 5-chlorosalicylic acid was dissolved in 250 mL of N, N-dimethylformamide, and 120 g (869 mmol) of potassium carbonate and 69.9 mL of ethane iodide ( 136 g, 869 mmol) was added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and ethyl acetate was added for extraction. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration and concentration of the filtrate, the resulting crude product was purified using silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 95/5 to 70/30) to give the title compound 58. 6 g (yield 88.3%) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.73 (1H, d, J = 2.4 Hz), 7.37 (1H, dd, J = 8.8, 2.4 Hz), 6.88 (1H, d, J = 8.8 Hz), 4.35 ( 2H, q, J = 7.1 Hz), 4.08 (2H, q, J = 7.1 Hz), 1.44 (3H, t, J = 7.1 Hz), 1.37 (3H, t, J = 7.1 Hz).

(Step 4) 5-Chloro-2-ethoxybenzoic acid 58.6 g (256 mmol) of ethyl 5-chloro-2-ethoxybenzoate synthesized in Step 3 is dissolved in 300 mL of ethanol, and 50 mL of water and 100 mL of 5N aqueous sodium hydroxide solution are added. And stirred at room temperature for 20 hours. The reaction solution was evaporated under reduced pressure to remove ethanol, neutralized by adding 5N hydrochloric acid under ice-cooling, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration and concentration of the filtrate, 51.4 g (yield 100%) of the title compound was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 10.88 (1H, s), 8.17 (1H, t, J = 2.4 Hz), 7.51 (1H, dd, J = 8.8, 2.4 Hz), 7.00 (1H, d, J = 8.8 Hz), 4.33 (2H, q, J = 7.0 Hz), 1.58 (3H, t, J = 7.0 Hz).

(Step 5) Ethyl 4-[(5-chloro-2-ethoxybenzoyl) amino] -3,3-dimethylbutanoate 21.8 g (109 mmol) of 5-chloro-2-ethoxybenzoic acid synthesized in Step 4 and the step 21.5 g (110 mmol) of ethyl 3,3-dimethyl-4-aminobutanoate synthesized in 2 was dissolved in 300 mL of ethanol and 19.2 mL (14.2 g, 110 mmol) of N, N-diisopropylethylamine, and 4- ( 4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride n hydrate 38.6 g (131 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure, water and saturated aqueous sodium hydrogen carbonate were added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The crude product obtained after filtration and concentration of the filtrate was purified using silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 90 / 10-50 / 50) to give 36.7 g of the title compound. (Yield 98.5%) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.19 (1H, d, J = 2.4 Hz), 8.16-8.14 (1H, br m), 7.36 (1H, dd, J = 8.8, 2.4 Hz), 6.90 (1H, d, J = 8.8 Hz), 4.20 (2H, q, J = 7.1 Hz), 4.13 (2H, q, J = 7.1 Hz), 3.43 (2H, d, J = 6.3 Hz), 2.28 (2H, s) , 1.56 (2H, s), 1.52 (3H, t, J = 7.1 Hz), 1.26 (3H, t, J = 7.1 Hz), 1.08 (6H, s).

(Step 6) 4-[(5-Chloro-2-ethoxybenzoyl) amino] -3,3-dimethylbutanoic acid (Intermediate 1a)
36.7 g (107 mmol) of ethyl 4-[(5-chloro-2-ethoxybenzoyl) amino] -3,3-dimethylbutanoate synthesized in Step 5 was dissolved in 300 mL of ethanol, and 150 mL of 2N aqueous sodium hydroxide solution was added. And stirred for 24 hours at room temperature. Ethanol was distilled off under reduced pressure, and 2N hydrochloric acid was added to the residue for neutralization, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate gave 32.5 g (96.9% yield) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.56-8.54 (1H, br m), 8.21 (1H, d, J = 2.4 Hz), 7.43 (1H, dd, J = 8.8, 2.4 Hz), 6.94 (1H, d, J = 8.8 Hz), 4.23 (2H, q, J = 7.0 Hz), 3.42 (2H, d, J = 6.8 Hz), 2.28 (2H, s), 1.53 (3H, t, J = 7.0 Hz) , 1.11 (6H, s).
Similarly, the intermediates in Table 1 were synthesized from the corresponding starting materials.

(Intermediate 1i) 4-[(5-chloro-2-ethoxybenzoyl) amino] -2-fluoro-3,3-dimethylbutanoic acid

(Step 1) 3-Fluoro-1-[(4-methoxyphenyl) methyl] -4,4-dimethylpyrrolidin-2-one 3-hydroxy- synthesized by the method described in Tetrahedron Asymmetry 2010, 21, 1241-2135 A solution of 500 mg (2.00 mmol) of 1-[(4-methoxyphenyl) methyl] -4,4-dimethylpyrrolidin-2-one and 0.480 ml (475 mg, 6.00 mmol) of pyridine in 10 ml of methylene chloride was ice-cooled, 0.400 ml (688 mg, 2.44 mmol) of trifluoromethanesulfonic anhydride was added dropwise and stirred at the same temperature for 30 minutes. The reaction solution was diluted with methylene chloride, washed successively with a saturated aqueous sodium bicarbonate solution, a saturated aqueous copper sulfate solution, and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the residue obtained by concentrating the filtrate was dissolved in 16 ml of tetrahydrofuran, 4 ml of ice-cooled 1N tetra-n-butylammonium fluoride / tetrahydrofuran solution was added, and the mixture was returned to room temperature and stirred for 1 hour. After evaporating the solvent under reduced pressure, the mixture was diluted with ethyl acetate, washed with saturated brine (twice), and dried over anhydrous sodium sulfate. After filtration, the crude product obtained by concentrating the filtrate was purified using silica gel column chromatography (elution solvent; hexane / ethyl acetate = 75/25) to give 435 mg (yield: 86.5%) of the title compound as an oil. Obtained as material.
¹ H-NMR (CDCl ₃ ) δ: 7.16 (2H, d, J = 8.6 Hz), 6.87 (2H, d, J = 8.6 Hz), 4.64 (1H, d, J = 53 Hz), 4.47 (1H, d, J = 4.5 Hz), 4.33 (1H, d, J = 4.5 Hz), 3.80 (3H, s), 2.96 (1H, dd, J = 10, 1.8 Hz), 2.90 (1H, d, J = 10 Hz), 1.15 (3H, s), 1.04 (3H, s).

(Step 2) 3-Fluoro-4,4-dimethylpyrrolidin-2-one 3-fluoro-1-[(4-methoxyphenyl) methyl] -4,4-dimethylpyrrolidin-2-one 1 synthesized in Step 1 24 ml of an acetonitrile solution of .20 g (4.77 mmol) was ice-cooled, and 5 ml of an aqueous solution of 5.23 g (9.54 mmol) of ammonium hexanitratocerium (IV) was added dropwise, returned to room temperature, and stirred for 3 hours. To the reaction solution, 2.5 g of potassium carbonate was added and stirred for 10 minutes, and the insoluble material was filtered through Celite. The obtained filtrate was concentrated, azeotroped with ethanol several times, dissolved in chloroform, and dried over anhydrous sodium sulfate. After filtration, the crude product obtained by concentrating the filtrate was purified using silica gel column chromatography (elution solvent; hexane / ethyl acetate = 34/66) to obtain 395 mg (yield 63.1%) of the title compound as a solid. Got as.
¹ H-NMR (CDCl ₃ ) δ: 7.14 (1H, br), 4.61 (1H, d, J = 52 Hz), 3.10-3.17 (2H, m), 3.14 (3H, s), 3.12 (3H, s ).

(Step 3) Ethyl 4-amino-2-fluoro-3,3-dimethylbutanoate hydrochloride 350 mg (2.67 mmol) of 6N hydrochloric acid synthesized in Step 2 of 3-fluoro-4,4-dimethylpyrrolidin-2-one 10 ml was heated to reflux for 16 hours. After concentration, the residue obtained by azeotroping with ethanol several times was dissolved in 10 ml of ethanol, acetyl chloride (0.65 ml, 9.11 mmol) was added at room temperature, and the mixture was heated to reflux for 2 hours. The reaction solution was returned to room temperature and concentrated to quantitatively obtain 570 mg of the title compound as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 8.23 (3H, brs), 5.10 (1H, dd, J = 48, 1.8 Hz), 4.28-4.19 (2H, m), 2.83 (2H, q, J = 13 Hz), 1.26-1.22 (3H, m), 1.04 (3H, s), 1.01 (3H, s).

(Step 4) 4-[(5-Chloro-2-ethoxybenzoyl) amino] -2-fluoro-3,3-dimethylbutanoic acid 3,3-dimethyl-4-aminobutanoic acid in Step 5 of the synthesis of intermediate 1a Using ethyl 4-amino-2-fluoro-3,3-dimethylbutanoate hydrochloride synthesized in Step 3 instead of ethyl, the same reaction as in Step 5 and Step 6 of the synthesis of Intermediate 1a is performed thereafter. The title compound was obtained as a solid. .
¹ H-NMR (CDCl ₃ ) δ: 8.72 (1H, t, J = 5.8 Hz), 8.19 (1H, d, J = 3.0 Hz), 7.44 (1H, dd, J = 8.8, 2.7 Hz), 6.95 ( 1H, d, J = 9.1 Hz), 4.67 (1H, d, J = 48.0 Hz), 4.24 (2H, q, J = 6.9 Hz), 3.65 (1H, dd, J = 14.6, 7.3 Hz), 3.26 ( 1H, ddd, J = 15.0, 6.2, 4.1 Hz), 1.55 (3H, t, J = 7.0 Hz), 1.17 (3H, d, J = 1.8 Hz), 1.14 (3H, s).
MS (ESI) m / z: 332 [(M + H) ⁺ ].

(Intermediate 2a) 5-[(5-chloro-2-ethoxy-3-pyridyl) amino] -3,3-dimethyl-5-oxopentanoic acid

(Step 1) 2,5-dichloro-3-nitropyridine 10.0 g (57.6 mmol) of 5-chloro-3-nitropyridin-2-amine was dissolved in 100 mL of concentrated hydrochloric acid and stirred at -10 ° C. A liquid in which 9.94 g (144 mmol) of sodium nitrite was dissolved in 20 mL of water was added dropwise thereto over 30 minutes, and after addition, the mixture was stirred at 0 ° C. for 1 hour. The reaction solution was adjusted to pH 9 with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. Insoluble matter was removed by filtration, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Filtration was performed, and the filtrate was distilled off under reduced pressure to obtain 6.50 g (yield 58.5%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.60 (1H, d, J = 2.6 Hz), 8.24 (1H, d, J = 2.6 Hz).

(Step 2) 5-Chloro-2-ethoxy-3-nitropyridine 2.00 g (31.1 mmol) of 2,5-dichloro-3-nitropyridine synthesized in Step 1 was dissolved in 30 mL of ethanol, and 21% sodium ethoxy. 20 mL of a doethanol solution was added and stirred at 70 ° C. for 5 hours. After returning to room temperature, the reaction mixture was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 100/0 to 85/15). 39 g (53.8%) were obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.33 (1H, d, J = 2.3 Hz), 8.24 (1H, d, J = 2.3 Hz), 4.55 (2H, q, J = 7.1 Hz), 1.45 (3H, t, J = 7.1 Hz).

(Step 3) 5-chloro-2-ethoxypyridin-3-amine 3.39 g (16.7 mmol) of 5-chloro-2-ethoxy-3-nitropyridine synthesized in Step 2 was dissolved in 30 mL of ethanol, and 5% 0.40 g of platinum sulfide carbon was added, and the mixture was stirred at room temperature for 5 hours in a hydrogen atmosphere. The crude product obtained after filtration and concentration of the filtrate was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 95/5 to 75/25) to give 2.66 g (yield) of the title compound. 92.3%) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.47 (1H, d, J = 2.3 Hz), 6.85 (1H, d, J = 2.3 Hz), 4.37 (2H, q, J = 7.1 Hz), 3.87 (2H, s), 1.40 (3H, t, J = 7.1 Hz).

(Step 4) methyl 5-[(5-chloro-2-ethoxy-3-pyridyl) amino] -3,3-dimethyl-5-oxopentanoate 5-methoxy-3,3-dimethyl-5-oxopentanoic acid 1.92 g (11.0 mmol) was dissolved in 30 mL of methylene chloride, and a catalytic amount of N, N-dimethylformamide was added and stirred at room temperature. Oxalyl chloride 1.86mL (2.79g, 22.0mmol) was dripped here, and it stirred at room temperature after addition for 30 minutes. The solvent was distilled off under reduced pressure, dried, and then dissolved in 15 mL of methylene chloride. Here, 1.73 g (10.0 mmol) of 5-chloro-2-ethoxypyridin-3-amine synthesized in Step 3 and 5.58 mL (4.05 g, 40.0 mmol) of triethylamine were dissolved in 15 mL of methylene chloride. The mixture was further stirred at room temperature for 4 hours. Water was added, extraction was performed with methylene chloride, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 95/5 to 65/35) to give 3.18 g of the title compound ( Yield 96.7%) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.75 (1H, s), 8.68 (1H, d, J = 2.3 Hz), 7.76 (1H, d, J = 2.3 Hz), 4.39 (2H, q, J = 7.1 Hz), 3.73 (3H, s), 2.51 (2H, s), 2.42 (2H, s), 1.41 (3H, t, J = 7.1 Hz), 1.13 (6H, s).

(Step 5) 5-[(5-Chloro-2-ethoxy-3-pyridyl) amino] -3,3-dimethyl-5-oxopentanoic acid (Intermediate 2a)
3.18 g (9.67 mmol) of methyl 5-[(5-chloro-2-ethoxy-3-pyridyl) amino] -3,3-dimethyl-5-oxopentanoate synthesized in Step 4 was dissolved in 40 mL of ethanol. 2N aqueous sodium hydroxide solution (20 mL) was added, and the mixture was stirred at room temperature for 3 days. Ethanol was distilled off under reduced pressure, and the residue was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate gave 2.85 g (yield 93.4%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.65 (1H, d, J = 2.3 Hz), 8.25 (1H, s), 7.81 (1H, d, J = 2.3 Hz), 4.42 (2H, q, J = 7.1 Hz), 2.53 (2H, s), 2.49 (2H, s), 1.40 (3H, t, J = 7.1 Hz), 1.19 (6H, s).
Similarly, the intermediates in Table 2 were synthesized from the corresponding starting materials.

(Intermediate 2d) 2- {1- [2- (5-chloro-2-ethoxyanilino) -2-oxoethyl] cyclopentyl} acetic acid

(Step 1) 2- {1- [2- (5-chloro-2-ethoxyanilino) -2-oxoethyl] cyclopentyl} acetic acid 1.1-cyclopentanediacetic anhydride 2.50 g (14.9 mmol) and 3.06 g (17.8 mmol) of 5-chloro-2-ethoxyaniline was dissolved in 20 mL of toluene, and 4.94 mL (3.61 g, 35.7 mmol) of triethylamine was added thereto, followed by stirring at 90 ° C. for 4 hours. The mixture was brought to room temperature, 5N hydrochloric acid was added, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain 4.79 g (yield 94.8%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.38 (1H, d, J = 2.4 Hz), 8.20 (1H, s), 7.03 (1H, dd, J = 8.8, 2.4 Hz), 6.79 (1H, d, J = 8.8 Hz), 4.09 (2H, q, J = 6.8 Hz), 2.58 (2H, s), 2.54 (2H, s), 1.76-1.74 (4H, m), 1.68-1.64 (4H, m), 1.44 (3H, t, J = 6.8 Hz).

(Intermediate 3a) 4-[(5-chloro-2-methylbenzofuran-7-carbonyl) amino] -3,3-dimethylbutanoic acid

(Step 1) Methyl 2-allyloxy-5-chlorobenzoate 11.2 g (60.0 mmol) of methyl 5-chlorosalicylate was dissolved in 50 mL of N, N-dimethylformamide, and 8.29 g (60.0 mmol) of potassium carbonate and Allyl bromide (5.08 mL, 7.26 g, 60.0 mmol) was added, and the mixture was stirred at 60 ° C. for 4 hours. The mixture was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 100/0 to 70/30) to give 12.9 g of the title compound ( Yield 94.6%) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.78 (1H, d, J = 2.9 Hz), 7.39 (1H, dd, J = 9.2, 2.9 Hz), 6.90 (1H, d, J = 9.2 Hz), 6.07- 6.02 (1H, m), 5.50 (1H, d, J = 17.2 Hz), 5.31 (1H, d, J = 10.3 Hz), 4.61-4.61 (2H, m), 3.90 (3H, s).

(Step 2) Methyl 3-allyl-5-chloro-2-hydroxybenzoate 12.9 g (56.8 mmol) of methyl 2-allyloxy-5-chlorobenzoate synthesized in Step 1 was added to 25 mL of N-methyl-2-pyrrolidone. And stirred at 200 ° C. for 7 hours. The mixture was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by concentrating the filtrate was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 100/0 to 70/30), and 11.0 g of the title compound ( Yield 85.3%) was obtained as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 10.98 (1H, s), 7.70 (1H, d, J = 2.9 Hz), 7.29 (1H, d, J = 2.9 Hz), 5.99-5.96 (1H, m), 5.13-5.09 (2H, m), 3.95 (3H, s), 3.41-3.40 (2H, m).

(Step 3) Methyl 5-chloro-2-methyl-2,3-dihydrobenzofuran-7-carboxylate 11.0 g (48.4 mmol) of methyl 3-allyl-5-chloro-2-hydroxybenzoate synthesized in Step 2 ) Was dissolved in 100 mL of methylene chloride and stirred at 0 ° C. To this, 13.5 g (58.1 mmol) of zirconium tetrachloride was added little by little, and the mixture was stirred at room temperature for 18 hours after completion of the addition. Water was added to the reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by concentrating the filtrate was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 95/5 to 70/30) to give 5.80 g of the title compound ( Yield 52.9%) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.69-7.68 (1H, m), 7.26-7.26 (1H, m), 5.11-5.09 (1H, m), 3.90 (3H, s), 3.35-3.30 (1H, m), 2.83-2.80 (1H, m), 1.52 (3H, d, J = 5.9 Hz).

(Step 4) Methyl 5-chloro-2-methylbenzofuran-7-carboxylate 5.22 g (23.0 mmol) of methyl 5-chloro-2-methyl-2,3-dihydrobenzofuran-7-carboxylate synthesized in Step 3 ) Is dissolved in 50 mL of carbon tetrachloride, 4.31 g (24.2 mmol) of N-bromosuccinimide and 1.13 g (6.90 mmol) of 2,2′-azobis (isobutyronitrile) are added, and the mixture is heated for 6 hours. Refluxed. The temperature was returned to room temperature, and the precipitate was removed by filtration. The filtrate was extracted with methylene chloride, washed with water, saturated aqueous sodium bicarbonate, and saturated brine in that order, and then dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by concentrating the filtrate was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 95/5 to 75/25) to give 3.82 g of the title compound ( Yield 73.9%) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.82 (1H, d, J = 2.0 Hz), 7.61 (1H, d, J = 2.0 Hz), 6.39 (1H, d, J = 1.0 Hz), 4.00 (3H, s), 2.53 (3H, d, J = 1.0 Hz).

(Step 5) 5-chloro-2-methylbenzofuran-7-carboxylic acid 3.82 g (17.0 mmol) of methyl 5-chloro-2-methylbenzofuran-7-carboxylate synthesized in Step 4 was dissolved in 90 mL of methanol. 20 mL of 2N sodium hydroxide aqueous solution was added, and it stirred at room temperature for 5 hours. The reaction solution was evaporated under reduced pressure to remove methanol, neutralized with 2N hydrochloric acid under ice cooling, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration and concentration of the filtrate, 3.57 g (yield 99.7%) of the title compound was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.90 (1H, d, J = 2.4 Hz), 7.68 (1H, d, J = 2.4 Hz), 6.43 (1H, s), 2.55 (3H, s).

(Step 6) 4-[(5-Chloro-2-methylbenzofuran-7-carbonyl) amino] -3,3-dimethylbutanoic acid 5-chloro-2-methylbenzofuran-7-carboxylic acid synthesized in Step 5 3.85 g (18.3 mmol) was dissolved in 100 mL of methylene chloride, and a catalytic amount of N, N-dimethylformamide was added and stirred at room temperature. To this, 2.32 mL (3.48 g, 27.4 mmol) of oxalyl chloride was added dropwise, followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure, dried, and then dissolved in 100 mL of methylene chloride. Here, 3.58 g (18.3 mmol) of ethyl 3,3-dimethyl-4-aminobutanoate obtained in Step 2 of the synthesis of Intermediate 1a and 5.51 mL (5.39 g, 54.9 mmol) of pyridine were added. In addition, the mixture was stirred at room temperature for 13 hours. Water was added and extracted with methylene chloride. The organic layer was washed with 1N hydrochloric acid and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 90/10 to 40/60) to give 5.12 g of the title compound ( Yield 79.5%) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.97 (1H, d, J = 2.0 Hz), 7.84 (1H, s), 7.56 (1H, d, J = 2.0 Hz), 6.44 (1H, d, J = 1.0 Hz), 4.16 (2H, q, J = 7.1 Hz), 3.50 (2H, d, J = 6.3 Hz), 2.52 (3H, d, J = 1.0 Hz), 2.35 (2H, s), 1.27 (3H, t, J = 7.1 Hz), 1.12 (6H, s).

(Step 7) 4-[(5-Chloro-2-methylbenzofuran-7-carbonyl) amino] -3,3-dimethylbutanoic acid (Intermediate 3a)
Ethyl 4-[(5-chloro-2-methylbenzofuran-7-carbonyl) amino] -3,3-dimethylbutanoate synthesized in Step 6 was dissolved in 50 mL of ethanol and dissolved in 2N water. 20 mL of an aqueous sodium oxide solution was added and stirred at room temperature for 15 hours. The reaction mixture was evaporated under reduced pressure, the residue was neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain 4.56 g (yield 96.8%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.98 (1H, d, J = 2.4 Hz), 7.88 (1H, br s), 7.59 (1H, d, J = 2.4 Hz), 6.46 (1H, d, J = 1.0 Hz), 3.53 (2H, d, J = 6.8 Hz), 2.52 (3H, d, J = 1.0 Hz), 2.35 (2H, s), 1.16 (6H, s).

(Intermediate 3b) 4-{[5-chloro-2- (methoxymethyl) benzofuran-7-carbonyl] amino} -3,3-dimethylbutanoic acid

(Step 1) Methyl 2- (bromomethyl) -5-chlorobenzofuran-7-carboxylate 2.25 g of methyl 2-methyl-5-chlorobenzofuran-7-carboxylate synthesized in Step 4 of the synthesis of intermediate 3a (10 0.0 mmol) is dissolved in 25 mL of carbon tetrachloride, 1.87 g (10.5 mmol) of N-bromosuccinimide and 0.411 g (2.50 mmol) of 2,2′-azobis (isobutyronitrile) are added, and 9 Heated to reflux for hours. It returned to room temperature and stirred for 72 hours. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. Water was added to the residue, extracted with methylene chloride, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain 3.56 g (yield 100%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.94 (1H, d, J = 2.0 Hz), 7.70 (1H, d, J = 2.0 Hz), 6.78 (1H, s), 4.62 (2H, s), 4.02 ( 3H, s).

(Step 2) Methyl 5-chloro-2- (methoxymethyl) benzofuran-7-carboxylate 3.56 g (10.0 mmol) of methyl 2- (bromomethyl) -5-chlorobenzofuran-7-carboxylate synthesized in Step 1 Was dissolved in 20 mL of tetrahydrofuran and stirred at 0 ° C. To this, 2.23 mL (2.12 g, 11.0 mmol) of 28% sodium methoxide methanol solution was added dropwise, and the mixture was stirred at room temperature for 10 minutes after the addition was completed. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the resulting crude product was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 100/0 to 75/25). Purification gave 1.73 g (yield 67.9%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.90 (1H, d, J = 2.0 Hz), 7.71 (1H, d, J = 2.0 Hz), 6.71 (1H, s), 4.62 (2H, s), 4.00 ( 3H, s), 3.48 (3H, s).
Thereafter, the reaction was performed in the same manner as in Step 5 of Intermediate 3a to synthesize the following Intermediate 3b.

Example 1 5-Chloro-2-ethoxy-N- (3-fluoro-2,2-dimethyl-4-{[1-methyl-5- (1-methylazetidin-3-yl) -3- Oxo-2-phenyl-pyrazol-4-yl] amino} -4-oxo-butyl) benzamide

(Step 1) 3- (4-Amino-2-methyl-5-oxo-1-phenylpyrazol-3-yl) azetidine-1-carboxylate tert-butyl 3- (tert-butoxy) of Step 95 of Example 95 Using 1-tert-butoxycarbonylazetidine-3-carboxylic acid instead of carbonylamino) propionic acid, the reaction was carried out in the same manner as in Step 6 of Example 95 to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.48-7.44 (4H, m), 7.27-7.24 (1H, m), 4.35-4.27 (4H, m), 3.68-3.64 (1H, m), 3.23 (2H, s), 2.78 (3H, s), 1.47 (9H, s).

(Step 2) tert-butyl 3- [4-({4-[(5-chloro-2-ethoxybenzoyl) amino] -2-fluoro-3,3-dimethylbutanoyl} amino) -2-methyl-5 -Oxo-1-phenylpyrazol-3-yl] azetidine-1-carboxylate tert-butyl 3- (4-amino-2-methyl-5-oxo-1-phenylpyrazol-3-yl) synthesized in Step 1 Azetidine-1-carboxylate 97.0 mg (0.282 mmol), intermediate 1i 68.8 mg (0.207 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′— To a solution of 105 mg (0.276 mmol) of tetramethylronium hexafluorophosphate (HATU) in 1.5 mL of N, N-dimethylformamide, It was stirred at room temperature for 15 hours N- diisopropylethylamine 0.0560mL (41.6mg, 0.322mmol) added. To the reaction mixture was added 5.0 mL of saturated aqueous sodium bicarbonate / 10 mL of water, and the mixture was extracted with ethyl acetate. The organic layer was extracted once with saturated aqueous sodium bicarbonate / water (1: 2), once with water, and saturated brine. Washed once and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by amino silica gel-silica gel column chromatography (Biotage, hexane / ethyl acetate → ethyl acetate / methanol = 50/50 to 0/100 → 100/0 to 90/10). Thus, 119 mg (yield: 87.4%) of the title compound was obtained as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 8.32-8.25 (2H, br m), 8.18 (1H, d, J = 2.4 Hz), 7.51-7.42 (4H, m), 7.37 (1H, dd, J = 8.5 , 3.0 Hz), 7.34-7.29 (1H, m), 6.91 (1H, d, J = 9.1 Hz), 4.83 (1H, d, J = 48.0 Hz), 4.30 (2H, td, J = 8.8, 2.0 Hz ), 4.23-4.16 (4H, m), 4.06-3.97 (1H, m), 3.67 (1H, ddd, J = 14.1, 7.1, 2.6 Hz), 3.56 (1H, dd, J = 14.0, 6.1 Hz), 3.03 (3H, s), 1.53 (3H, t, J = 7.0 Hz), 1.45 (9H, s), 1.19 (3H, s), 1.16 (3H, s).
MS (ESI) m / z: 658 [(M + H) ⁺ ].

(Step 3) N- (4-{[5- (azetidin-3-yl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino} -3-fluoro-2,2-dimethyl -4-oxobutyl) -5-chloro-2-ethoxybenzamide tert-butyl 3- [4-({4-[(5-chloro-2-ethoxybenzoyl) amino] -2-fluoro-3 synthesized in Step 1 , 3-Dimethylbutanoyl} amino) -2-methyl-5-oxo-1-phenylpyrazol-3-yl] azetidine-1-carboxylate in a solution of 117 mg (0.177 mmol) of methylene chloride in trifluoroacetic acid 1.7 mL was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (Biotage, ethyl acetate / methanol = 100/0 to 80/20) to give 90.4 mg (yield 91. mg) of the title compound. 5%) was obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 8.31-8.23 (2H, br m), 8.17 (1H, d, J = 2.4 Hz), 7.49-7.40 (4H, m), 7.37 (1H, dd, J = 8.8 , 2.7 Hz), 7.32-7.27 (1H, m), 6.90 (1H, d, J = 8.5 Hz), 4.82 (1H, d, J = 48.0 Hz), 4.19 (2H, q, J = 6.9 Hz), 4.16-4.13 (1H, m), 4.04-3.98 (2H, m), 3.95-3.88 (2H, m), 3.76-3.68 (1H, m), 3.52 (1H, dd, J = 14.0, 6.1 Hz), 3.03 (3H, s), 1.52 (3H, t, J = 7.0 Hz), 1.19 (3H, d, J = 1.2 Hz), 1.17 (3H, s).
MS (ESI) m / z: 558 [(M + H) ⁺ ].

(Step 4) 5-chloro-2-ethoxy-N- (3-fluoro-2,2-dimethyl-4-{[1-methyl-5- (1-methylazetidin-3-yl) -3-oxo 2-phenylpyrazol-4-yl] amino} -4-oxo-butyl) benzamide N- (4-{[5- (azetidin-3-yl) -1-methyl-3-oxo- synthesized in Step 2 2-phenylpyrazol-4-yl] amino} -3-fluoro-2,2-dimethyl-4-oxobutyl) -5-chloro-2-ethoxybenzamide 90.4 mg (0.162 mmol) in methylene chloride 3.0 mL 126 mg (0.595 mmol) of sodium triacetoxyborohydride, 0.0330 mL (34.6 mg, 0.576 mmol) of acetic acid, 0% formaldehyde (37% aqueous solution) 120 mL (1.61 mmol) was added in that order, and the mixture was stirred at room temperature for 3.5 hours. To the reaction mixture, 20 mL of saturated aqueous sodium hydrogen carbonate was added and extracted twice with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by amino silica gel column chromatography (Biotage, hexane / ethyl acetate → ethyl acetate / methanol = 50/50 to 0/100 → 100/0 to 90/10), The title compound (79.7 mg, yield 86.0%) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.33 (1H, br d, J = 3.6 Hz), 8.29 (1H, br t, J = 6.4 Hz), 8.18 (1H, d, J = 3.0 Hz), 7.49- 7.35 (5H, m), 7.32-7.27 (1H, m), 6.90 (1H, d, J = 8.5 Hz), 4.82 (1H, d, J = 48.0 Hz), 4.19 (2H, q, J = 6.9 Hz ), 3.82-3.68 (4H, m), 3.50 (1H, dd, J = 14.0, 5.5 Hz), 3.35 (2H, q, J = 6.9 Hz), 3.01 (3H, s), 2.35 (3H, s) , 1.53 (3H, t, J = 7.0 Hz), 1.20 (3H, s), 1.17 (3H, s).
MS (ESI) m / z: 572 [(M + H) ⁺ ]
The following Examples 2 to 6 were synthesized in the same manner.

Example 7 5-Chloro-N- (4-{[5- (3-hydroxy-3-methylcyclobutyl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino}- 2,2-Dimethyl-4-oxobutyl) -2-methylbenzofuran-7-carboxamide

(Step 1) 5- {3- [tert-butyl (dimethyl) silyl] oxy-3-methylcyclobutyl} -2-phenyl-4H-pyrazol-3-one 3- synthesized by the method described in US2011 / 112052 [Tert-Butyl- (dimethyl) silyl] oxy-3-methylcyclobutanecarboxylic acid (5.00 g, 20.5 mmol) was dissolved in tetrahydrofuran (50 ml), and N, N-dicyclohexylcarbodiimide (4.78 g, 24.6 mmol) was added. After stirring at room temperature for 1 hour, 1.95 g (20.5 mmol) of magnesium chloride and 4.18 g (24.6 mmol) of monoethyl potassium malonate were added, and the mixture was further stirred for 3 hours. The reaction solution was diluted with ethyl acetate, and 100 ml of 1N hydrochloric acid was added under ice cooling. The organic layer was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the resulting crude product was dissolved in 50 ml of toluene, 2.42 ml (2.66 g, 24.6 mmol) of phenylhydrazine was added, and the mixture was stirred at 90 ° C. for 5 hours. After allowing to cool to room temperature, the reaction mixture is concentrated, and the resulting crude product is purified using silica gel column chromatography (Shoko Scientific, elution solvent; hexane / ethyl acetate = 97/3 to 80/20). The title compound (4.09 g, yield 55.6%) was obtained as an oily substance. Diastereomers were separated and removed by column purification.
¹ H-NMR (CDCl ₃ ) δ: 7.86 (2H, d, J = 7.8 Hz), 7.39 (2H, t, J = 8.0 Hz), 7.18 (1H, t, J = 7.4 Hz), 3.45 (2H, s), 2.94-2.85 (1H, m), 2.37-2.29 (4H, m), 1.45 (3H, s), 0.89 (9H, s), 0.09 (6H, s).

(Step 2) 5- {3- [tert-Butyl (dimethyl) silyl] oxy-3-methylcyclobutyl} -1-methylphenylpyrazol-3-one 5- {3- [tert-butyl synthesized in Step 1 (Dimethyl) silyl] oxy-3-methylcyclobutyl} -2-phenyl-4H-pyrazol-3-one 4.09 g (11.4 mmol) was dissolved in 60 ml of methylene chloride, and N, N-diisopropyl was dissolved at 0 ° C. 3.98 ml (2.95 g, 22.8 mmol) of amine and 1.55 ml (2.25 g, 13.7 mmol) of methyl trifluoromethanesulfonate were added, and the mixture was warmed to room temperature and stirred for 16 hours. Methanol was added to stop the reaction, and the organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by concentrating the filtrate was purified using silica gel column chromatography (Shoko Scientific, elution solvent; hexane / ethyl acetate = 90 / 10-20 / 80) to give the title compound 3 Obtained .89 g (91.6% yield) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 7.45 (2H, t, J = 7.8 Hz), 7.37 (2H, d, J = 7.8 Hz), 7.29 (1H, d, J = 7.8 Hz), 5.44 (1H, s), 2.99 (3H, s), 2.88-2.79 (1H, m), 2.51-2.44 (2H, m), 2.34-2.26 (2H, m), 1.47 (3H, s), 0.88 (9H, s) , 0.09 (6H, s).

(Step 3) 4-amino-5- {3- [tert-butyl (dimethyl) silyl] oxy-3-methylcyclobutyl} -1-methyl-2-phenylpyrazol-3-one 5-synthesized in Step 2 {3- [tert-Butyl (dimethyl) silyl] oxy-3-methylcyclobutyl} -1-methylphenylpyrazol-3-one 3.89 g (10.5 mmol) was dissolved in 50 ml of acetonitrile, and sublimated at 0 ° C. 1.24 ml (1.08 g, 10.5 mmol) of tert-butyl nitrate was added and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by concentrating the filtrate was dissolved in 150 ml of a mixed solution of ethanol-0.5N hydrochloric acid (2: 1), 10 g of zinc powder was added at 0 degree, and the mixture was vigorously stirred for 30 minutes. Saturated aqueous sodium hydrogen carbonate was added for neutralization, and the reaction solution was filtered through celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified using silica gel column chromatography (SHOKO Scientific, elution solvent; hexane / ethyl acetate = 90 / 10-50 / 50) to give 0.990 g of the title compound (yield) 24.3%) was obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 7.49 (2H, d, J = 7.8 Hz), 7.43 (2H, t, J = 7.8 Hz), 7.22 (1H, t, J = 7.8 Hz), 3.07-3.02 ( 1H, m), 2.96-2.87 (1H, m), 2.74 (3H, s), 2.59-2.51 (2H, m), 2.50-2.44 (2H, m), 1.48 (3H, s), 0.89 (9H, s), 0.10 (6H, s).

(Step 4) 4-amino-5- (3-hydroxy-3-methylcyclobutyl) -1-methyl-2-phenylpyrazol-3-one 4-amino-5- {3- [tert -Butyl (dimethyl) silyl] oxy-3-methylcyclobutyl} -1-methyl-2-phenylpyrazol-3-one 0.990 g (2.56 mmol) was dissolved in 30 ml of tetrahydrofuran, and tetrabutylammonium fluoride (1M 7.67 ml (7.67 mmol) of tetrahydrofuran solution was added and stirred for 12 hours. The reaction solution is concentrated, and the resulting crude product is purified using silica gel column chromatography (Shoko Scientific, elution solvent: hexane / ethyl acetate = 90/10 to ethyl acetate / methanol = 90/10). The title compound (0.650 g, yield 92.9%) was obtained as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.49-7.41 (4H, m), 7.24-7.22 (1H, m), 3.02-2.93 (1H, m), 2.76 (3H, s), 2.60-2.51 (4H, m), 1.49 (3H, s).
MS (ESI) m / z: 274 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 5 of Example 26, and the following Example 7 was synthesized.

Example 8 trans-5-chloro-N- [4-({5- [3- (dimethylamino) cyclobutyl] -1-methyl-3-oxo-2-phenylpyrazol-4-yl} amino)- 2,2-Dimethyl-4-oxobutyl] -2-ethoxybenzamide

(Step 1) trans-tert-butyl N- [3- (4-amino-2-methyl-5-oxo-1-phenylpyrazol-3-yl) cyclobutyl] carbamate 3- [tert -Transaction of trans-3- (tert-butoxycarbonylamino) cyclobutanecarboxylic acid instead of -butyl- (dimethyl) silyl] oxy-3-methylcyclobutanecarboxylic acid, followed by the same reaction as in Step 7 of Example 7 To give the title compound as an oil.
¹ H-NMR (CDCl ₃ ) δ: 7.58-7.40 (5H, m), 4.91-4.81 (1H, m), 4.34-4.25 (1H, m), 3.51-3.45 (1H, m), 3.15-2.97 ( 1H, m), 2.96-2.85 (2H, m), 2.70 (3H, s), 2.43-2.31 (2H, m), 1.46 (9H, s).
Thereafter, the reaction was carried out in the same manner as in Step 5 of Example 26 and Steps 3 to 4 of Example 1, and the following Example 8 was synthesized.

Example 9 cis-5-chloro-N- [4-({5- [3- (dimethylamino) cyclobutyl] -1-methyl-3-oxo-2-phenylpyrazol-4-yl} amino)- 2,2-Dimethyl-4-oxobutyl] -2-ethoxybenzamide

(Step 1) cis-tert-butyl N- [3- (4-amino-2-methyl-5-oxo-1-phenylpyrazol-3-yl) cyclobutyl] carbamate 3- [tert Using cis-3- (tert-butoxycarbonylamino) cyclobutanecarboxylic acid instead of -butyl- (dimethyl) silyl] oxy-3-methylcyclobutanecarboxylic acid, the reaction is carried out in the same manner as in Step 7 of Example 7 thereafter. To give the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.53-7.17 (5H, m), 4.87-4.71 (2H, m), 4.14-4.03 (1H, m), 2.96 (3H, s), 2.82-2.63 (3H, m), 2.46-2.25 (2H, m), 1.41 (9H, s).
Thereafter, the reaction was conducted in the same manner as in Step 5 of Example 26 and Steps 3 to 4 of Example 1, and the following Example 9 was synthesized.

Example 10 5-Chloro-2-ethoxy-4-fluoro-N- (4-{[5- (3-hydroxycyclobutyl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl Amino} -2,2-dimethyl-4-oxobutyl) benzamide

(Step 1) 5- {3-Benzyloxycyclobutyl} -2-phenyl-1H-pyrazol-3-one 3- [tert-butyl- (dimethyl) silyl] oxy-3-methyl of Step 1 of Example 7 The same reaction was carried out using 3-benzyloxycyclobutanecarboxylic acid instead of cyclobutanecarboxylic acid to obtain a low polar isomer (intermediate 10a) and a high polar isomer (intermediate 10b) as solids, respectively.
Intermediate 10a
¹ H-NMR (CDCl ₃ ) δ: 7.88 (2H, d, J = 7.4 Hz), 7.46-7.29 (7H, m), 7.22-7.16 (1H, m), 4.46 (2H, s), 4.34-4.22 (1H, m), 3.43 (2H, s), 3.36-3.24 (1H, m), 2.63-2.53 (2H, m), 2.48-2.37 (2H, m).
Intermediate 10b
1H-NMR (CDCl ₃ ) δ: 7.86 (2H, d, J = 7.8 Hz), 7.41-7.30 (7H, m), 7.22-7.15 (1H, m), 4.47 (2H, s), 4.11-4.04 ( 1H, m), 3.44 (2H, s), 2.97-2.83 (1H, m), 2.67-2.55 (2H, m), 2.27-2.15 (2H, m).

(Step 2) 4-Amino-5- (3-benzyloxycyclobutyl) -1-methyl-2-phenylpyrazol-3-one 5- {3- [tert-butyl (dimethyl) of Step 2 of Example 7 [Silyl] oxy-3-methylcyclobutyl} -2-phenyl-4H-pyrazol-3-one, using the intermediate 10a synthesized in Step 1, followed by the same reaction as in Step 7 of Example 7 To give the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.50-7.21 (10H, m), 4.49 (2H, s), 4.34-4.27 (1H, m), 3.63-3.53 (1H, m), 3.06-2.98 (1H, m), 2.81-2.74 (2H, m), 2.73 (3H, s), 2.58-2.47 (2H, m).

(Step 3) 4-amino-5- (3-hydroxycyclobutyl) -1-methyl-2-phenylpyrazol-3-one 4-amino-5- (3-benzyloxycyclobutyl)-synthesized in Step 2 0.610 g (1.75 mmol) of 1-methyl-2-phenylpyrazol-3-one was dissolved in 20 ml of methanol, 160 mg of palladium hydroxide carbon catalyst was added, and the mixture was stirred at room temperature for 36 hours in a hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified using silica gel column chromatography (Shoko Scientific, elution solvent: hexane / ethyl acetate → methanol / ethyl acetate = 50 / 50-0 / 100 → 0 / 100-5 / 95). The title compound (0.340 g, yield 74.0%) was obtained as a solid.
¹ H-NMR (CD ₃ OD) δ: 7.52-7.47 (2H, m), 7.45-7.42 (2H, m), 7.36-7.31 (1H, m), 4.51-4.42 (1H, m), 3.67-3.58 (1H, m), 2.87-2.78 (5H, m), 2.42-2.35 (2H, m).
Thereafter, the reaction was carried out in the same manner as in Step 5 of Example 26 to synthesize Example 10 below.

Example 11 5-Chloro-2-ethoxy-4-fluoro-N- (4-{[5- (3-hydroxycyclobutyl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl Amino} -2,2-dimethyl-4-oxobutyl) benzamide

(Step 1) 4-amino-5- (3-hydroxycyclobutyl) -1-methyl-2-phenylpyrazol-3-one Using the intermediate 10b synthesized in Step 1 of Example 10, the following examples were used. The reaction was carried out in the same manner as in Steps 2 to 3 of 10 to obtain the title compound as a solid.
¹ H-NMR (CD ₃ OD) δ: 7.58-7.31 (5H, m), 4.26-4.19 (1H, m), 3.02-2.94 (1H, m), 2.81 (3H, s), 2.80-2.74 (2H , m), 2.36-2.27 (2H, m).
Thereafter, the reaction was carried out in the same manner as in Step 5 of Example 26, and the following Example 5 was synthesized.

Example 12 5-Chloro-2-ethoxy-N- (4-{[5- (3-methoxycyclobutyl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino}- 2,2-Dimethyl-4-oxobutyl) benzamide

(Step 1) 4-Amino-5- (3-methoxycyclobutyl) -1-methyl-2-phenylpyrazol-3-one 3- [tert-butyl- (dimethyl) silyl] oxy of Step 1 of Example 7 Using 3-methoxycyclobutanecarboxylic acid instead of -3-methylcyclobutanecarboxylic acid, the reaction is carried out in the same manner as in Step 7 of Example 7 and Steps 4 to 5 of Example 39, and the title compound is converted into a solid Got as.
¹ H-NMR (CDCl ₃ ) δ: 7.51-7.48 (2.0H, m), 7.45-7.40 (2.0H, m), 7.25-7.20 (1.0H, m), 4.15-4.08 (0.5H, m), 3.96-3.89 (0.5H, m), 3.60-3.48 (0.5H, m), 3.32-3.25 (3.5H, m), 3.19-3.03 (2.0H, m), 3.00-2.90 (1.0H, m), 2.79-2.71 (4.0H, m), 2.47-2.34 (2.0H, m).
Thereafter, the reaction was carried out in the same manner as in Step 5 of Example 26, and the following Examples 12 to 14 were synthesized. Example 12 (low polarity isomer) and Example 13 (high polarity isomer) were separated on a column. Example 14 is a diastereomeric mixture.

Example 15 5-Chloro-N- [4-({5-[(1R, 3S) -3- (dimethylamino) cyclopentyl] -1-methyl-3-oxo-2-phenylpyrazol-4-yl } Amino) -2,2-dimethyl-4-oxobutyl] -2-ethoxybenzamide

(Step 1) tert-Butyl N-[(1S, 3R) -3- (4-amino-2-methyl-5-oxo-1-phenylpyrazol-3-yl) cyclopentyl] carbamate In Step 1 of Example 7 In the following examples, (1S, 3R) -3- (tert-butoxycarbonylamino) cyclopentanecarboxylic acid was used instead of 3- [tert-butyl- (dimethyl) silyl] oxy-3-methylcyclobutanecarboxylic acid. The reaction was conducted in the same manner as in Step 7 of 7 to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.51-7.40 (3H, m), 7.32-7.22 (2H, m), 5.34-5.25 (1H, m), 4.16-4.05 (1H, m), 3.76-3.69 ( 1H, m), 3.04-2.94 (2H, m), 2.85 (3H, s), 2.50-2.42 (1H, m), 2.14-1.67 (4H, m), 1.46 (9H, s).
MS (ESI) m / z: 373 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 2 to Step 4 of Example 1, and the following Examples 15 to 16 were synthesized.

Example 17 3- [4-({4-[(5-Chloro-2-ethoxybenzoyl) amino] -3,3-dimethylbutanoyl} amino) -2-methyl-5-oxo-1-phenyl Pyrazol-3-yl] pyrrolidine-1-carboxylate tert-butyl

(Step 1) 3- [tert-Butyl- (dimethyl) -3- (2-methyl-5-oxo-1-phenylpyrazol-3-yl) pyrrolidine-1-carboxylate tert-butyl Example 7 Step 1 The reaction is carried out in the same manner as in Step 2 of Example 7 using 1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid instead of silyl] oxy-3-methylcyclobutanecarboxylic acid. Obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.51-7.44 (2H, m), 7.41-7.36 (2H, m), 7.34-7.29 (1H, m), 5.50 (1H, s), 3.91-3.75 (1H, m), 3.68-3.52 (1H, m), 3.48-3.33 (2H, m), 3.28-3.17 (1H, m), 3.11 (3H, s), 2.38-2.27 (1H, m), 2.15-2.00 ( 1H, m), 1.49 (9H, s).

(Step 2) 3- (2-Methyl-5-nitro-5-nitro-5-oxo-1-phenylpyrazol-3-yl) pyrrolidine-1-carboxylate tert-butyl 3- (2-methyl-5) synthesized in Step 1 Concentrated nitric acid (14.7 mL) was added to 2.52 g (7.34 mmol) of tert-butyl-oxo-1-phenylpyrazol-3-yl) pyrrolidine-1-carboxylate at room temperature, and the mixture was stirred at room temperature for 24 hours. After adding ice to the reaction solution, 15.0 mL of 8N aqueous sodium hydroxide solution was added in an ice bath. After raising the temperature to room temperature, 50 mL of 1,4-dioxane and 7.46 g (36.7 mmol) of di-tert-butyl dicarbonate were added and stirred at room temperature for 1 hour. After extraction with methylene chloride and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, elution solvent: hexane / ethyl acetate → ethyl acetate / methanol = 50/50 to 0/100 → 100/0 to 95/5) to give the title compound 0 Obtained .835 g (29.3% yield) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.58-7.47 (3H, m), 7.35-7.31 (2H, m), 4.25-4.13 (1H, m), 3.89-3.73 (3H, m), 3.51-3.43 ( 1H, m), 3.47 (3H, s), 2.57-2.44 (1H, m), 2.40-2.27 (1H, m), 1.48 (9H, s).

(Step 3) tert-Butyl 3- (4-amino-2-methyl-5-oxo-1-phenylpyrazol-3-yl) pyrrolidine-1-carboxylate 3- (2-methyl-4 synthesized in Step 2 -Nitro-5-oxo-1-phenylpyrazol-3-yl) pyrrolidine-1-carboxylate tert-butyl 0.830 g (2.14 mmol) was dissolved in methanol 21 mL, 5% palladium on carbon catalyst 0. 415 g was added. The reaction system was replaced with hydrogen gas and stirred at 50 ° C. for 4 hours. After allowing to cool, the reaction system was replaced with nitrogen gas, and the reaction solution was filtered through Celite and washed with ethanol. The filtrate and washings were concentrated under reduced pressure to obtain 0.618 g (yield 80.7%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.51-7.41 (4H, m), 7.28-7.22 (1H, m), 3.82-3.19 (5H, m), 3.12 (2H, br s), 2.84 (3H, s ), 2.38-2.22 (2H, m), 1.49 (9H, s).
Thereafter, the reaction was carried out in the same manner as in Step 2 to Step 4 of Example 1, and the following Examples 17 to 23 were synthesized.

(Example 24 and Example 25) 5-chloro-N- (2,2-dimethyl-4-{[1-methyl-5-((3S) -1-methylpyrrolidin-3-yl) -3-oxo -2-phenylpyrazol-4-yl] amino} -4-oxobutyl) -2-ethoxybenzamide / 5-chloro-N- (2,2-dimethyl-4-{[1-methyl-5-((3R) -1-methylpyrrolidin-3-yl) -3-oxo-2-phenylpyrazol-4-yl] amino} -4-oxobutyl) -2-ethoxybenzamide (Step 1) 5-chloro- synthesized in Example 19 N- (2,2-dimethyl-4-{[1-methyl-5- (1-methylpyrrolidin-3-yl) -3-oxo-2-phenylpyrazol-4-yl] amino} -4-oxobutyl) -2-Ethoxybenzamide .00g a (7.04 mmol) chiral column (Daicel CHIRALPAK AD-H, eluting solvent; n-hexane / ethanol = 40/60, flow rate 10 mL / min) was resolved using. The previously eluted fractions were collected and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 50 mL of ethyl acetate, 200 mL of n-hexane was added, and the precipitated solid was collected by filtration (+)-5. -Chloro-N- (2,2-dimethyl-4-{[1-methyl-5-((3S) -1-methylpyrrolidin-3-yl) -3-oxo-2-phenylpyrazol-4-yl] Amino} -4-oxobutyl) -2-ethoxybenzamide (1.87 g, 46.8% yield) was obtained as a solid. The same operation was performed on the fraction eluted later (-)-5-chloro-N- (2,2-dimethyl-4-{[1-methyl-5-((3R) -1-methylpyrrolidine-3 -Il) -3-oxo-2-phenylpyrazol-4-yl] amino} -4-oxobutyl) -2-ethoxybenzamide (1.89 g, 47.2% yield) was obtained as a solid. The absolute configuration was determined by synthesizing the title substance from the corresponding optically active raw material.

Example 26 5-Chloro-N- (2,2-dimethyl-4-{[1-methyl-5- (1-methylpyrrolidin-3-yl) -3-oxo-2-phenylpyrazole-4- Yl] amino} -4-oxobutyl) -4-fluoro-2- (methoxymethoxy) benzamide

(Step 1) 1- (2,2,2-trifluoroacetyl) pyrrolidine-3-carboxylic acid Pyrrolidine-3-carboxylic acid hydrochloride is suspended in 50 mL of tetrahydrofuran, and ethyl 2,2,2-trifluoroacetate is added. 15 mL (3.75 g, 26.4 mmol) was added at room temperature, followed by ice cooling. To this, 4.10 mL (3.80 g, 33.0 mmol) of 1,1,3,3-tetramethylguanidine was added dropwise. After the addition, the reaction solution was warmed to room temperature and stirred for 1 hour. Methanol 50mL was added to the reaction liquid, and it stirred for 0.5 hour. To the reaction mixture was added 25 mL of 5N hydrochloric acid, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 1.83 g (yield 65.7%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 3.97-3.59 (4H, m), 3.28-3.12 (1H, m), 2.36-2.20 (2H, m).

(Step 2) 2-Phenyl-5- [1- (2,2,2-trifluoroacetyl) pyrrolidin-3-yl] -1H-pyrazol-3-one Tetrahydrofuran-2-carboxylic acid of Step 39 of Example 39 Using 1- (2,2,2-trifluoroacetyl) pyrrolidine-3-carboxylic acid synthesized in Step 1 instead of the acid, the reaction was carried out in the same manner as in Step 39 of Example 39. The compound was obtained as a solid.
NMR

(Step 3) 1-methyl-2-phenyl-5- [1- (2,2,2-trifluoroacetyl) pyrrolidin-3-yl] pyrazol-3-one 2-phenyl-5-synthesized in Step 2 [1- (2,2,2-trifluoroacetyl) pyrrolidin-3-yl] -1H-pyrazol-3-one (58.5 g, 180 mmol) was dissolved in 58.5 mL of N, N-dimethylformamide and ice bath. After adding 56.0 mL (128 g, 899 mmol) of lower iodomethane, the mixture was stirred at 100 ° C. for 6 hours while sealed in a metal pressure vessel. After allowing to cool, the reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration and washed with a mixed solvent of hexane and ethyl acetate (2: 1) to obtain 38.2 g (yield 62.6%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.51-7.45 (2H, m), 7.40-7.29 (3H, m), 5.52 (1H, s), 4.14-4.07 (1H, m), 4.00-3.60 (3H, m), 3.44-3.26 (1H, m), 3.14-3.11 (3H, m), 2.55-2.38 (1H, m), 2.33-2.07 (1H, m).

(Step 4) 4-Amino-1-methyl-2-phenyl-5- [1- (2,2,2-trifluoroacetyl) pyrrolidin-3-yl] pyrazol-3-one In Step 4 of Example 39 Instead of 1-methyl-2-phenyl-5-tetrahydrofuran-2-ylpyrazol-3-one, 1-methyl-2-phenyl-5- [1- (2,2,2-trimethyl) synthesized in Step 3 was used. Fluoroacetyl) pyrrolidin-3-yl] pyrazol-3-one was used in the same manner as in Step 39 of Example 39 to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.52-7.42 (4H, m), 7.31-7.24 (1H, m), 4.12-3.81 (3H, m), 3.80-3.60 (1H, m), 3.46-3.25 ( 1H, m), 3.06 (2H, br s), 2.89-2.84 (3H, m), 2.62-2.33 (2H, m).

(Step 5) 5-chloro-N- [2,2-dimethyl-4-({1-methyl-3-oxo-2-phenyl-5- [1- (2,2,2-trifluoroacetyl) pyrrolidine -3-yl] pyrazol-4-yl} amino) -4-oxobutyl] -4-fluoro-2- (methoxymethoxy) benzamide 4-amino-1-methyl-2-phenyl-5- [synthesized in Step 4 1- (2,2,2-trifluoroacetyl) pyrrolidin-3-yl] pyrazol-3-one 0.709 g (2.00 mmol) was dissolved in ethanol to give 4- (4,6-dimethoxy-1,3 , 5-triazin-2-yl) -4-methylmorpholine (DMT-MM) (0.649 g, 2.20 mmol) was added, and the mixture was stirred at room temperature. The intermediate 1f0.649g (2.20mmol) was added here, and it stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure, water and saturated brine were added to the resulting residue, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated, and the resulting crude product was subjected to silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate → ethyl acetate / methanol = 30 / 70 to 0/100 → 100/0 → 80/20) to obtain 0.575 g (yield 42.0%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 9.43 (0.45H, s), 9.23 (0.55H, s), 8.24 (1H, dd, J = 8.8, 2.4 Hz), 8.08 (1H, t, J = 6.8 Hz ), 7.46-7.43 (4H, m), 7.30-7.28 (1H, m), 7.07 (1H, dd, J = 10.3, 2.4 Hz), 5.32 (2H, s), 4.16-3.92 (2H, m), 3.75-3.44 (6H, m), 3.13 (2H, d, J = 6.8 Hz), 2.58-2.41 (2H, m), 2.29-2.20 (2H, m), 1.13 (3H, s), 1.12 (3H, s).

(Step 6) 5-chloro-N- {2,2-dimethyl-4-[(1-methyl-3-oxo-2-phenyl-5-pyrrolidin-3-yl-pyrazol-4-yl) -4- Oxobutyl] -4-fluoro-2- (methoxymethoxy) benzamide 5-chloro-N- [2,2-dimethyl-4-({1-methyl-3-oxo-2-phenyl-5) synthesized in Step 5 [1- (2,2,2-trifluoroacetyl) pyrrolidin-3-yl] pyrazol-4-yl} amino) -4-oxobutyl] -4-fluoro-2- (methoxymethoxy) benzamide 0.573 g (0 838 mmol) was dissolved in 4.0 mL of ethanol, 2.0 mL of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, water and saturated brine were added to the resulting residue, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated to obtain 0.473 g (yield 96.0%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.81 (1H, s), 8.25-8.23 (2H, m), 7.45-7.42 (4H, m), 7.28-7.28 (1H, m), 7.07 (1H, d, J = 10.7 Hz), 5.33 (2H, s), 3.64-3.56 (2H, m), 3.51 (3H, s), 3.32-3.27 (3H, m), 3.20-3.16 (1H, m), 3.14 (3H , s), 2.99-2.97 (1H, m), 2.26-2.23 (3H, m), 2.18-2.14 (1H, m), 1.14 (6H, s).

(Step 7) 5-chloro-N- (2,2-dimethyl-4-{[1-methyl-5- (1-methylpyrrolidin-3-yl) -3-oxo-2-phenylpyrazol-4-yl] ] Amino} -4-oxobutyl) -4-fluoro-2- (methoxymethoxy) benzamide 5-chloro-N- {2,2-dimethyl-4-[(1-methyl-3-oxo-) synthesized in Step 6 2-phenyl-5-pyrrolidin-3-yl-pyrazol-4-yl) -4-oxobutyl] -4-fluoro-2- (methoxymethoxy) benzamide (0.471 g, 0.801 mmol) was added to methylene chloride / methanol (1 / 1) Dissolved in 8 mL, added 0.50 mL of 37% aqueous formaldehyde solution, and stirred at room temperature. To this, 0.849 g (4.00 mmol) of sodium triacetoxyborohydride was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was neutralized with water and saturated aqueous sodium hydrogen carbonate, and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The resulting crude product was subjected to amino silica gel column chromatography (Biotage, elution solvent: hexane / ethyl acetate → ethyl acetate / methanol = 30 / 70 to 0/100 → 0/100 to 15/85). The obtained solid was suspended in ethyl acetate / diethyl ether, insoluble matter was collected by filtration and dried to obtain 0.391 g (yield 81.1%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.61 (1H, s), 8.32 (1H, t, J = 6.8 Hz), 8.25 (1H, d, J = 8.8 Hz), 7.45-7.42 (4H, m), 7.29-7.27 (1H, m), 7.06 (1H, d, J = 10.3 Hz), 5.34 (2H, s), 3.58 (2H, d, J = 6.8 Hz), 3.51 (3H, s), 3.48-3.47 (1H, m), 3.19 (3H, s), 2.98-2.96 (1H, m), 2.88-2.87 (1H, m), 2.73-2.71 (1H, m), 2.50-2.48 (1H, m), 2.40 (3H, s), 2.35-2.31 (1H, m), 2.28-2.24 (2H, m), 2.15-2.13 (1H, m), 1.14 (6H, s).
MS (ESI) m / z: 602 [(M + H) ⁺ ].
In the same manner, the following Examples 27 to 31 were synthesized.

Example 32 5-Chloro-N- (2,2-dimethyl-4-{[1-methyl-5- (1-methyl-3-piperidyl) -3-oxo-2-phenylpyrazol-4-yl] Amino} -4-oxobutyl) -2-ethoxybenzamide

(Step 1) tert-butyl 3- (4-amino-2-methyl-5-oxo-1-phenylpyrazol-3-yl) piperidine-1-carboxylate 3- [tert-butyl in Step 1 of Example 7 Using 1-tert-butoxycarbonylpiperidine-3-carboxylic acid instead of-(dimethyl) silyl] oxy-3-methylcyclobutanecarboxylic acid, the reaction was carried out in the same manner as in Step 7 of Example 7 to obtain the title The compound was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.51-7.40 (4H, m), 7.32-7.20 (1H, m), 4.31-4.04 (2H, m), 3.78-3.67 (1H, m), 3.16-3.03 ( 2H, m), 2.92-2.76 (1H, m), 2.86 (3H, s), 2.69-2.59 (1H, m), 2.15-2.06 (1H, m), 2.05-1.90 (1H, m), 1.86- 1.75 (1H, m), 1.70-1.36 (1H, m), 1.48 (9H, s).
Thereafter, the reaction was carried out in the same manner as in Step 2 to Step 4 of Example 1, and the following Examples 32 to 33 were synthesized.

Example 34 4- [4-({4-[(5-Chloro-2-ethoxybenzoyl) amino] -3,3-dimethylbutanoyl} amino) -2-methyl-5-oxo-1-phenyl Pyrazol-3-yl] piperidine-1-carboxylate tert-butyl

(Step 1) 4- (4-amino-2-methyl-5-oxo-1-phenylpyrazol-3-yl) piperidine-1-carboxylate tert-butyl 1-tert-butoxycarbonyl of Step 17 of Example 17 Using 1-tert-butoxycarbonylpiperidine-4-carboxylic acid instead of pyrrolidine-3-carboxylic acid, the reaction was carried out in the same manner as in Step 17 of Example 17 to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.51-7.40 (4H, m), 7.27-7.21 (1H, m), 4.36-4.20 (2H, m), 3.04 (2H, br s), 2.87-2.57 (3H , m), 2.84 (3H, s), 1.99-1.83 (4H, m), 1.49 (9H, s).
Thereafter, the reaction was carried out in the same manner as in Step 2 to Step 4 of Example 1, and the following Examples 34 to 37 were synthesized.

Example 38 5-Chloro-N- (2,2-dimethyl-4-{[1-methyl-5- (4-methylmorpholin-2-yl) -3-oxo-2-phenylpyrazole-4- Yl] amino} -4-oxobutyl) -2-ethoxybenzamide

(Step 1) tert-Butyl 2- (4-amino-2-methyl-5-oxo-1-phenylpyrazol-3-yl) morpholine-4-carboxylate 3- [tert-Butyl of Step 1 of Example 7 Using 1-tert-butoxycarbonylpiperidine-3-carboxylic acid instead of-(dimethyl) silyl] oxy-3-methylcyclobutanecarboxylic acid, the reaction was carried out in the same manner as in Step 7 of Example 7 to obtain the title The compound was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.53-7.36 (5H, m), 4.44 (1H, d, J = 10.3 Hz), 4.07-3.87 (2H, m), 3.70-3.52 (2H, m), 3.21 -3.08 (2H, m), 2.82 (3H, s), 1.61-1.42 (2H, m), 1.48 (9H, s).
MS (ESI) m / z: 375 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 2 to Step 4 of Example 1, and the following Example 38 was synthesized.

Example 39 5-Chloro-N- {2,2-dimethyl-4-[(1-methyl-3-oxo-2-phenyl-5-tetrahydrofuran-2-yl-pyrazol-4-yl) amino] -4-oxobutyl} -2-ethoxybenzamide

(Step 1) Ethyl 3-oxo-3-tetrahydrofuran-2-yl-propanoate Tetrahydrofuran-2-carboxylic acid (5.00 g, 43.1 mmol) was dissolved in tetrahydrofuran (50 mL), and 1,1′-carbonyldiimidazole (8. 38 g (51.7 mmol) was slowly added at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. To this reaction solution, 3.98 g (41.8 mmol) of magnesium chloride and 11.0 g (64.6 mmol) of monoethyl potassium malonate were slowly added and stirred at room temperature for 3 hours. The solvent was concentrated to about 1/3 volume under reduced pressure, diluted with water and ethyl acetate, adjusted to pH = 5 by adding 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 100/0 to 80/20), and 8.24 g of the title compound was quantitatively obtained as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 4.40-4.38 (1H, m), 4.20 (2H, q, J = 7.1 Hz), 3.93-3.91 (2H, m), 3.58 (2H, s), 2.20-2.18 (1H, m), 2.06-2.03 (1H, m), 1.95-1.88 (2H, m), 1.28 (3H, t, J = 7.1 Hz).

(Step 2) 2-Phenyl-5-tetrahydrofuran-2-yl-1H-pyrazol-3-one 1.59 mL of phenylhydrazine (1.74 g, 16.1 mmol) and 3-oxo synthesized in Step 1 under a nitrogen atmosphere 3.00 g (16.1 mmol) of ethyl-3-tetrahydrofuran-2-yl-propanoate was dissolved in 30 mL of toluene and heated to reflux for 4 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 100/0 to 60/40) to give 2.87 g (yield 77.4%) of the title compound as a solid. Obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.84-7.86 (2H, m), 7.37-7.42 (2H, m), 7.19 (1H, t, J = 7.3 Hz), 4.74 (1H, t, J = 6.7 Hz ), 3.87-3.97 (2H, m), 3.53-3.54 (2H, m), 2.21-2.30 (1H, m), 2.09-2.17 (1H, m), 1.99-2.06 (2H, m).
MS (APCI) m / z: 231 [(M + H) ⁺ ].

(Step 3) 1-methyl-2-phenyl-5-tetrahydrofuran-2-yl-pyrazol-3-one 2-phenyl-5-tetrahydrofuran-2-yl-1H-pyrazol-3-one 2 synthesized in Step 2 .71 g (11.8 mmol) was dissolved in 15 mL of N, N-dimethylformamide, 3.66 mL (g, 58.9 mmol) of methane iodide was added, and the mixture was stirred at 130 ° C. for 0.5 hour while being irradiated with microwaves. . After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate → ethyl acetate / methanol = 100/0 to 0/100 → 100/0). To 95/5) to obtain 1.47 g (yield 55.6%) of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.45-7.49 (2H, m), 7.37-7.40 (2H, m), 7.31-7.35 (1H, m), 5.54 (1H, s), 4.82-4.85 (1H, m), 3.91-4.03 (2H, m), 3.19 (3H, s), 2.33-2.39 (1H, m), 2.02-2.14 (3H, m).
MS (APCI) m / z: 245.2 [(M + H) ⁺ ].

(Step 4) 1-methyl-4-nitro-2-phenyl-5-tetrahydrofuran-2-yl-pyrazol-3-one 1-methyl-2-phenyl-5-tetrahydrofuran-2-yl-synthesized in Step 3 1.47 g (6.02 mmol) of pyrazol-3-one was dissolved in 20 mL of trifluoroacetic acid, 1.16 mL (18.1 mmol) of concentrated nitric acid was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water and extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was distilled off under reduced pressure to obtain 1.51 g (yield: 86.5%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.47-7.56 (3H, m), 7.31-7.33 (2H, m), 5.88 (1H, dd, J = 9.2, 6.7 Hz), 4.09-4.14 (1H, m) , 3.97-4.03 (1H, m), 3.58 (3H, s), 2.74-2.82 (1H, m), 2.07-2.25 (2H, m), .1.90-1.99 (1H, m)
MS (APCI) m / z: 290 [(M + H) ⁺ ].

(Step 5) 4-amino-1-methyl-2-phenyl-5-tetrahydrofuran-2-yl-pyrazol-3-one 1-methyl-4-nitro-2-phenyl-5-tetrahydrofuran-synthesized in Step 4 1.51 g (5.22 mmol) of 2-yl-pyrazol-3-one was dissolved in 30 mL of methanol and 30 mL of ethyl acetate, 1.00 g of 10% palladium carbon catalyst (M type) was added, and the mixture was stirred for 4 hours in a hydrogen atmosphere. . The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, elution solvent; methylene chloride / methanol = 100/0 to 95/5), and 0.976 g (yield 72.1%) of the title compound was obtained as an oily substance. Got as.
¹ H-NMR (CDCl ₃ ) δ: 7.41-7.51 (4H, m), 7.22-7.26 (1H, m), 4.85-4.89 (1H, m), 4.04-4.09 (1H, m), 3.88-3.94 ( 1H, m), 3.52 (2H, br s), 2.79 (3H, s), 2.24-2.33 (1H, m), 2.01-2.19 (3H, m).
MS (APCI) m / z: 260.2 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 2 of Example 1, and the following Examples 39 to 41 were synthesized.

Example 42 5-Chloro-N- {2,2-dimethyl-4-[(1-methyl-3-oxo-2-phenyl-5-tetrahydrofuran-3-yl-pyrazol-4-yl) amino] -4-oxobutyl} -2-ethoxybenzamide

(Step 1) 4-amino-1-methyl-2-phenyl-5-tetrahydrofuran-3-yl-pyrazol-3-one Tetrahydrofuran-3-carboxylic acid instead of tetrahydrofuran-2-carboxylic acid in Step 1 of Example 39 Using the acid, the reaction was carried out in the same manner as in Step 39 of Example 39 to obtain the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.52-7.41 (4H, m), 7.26-7.22 (1H, m), 4.27 (1H, dd, J = 9.1, 3.0 Hz), 4.16-4.10 (1H, m) , 3.90 (1H, dd, J = 9.1, 6.7 Hz), 3.85-3.79 (1H, m), 3.50 (2H, br s), 3.32-3.26 (1H, m), 2.83 (3H, s), 2.41- 2.33 (1H, m), 2.22-2.14 (1H, m).
MS (APCI) m / z: 260 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 2 of Example 1, and the following Examples 42 to 43 were synthesized.

Example 44 5-Chloro-N- {2,2-dimethyl-4-[(1-methyl-3-oxo-2-phenyl-5-tetrahydropyran-2-yl-pyrazol-4-yl) amino ] -4-Oxobutyl} -2-ethoxybenzamide

(Step 1) 4-Amino-1-methyl-2-phenyl-5-tetrahydropyran-2-yl-pyrazol-3-one Tetrahydropyran-2 instead of tetrahydrofuran-2-carboxylic acid in Step 1 of Example 39 The reaction was carried out using carboxylic acid in the same manner as in Step 39 of Example 39 to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.54-7.41 (4H, m), 7.32-7.24 (1H, m), 4.48-4.43 (1H, m), 4.20 (2H, br s), 4.16-4.14 (1H , m), 3.60-3.54 (1H, m), 2.89 (3H, s), 1.99-1.96 (1H, m), 1.90-1.84 (2H, m), 1.77-1.58 (3H, m).
MS (APCI) m / z: 274 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 2 of Example 1, and the following Examples 44 to 45 were synthesized.

Example 46 5-Chloro-N- {2,2-dimethyl-4-[(1-methyl-3-oxo-2-phenyl-5-tetrahydropyran-3-yl-pyrazol-4-yl) amino ] -4-Oxobutyl} -2-ethoxybenzamide

(Step 1) 4-Amino-1-methyl-2-phenyl-5-tetrahydropyran-3-yl-pyrazol-3-one Tetrahydropyran-3 instead of tetrahydrofuran-2-carboxylic acid in Step 1 of Example 39 The reaction was carried out using carboxylic acid in the same manner as in Step 39 of Example 39 to obtain the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.51-7.41 (4H, m), 7.25-7.22 (1H, m), 4.07 (1H, dd, J = 11.9, 5.8 Hz), 3.92 (1H, dd, J = 11.9, 3.4 Hz), 3.78 (2H, t, J = 5.2 Hz), 3.60 (2H, br s), 2.80-2.74 (4H, m), 2.14-2.03 (1H, m), 2.01-1.94 (1H, m), 1.81-1.72 (1H, m), 1.67-1.58 (1H, m).
MS (APCI) m / z: [274 (M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 2 of Example 1, and the following Examples 46 to 47 were synthesized.

Example 48 5-Chloro-N- {2,2-dimethyl-4-[(1-methyl-3-oxo-2-phenyl-5-tetrahydropyran-4-yl-pyrazol-4-yl) amino ] -4-Oxobutyl} -2-ethoxybenzamide

(Step 1) 4-Amino-1-methyl-2-phenyl-5-tetrahydropyran-4-yl-pyrazol-3-one Tetrahydropyran-4 instead of tetrahydrofuran-2-carboxylic acid in Step 1 of Example 39 The reaction was carried out using carboxylic acid in the same manner as in Step 39 of Example 39 to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.50-7.41 (4H, m), 7.26-7.22 (1H, m), 4.13-4.09 (2H, m), 3.54-3.50 (2H, m), 3.09 (2H, br s), 2.85 (3H, s), 2.81-2.73 (1H, m), 2.17-2.04 (2H, m), 1.82-1.78 (2H, m).
MS (APCI) m / z: [274 (M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 2 of Example 1, and the following Examples 48 to 49 were synthesized.

Example 50 5-Chloro-N- (4-{[5- (1,4-dioxan-2-yl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino}- 2,2-Dimethyl-4-oxobutyl) -2-ethoxybenzamide

(Step 1) 4-amino-5- (1,4-dioxane-2-yl) -1-methyl-2-phenylpyrazol-3-one 1,4 instead of tetrahydrofuran-2-carboxylic acid of Example 39 Using dioxane-2-carboxylic acid, the reaction was carried out in the same manner as in Step 39 of Example 39 to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.53-7.40 (4H, m), 7.31-7.22 (1H, m), 4.62 (1H, dd, J = 7.9, 3.0 Hz), 4.01-3.73 (6H, m) , 2.83 (3H, s).
MS (ESI) m / z: 276 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 2 of Example 1, and the following Examples 50 to 54 were synthesized.

Example 55 N- (5-Chloro-2-methoxyphenyl) -3,3-dimethyl-N '-(1-methyl-3-oxo-2,5-diphenylpyrazol-4-yl) pentanediamide

(Step 1) 2,5-diphenyl-1H-pyrazol-3-one Under a nitrogen atmosphere, phenylhydrazine 0 was added to a 4.0 mL acetic acid solution of 0.577 g (3.00 mmol) of ethyl 3-oxo-3-phenylpropionate. .295 mL (0.324 g, 3.00 mmol) was added and stirred at 110 ° C. for 5 hours. After allowing to cool to room temperature, the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (Yamazensha, elution solvent; chloroform only). After concentration under reduced pressure, the resulting solid was suspended in diisopropyl ether, filtered and dried to obtain 0.540 g (yield 76.2%) of the title compound as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 11.81 (1H, s), 7.83-7.81 (4H, m), 7.50-7.27 (6H, m), 6.02 (1H, s).
MS (API) m / z: [237 (M + H) ⁺ ].

(Step 2) 1-methyl-2,5-diphenylpyrazol-3-one 0.535 g (2.26 mmol) of 2,5-diphenyl-1H-pyrazol-3-one synthesized in Step 1 0.352 mL (0.804 g, 5.66 mmol) of methane iodide was added to a 3.0 mL formamide solution, and the mixture was stirred at 100 ° C. for 15 and a half hours in a sealed tube. After allowing to cool to room temperature, the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (Yamazensha, elution solvent; ethyl acetate / methanol = 99/1) to give 0.468 g (82.6%) of the title compound as a solid. Obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.57-7.48 (9H, m), 7.32-7.28 (1H, m), 5.83 (1H, s), 3.02 (3H, s).
MS (API) m / z: [251 (M + H) ⁺ ].

(Step 3) 1-methyl-4-nitro-2,5-diphenylpyrazol-3-one To 0.460 g (1.84 mmol) of 1-methyl-2,5-diphenylpyrazol-3-one synthesized in Step 2 70% nitric acid (3.0 mL) was added, and the mixture was stirred at 70 ° C. for 2 hr. After cooling to room temperature, ice water was added to the reaction solution, extracted with chloroform three times, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (Yamazensha, elution solvent; chloroform / ethyl acetate = 81/19 to 60/40) to give 0.335 g of the title compound (yield 61. 7%) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.63-7.42 (10H, m), 3.21 (3H, s).
MS (API) m / z: [296 (M + H) ⁺ ].

(Step 4) 4-Amino-1-methyl-2,5-diphenylpyrazol-3-one 0.330 g of 1-methyl-4-nitro-2,5-diphenylpyrazol-3-one synthesized in Step 3 (1 0.15 g of 5% palladium on carbon (containing water) was added to a 15.0 mL solution of .12 mmol) in methanol and stirred at room temperature for 15 hours in a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure, and the resulting solid was suspended in diisopropyl ether, collected by filtration and dried to obtain 0.200 g (yield 67.5%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.66-7.39 (9H, m), 7.28-7.24 (1H, m), 3.51 (2H, s), 2.77 (3H, s).
MS (API) m / z: [266 (M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 2 of Example 1, and Example 55 below was synthesized.

Example 56 N- (4-{[5- (4-aminophenyl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino} -2,2-dimethyl-4-oxobutyl ) -5-Chloro-2-ethoxybenzamide

(Step 1) 4-[(2,2,2-trifluoroacetyl) amino] benzoic acid 20.3 mL (40.9 g, 145 mmol) of trifluorobenzoic anhydride was dissolved in 150 mL of tetrahydrofuran, and 4-amino Benzoic acid 10.0 g (72.9 mmol) was added in several portions. The reaction solution was stirred at room temperature for 5.5 hours and then concentrated under reduced pressure. The solid produced by adding 50 mL of water to the residue was collected by filtration and dried under reduced pressure to obtain 18.4 g (yield 81.3%) of the title compound as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 11.53 (1H, s), 7.99 (2H, d, J = 8.5 Hz), 7.82 (2H, d, J = 8.5 Hz).
MS (APCI) m / z: [232 (MH) ^- ].

(Step 2) N- [4- (4-Amino-2-methyl-5-oxo-1-phenylpyrazol-3-yl) phenyl] -2,2,2-trifluoroacetamide Tetrahydrofuran-2 of Example 39 Using 4-[(2,2,2-trifluoroacetyl) amino] benzoic acid synthesized in Step 1 instead of carboxylic acid, the reaction was carried out in the same manner as in Step 39 of Example 39, and the title The compound was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.53 (1H, br s), 7.77 (2H, d, J = 8.5 Hz), 7.63-7.60 (4H, m), 7.47 (2H, t, J = 7.9 Hz) , 7.29-7.26 (1H, m), 3.52 (2H, br s), 2.76 (3H, s).
MS (APCI) m / z: [377 (M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 5 of Example 1 and Steps 6 to 7 of Example 26, and the following Examples 56 to 57 were synthesized.

Example 58 N- (4-{[5- (3-aminophenyl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino} -2,2-dimethyl-4-oxobutyl ) -5-Chloro-2-ethoxybenzamide

(Step 1) N- [3- (4-Amino-2-methyl-5-oxo-1-phenylpyrazol-3-yl) phenyl] -2,2,2-trifluoroacetamide Example 56, Step 1 Using 3-aminobenzoic acid instead of 4-aminobenzoic acid, the reaction was carried out in the same manner as in Step 2 of Example 56 to obtain the title compound as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 11.37 (1H, br s), 7.88 (1H, br s), 7.74 (1H, d, J = 7.9 Hz), 7.63 (2H, d, J = 7.9 Hz ), 7.58-7.50 (4H, m), 7.30 (1H, t, J = 7.3 Hz), 4.61 (2H, s), 2.67 (3H, s).
MS (APCI) m / z: 377 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 5 of Example 1 and Steps 6 to 7 of Example 26, and the following Examples 58 to 59 were synthesized.

Example 60 N- (4-{[5- (2-aminophenyl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino} -2,2-dimethyl-4-oxobutyl ) -5-Chloro-2-ethoxybenzamide

(Step 1) N- [2- (4-Amino-2-methyl-5-oxo-1-phenylpyrazol-3-yl) phenyl] -2,2,2-trifluoroacetamide Example 56, Step 1 Using 2-aminobenzoic acid instead of 4-aminobenzoic acid, the reaction was carried out in the same manner as in Step 2 of Example 56 to obtain the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 10.65 (1H, br s), 8.23 (1H, d, J = 8.5 Hz), 7.61-7.54 (4H, m), 7.54-7.47 (2H, m), 7.41- 7.37 (1H, m), 7.34-7.30 (1H, m), 3.50 (2H, br s), 2.74 (3H, s).
MS (APCI) m / z: 377 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 5 of Example 1 and Steps 6 to 7 of Example 26, and the following Examples 60 to 61 were synthesized.

Example 62 5-Chloro-N- (2,2-dimethyl-4-{[1-methyl-3-oxo-2-phenyl-5- (4-pyridyl) pyrazol-4-yl] amino}- 4-oxobutyl) -2-ethoxybenzamide

(Step 1) ethyl 5- (2-chloro-4-pyridyl) -methyl-2-phenylpyrazol-3-one 3- (2-chloro-4-pyridyl) -3-oxopropanoate (9. 1-methyl-2-phenylhydrazine 1 synthesized by the method described in document US2008 / 262020, dissolved in a mixed solvent of acetic acid / pyridine / water (0.51 mL / 0.73 mL / 0.73 mL) 0.000 g (8.19 mmol) was added, and the mixture was stirred at 105 ° C. for 2 hours. It returned to room temperature, water and saturated sodium hydrogencarbonate aqueous solution were added, and it extracted with the methylene chloride. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (Biotage, elution solvent: hexane / ethyl acetate → ethyl acetate / methanol = 50/50 to 0/100 → 100 / 0-90 / 10). The residue obtained by concentrating the fraction containing the desired product under reduced pressure was suspended in ethyl acetate, and the solid was collected by filtration and dried to obtain 0.995 g of the title compound (yield 42.5%). Obtained as a solid.
¹ H-NMR (CD ₃ OD) δ: 8.56 (1H, d, J = 5.5 Hz), 7.80 (1H, br s), 7.65 (1H, dd, J = 5.5, 1.5 Hz), 7.60-7.54 (4H , m), 7.48-7.44 (1H, m), 6.04 (1H, s), 3.15 (3H, s).
MS (ESI + APCI) m / z: 286 [(M + H) ⁺ ].

(Step 2) 5- (2-Chloro-4-pyridyl) -1-methyl-4-nitro-2-phenylpyrazol-3-one 5- (2-Chloro-4-pyridyl) -methyl synthesized in Step 1 2-phenylpyrazol-3-one (0.995 g, 3.48 mmol) was dissolved in 10 mL of trifluoroacetic acid, and 0.662 mL (10.5 mmol) of concentrated nitric acid was added under ice cooling. The reaction mixture was warmed to room temperature and stirred for 3 hours, water was added, and the mixture was extracted with methylene chloride. The extract was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 0.988 g (yield 85.8%) of the title compound as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 8.70 (1H, d, J = 4.9 Hz), 7.96 (1H, s), 7.77 (1H, dd, J = 4.9, 1.2 Hz), 7.66-7.63 (2H , m), 7.60-7.58 (1H, m), 7.56-7.54 (2H, m), 3.21 (3H, s).
MS (APCI) m / z: 331 [(M + H) ⁺ ].

(Step 3) 4-Amino-1-methyl-2-phenyl-5- (4-pyridyl) pyrazol-3-one 5- (2-chloro-4-pyridyl) -1-methyl-4 synthesized in Step 2 -Nitro-2-phenylpyrazol-3-one 0.988 g (2.99 mmol) was suspended in 10 mL of methanol, and 0.500 g of 10% palladium carbon catalyst (M type) was added. The reaction mixture was stirred under a hydrogen atmosphere at 60 ° C. for 7 hours and returned to room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with methylene chloride. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the residue obtained by concentrating the filtrate is purified by silica gel column chromatography (Biotage, elution solvent; 10% methanol-ethyl acetate / hexane = 70/30 to 20/80) to give the title compound 0.554 g (69.7% yield) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.75 (2H, d, J = 5.5 Hz), 7.65 (2H, d, J = 7.9 Hz), 7.51-7.46 (4H, m), 7.32-7.28 (2H, m ), 3.80 (2H, br s), 2.78 (3H, s).
MS (APCI) m / z: 267 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 2 of Example 1, and the following Examples 62 to 64 were synthesized.

Example 65 5-Chloro-N- (2,2-dimethyl-4-{[1-methyl-3-oxo-2-phenyl-5- (3-pyridyl) pyrazol-4-yl] amino}- 4-oxobutyl) -2-ethoxybenzamide

(Step 1) 5- (6-Chloro-3-pyridyl) -1-methyl-2-phenylpyrazol-3-one 3- (2-chloro-4-pyridyl) -3-oxo of Step 1 of Example 62 The reaction was conducted in the same manner using ethyl 3- (6-chloro-3-pyridyl) -3-oxo-propanoate instead of ethyl propanoate to obtain the title compound as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 8.79 (1H, d, J = 2.4 Hz), 8.22 (1H, dd, J = 8.5, 2.4 Hz), 7.77 (1H, d, J = 8.5 Hz), 7.58-7.51 (4H, m), 7.36-7.32 (1H, m), 6.06 (1H, s), 3.00 (3H, s).
MS (APCI) m / z: 286 [(M + H) ⁺ ].

(Step 2) 4-Amino-1-methyl-2-phenyl-5- (3-pyridyl) pyrazol-3-one 1-methyl-2-phenyl-5-tetrahydrofuran-2-yl of Step 4 of Example 39 Using 5- (6-chloro-3-pyridyl) -1-methyl-2-phenylpyrazol-3-one synthesized in Step 1 instead of -pyrazol-3-one, hereinafter, Step 5 of Example 39 The reaction was carried out in the same manner as before to obtain the title compound as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 8.87 (1H, d, J = 1.8 Hz), 8.58 (1H, dd, J = 4.6, 1.8 Hz), 8.03 (1H, dt, J = 7.9, 1.8 Hz ), 7.68-7.66 (2H, m), 7.56-7.51 (3H, m), 7.32-7.28 (1H, m), 3.35 (2H, s), 2.65 (3H, s).
MS (APCI) m / z: 267 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 2 of Example 1, and the following Examples 65 to 67 were synthesized.

Example 68 5-Chloro-N- (2,2-dimethyl-4-{[1-methyl-5- (6-methyl-3-
Pyridyl) -3-oxo-2-phenylpyrazol-4-yl] amino} -4-oxobutyl) -2-ethoxybenzamide

(Step 1) 1-methyl-5- (6-methyl-3-pyridyl) -2-phenylpyrazol-3-one 5- (6-chloro-3-pyridyl) -1 synthesized in Step 1 of Example 65 -Methyl-2-phenylpyrazol-3-one (2.00 g, 7.00 mmol) was dissolved in 33 mL of a mixed solvent of 1,4-dioxane-water (10: 1), and 2.90 g (21. 0 mmol), 3.00 mL (10.5 mmol) of a 3.5 M trimethylboroxine-tetrahydrofuran solution and 0.810 g (0.700 mmol) of tetrakistriphenylphosphine palladium were added. The reaction mixture was stirred at 110 ° C. for 6 hours under a nitrogen atmosphere and returned to room temperature. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The extract was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the residue obtained by concentrating the filtrate under reduced pressure is purified by silica gel column chromatography (Biotage, elution solvent; 10% ethyl acetate-methanol / hexane = 70/30 to 20/80). As a result, 0.626 g (yield 33.7%) of the title compound was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.70 (1H, d, J = 2.4 Hz), 7.76 (1H, dd, J = 7.9, 2.4 Hz), 7.56-7.48 (4H, m), 7.33-7.30 (2H m), 5.86 (1H, s), 3.01 (3H, s), 2.66 (3H, s).
MS (APCI) m / z: 266 [(M + H) ⁺ ].

(Step 2) 4-Amino-1-methyl-5- (6-methyl-3-pyridyl) -2-phenylpyrazol-3-one 1-methyl-2-phenyl-5-tetrahydrofuran of Step 39 of Example 39 Instead of 2-yl-pyrazol-3-one, 1-methyl-5- (6-methyl-3-pyridyl) -2-phenylpyrazol-3-one synthesized in Step 3 was used, and the following examples were used. The reaction was conducted in the same manner as in Step 39 of 39 to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.73 (1H, d, J = 2.1 Hz), 7.80 (1H, dd, J = 8.2, 2.1 Hz), 7.65-7.63 (2H, m), 7.51-7.46 (2H , m), 7.33-7.26 (2H, m), 3.54 (2H, br s), 2.75 (3H, s), 2.64 (3H, s).
MS (APCI) m / z: 281 [(M + H) ⁺ ].
Thereafter, the reaction was performed in the same manner as in Step 2 of Example 1, and Example 68 below was synthesized.

Example 69 5-Chloro-N- (2,2-dimethyl-4-{[1-methyl-3-oxo-2-phenyl-5- (2-pyridyl) pyrazol-4-yl] amino}- 4-oxobutyl) -2-ethoxybenzamide

(Step 1) 5- (6-Chloro-2-pyridyl) -1-methyl-2-phenylpyrazol-3-one 3- (2-chloro-4-pyridyl) -3-oxo of Step 1 of Example 62 A similar reaction was performed using ethyl 3- (6-chloro-2-pyridyl) -3-oxopropanoate instead of ethyl propanoate to obtain the title compound as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 8.09 (1H, t, J = 7.6 Hz), 7.98 (1H, d, J = 7.9 Hz), 7.70 (1H, d, J = 7.9 Hz), 7.56- 7.49 (4H, m), 7.39-7.35 (1H, br m).

(Step 2) 4-Amino-1-methyl-2-phenyl-5- (2-pyridyl) pyrazol-3-one 1-methyl-2-phenyl-5-tetrahydrofuran-2-yl of Step 4 of Example 39 In place of 5-pyrazol-3-one, 5- (6-chloro-2-pyridyl) -1-methyl-2-phenylpyrazol-3-one synthesized in Step 1 was used, and Step 5 of Example 39 hereinafter. The reaction was carried out in the same manner as before to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.69 (1H, d, J = 4.3 Hz), 7.78 (1H, td, J = 7.7, 1.4 Hz), 7.72 (2H, d, J = 7.9 Hz), 7.50- 7.46 (2H, m), 7.43 (1H, d, J = 7.9 Hz), 7.29-7.25 (1H, m), 7.20-7.17 (1H, m), 4.98 (2H, br s), 2.88 (3H, s ).
Thereafter, the reaction was carried out in the same manner as in Step 2 of Example 1, and the following Examples 69 to 71 were synthesized.

Example 72 5-Chloro-N- (2,2-dimethyl-4-{[1-methyl-5- (6-methyl-2-pyridyl) -3-oxo-2-phenylpyrazol-4-yl] Amino} -4-oxobutyl) -2-ethoxybenzamide

(Step 1) 4-Amino-1-methyl-5- (6-methyl-2-pyridyl) -2-phenylpyrazol-3-one 5- (6-chloro-3-pyridyl) of Step 1 of Example 68 Instead of -1-methyl-2-phenylpyrazol-3-one, 5- (6-chloro-2-pyridyl) -1-methyl-2-phenylpyrazol-3-one synthesized in Step 1 of Example 69 was used. Thereafter, the reaction was carried out in the same manner as in Step 68 of Example 68 to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.72 (2H, d, J = 7.9 Hz), 7.67 (1H, t, J = 7.6 Hz), 7.47 (2H, t, J = 7.9 Hz), 7.28-7.22 ( 2H, m), 7.05 (1H, d, J = 7.3 Hz), 5.00 (2H, br s), 2.87 (3H, s), 2.62 (3H, s).
MS (APCI) m / z: 281 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 2 of Example 1, and Example 72 below was synthesized.

Example 73 5-Chloro-N- [2,2-dimethyl-4-({1-methyl-5-[(1-methylazetidin-3-yl) methyl] -3-oxo-2-phenyl Pyrazol-4-yl} amino) -4-oxobutyl] -2-ethoxybenzamide

(Step 1) 3- (2-Benzyloxy-2-oxoethylidene) azetidine-1-carboxylate tert-butyl 3-oxoazetidine-1-carboxylate tert-butyl 5.00 g (29.2 mmol) in a 150 mL toluene solution , 12.6 g (30.7 mmol) of benzyl (triphenylphosphoranylidene) acetate was added, and the mixture was stirred for 2 hours with heating under reflux. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (Yamazensha, elution solvent; hexane / ethyl acetate = 96/4 to 75/25) to give the title compound 10 .9 g (yield> 100%) was obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 7.39-7.31 (5H, m), 5.83 (1H, t, J = 2.1 Hz), 5.17 (2H, s), 4.83-4.81 (2H, m), 4.61-4.59 (2H, m), 1.45 (9H, s).

(Step 2) 2- (1-tert-butoxycarbonylazetidin-3-yl) acetic acid 55714173
To a solution of 10.9 g of tert-butyl 3- (2-benzyloxy-2-oxoethylidene) azetidine-1-carboxylate synthesized in Step 1 (29.2 mmol as 100% yield of Step 1) in 150 mL of ethanol was added 10 % Palladium carbon (containing water) (3.0 g) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The resulting solid was suspended in hexane, collected by filtration and dried to give 6.25 g (yield 99.4%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 4.10 (2H, t, J = 8.5 Hz), 3.63 (2H, dd, J = 9.2, 5.5 Hz), 2.93-2.83 (1H, m), 2.67 (2H, d , J = 7.9 Hz), 1.43 (9H, s).

(Step 3) 3-[(2-Methyl-5-oxo-1-phenylpyrazol-3-yl) methyl] azetidine-1-carboxylate tert-butyl 3- [tert-butyl- of Example 1, Step 1 Using 2- (1-tert-butoxycarbonylazetidin-3-yl) acetic acid synthesized in Step 2 instead of (dimethyl) silyl] oxy-3-methylcyclobutanecarboxylic acid, hereinafter, Step 2 of Example 7 The reaction was carried out in the same manner as before to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.48-7.44 (2H, m), 7.38-7.26 (3H, m), 5.32 (1H, s), 4.15 (2H, t, J = 8.2 Hz), 3.67 (2H , dd, J = 8.9, 5.2 Hz), 3.07 (3H, s), 2.95-2.81 (3H, m), 1.45 (9H, s).
MS (APCI) m / z: [344 (M + H) ⁺ ].

(Step 4) 3-[(4-Amino-2-methyl-5-oxo-1-phenylpyrazol-3-yl) methyl] azetidine-1-carboxylate tert-butyl 3-[(2 -Methyl-5-oxo-1-phenylpyrazol-3-yl) methyl] azetidine-1-carboxylate tert-butyl (0.750 g, 2.18 mmol) in acetonitrile (20 mL) was added 0.181 g (2. 62 mmol) was added and stirred at room temperature for 1 hour. Further, 0.310 g (4.37 mmol) of sodium nitrite was added and stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was dissolved in 10 mL of ethanol, 10 mL of 0.4N hydrochloric acid was added, 2.86 g (43.7 mmol) of zinc powder was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through celite, saturated aqueous sodium hydrogen carbonate was added to the filtrate, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, and then anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by amino silica gel column chromatography (Yamazen Co., elution solvent; ethyl acetate / methanol = 100/0 to 90/10), and further silica gel column chromatography (Yamazen Co., elution). Purification by a solvent; ethyl acetate / methanol = 100/0 to 90/10) afforded 0.274 g (yield <35.0%) of the title compound containing impurities as a solid.
MS (APCI) m / z: [359 (M + H) ⁺ ].

(Step 5) 3-{[4-({4-[(5-Chloro-2-ethoxybenzoyl) amino] -3,3-dimethylbutanoyl} amino) -2-methyl-5-oxo-1-phenyl Pyrazol-3-yl] methyl} azetidine-1-carboxylate tert-butyl 3-[(4-amino-2-methyl-5-oxo-1-failpyrazol-3-yl) mixed with impurities synthesized in Step 4 To an ethanol solution of 0.274 g of tert-butyl methyl] azetidine-1-carboxylate (all 0.764 mmol as the title compound), 240 mg (0.764 mmol) of intermediate 1a and 4- (4,6-dimethoxy-1,3, 5-Triazin-2-yl) -4-methylmorpholine (DMT-MM) (0.378 g, 0.994 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added to the residue, and the mixture was extracted 3 times with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (Yamazensha, elution solvent; ethyl acetate / methanol = 100/0 to 85/15) to obtain 0.313 g of the title compound (contained in 2 steps). 21.9%) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 9.29 (1H, s), 8.39 (1H, t, J = 6.7 Hz), 8.20-8.20 (1H, m), 7.46-7.37 (5H, m), 7.29-7.25 (1H, m), 6.91 (1H, d, J = 8.5 Hz), 4.23-4.03 (4H, m), 3.69 (2H, dd, J = 8.9, 4.6 Hz), 3.59 (2H, d, J = 6.7 Hz), 3.09 (3H, s), 3.02-2.97 (3H, m), 2.28 (2H, s), 1.53 (3H, t, J = 6.7 Hz), 1.43 (9H, s), 1.13 (6H, s ).
MS (APCI) m / z: [654 (M + H) ⁺ ].
Thereafter, the reaction was performed in the same manner as in Step 3 to Step 4 of Example 1, and the following Example 73 was synthesized.

Example 74 5-Chloro-N- [2,2-dimethyl-4-({1-methyl-5-[((5R) -1-methylpyrrolidin-2-yl) methyl] -3-oxo- 2-Phenylpyrazol-4-yl} amino-4-oxobutyl) -2-ethoxybenzamide

(Step 1) tert-Butyl (2R) -2-[(2-methyl-5-oxo-1-phenylpyrazol-3-yl) methyl] pyrrolidine-1-carboxylate 3- [of Step 1 of Example 7 2-[(2R) -1-tert-butoxycarbonylpyrrolidin-2-yl] acetic acid was used instead of tert-butyl- (dimethyl) silyl] oxy-3-methylcyclobutanecarboxylic acid. The reaction was carried out in the same manner as in Step 2 to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.46 (2H, t, J = 7.9 Hz), 7.37 (2H, dd, J = 7.9, 1.2 Hz), 7.29 (3H, t, J = 7.9 Hz), 5.41 ( 1H, s), 4.11-4.02 (1H, m), 3.47-3.32 (2H, m), 3.19 (3H, s), 3.15-3.04 (1H, m), 2.62-2.52 (1H, m), 2.03- 1.77 (4H, m), 1.49 (9H, s).
MS (ESI) m / z: 358 [(M + H) ⁺ ].

(Step 2) 1-methyl-2-phenyl-5-{[(2R) -1- (2,2,2-trifluoroacetyl) pyrrolidin-2-yl] methyl} pyrazol-3-one synthesized in Step 1 Tert-butyl (2R) -2-[(2-methyl-5-oxo-1-phenylpyrazol-3-yl) methyl] pyrrolidine-1-carboxylate 8.00 g (22.4 mmol) in a solution of ethanol 56 mL 4N hydrochloric acid-dioxane solution 56.0 mL (224 mmol) was added, and the mixture was stirred at 50 ° C. for 4 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was azeotroped with toluene and dried to obtain a deprotected product. 10.7 mL (61.4 mmol) of N, N-diisopropylethylamine was added to a solution of 6 g of the resulting deprotected product in 120 mL of methylene chloride under ice cooling, and then 23.1 mL (163.8 mmol) of trifluoroacetic anhydride was added. It was added dropwise over 10 minutes. After stirring for 1.5 hours under ice-cooling, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (Biotage, ethyl acetate / methanol = 100/0 to 90/10) to quantitatively obtain 7.79 g of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.51-7.44 (2H, m), 7.39-7.28 (3H, m), 5.47 (1H, s), 4.40-4.35 (1H, m), 3.78-3.69 (2H, m), 3.21 (3H, s), 3.22-3.15 (1H, m), 2.64-2.55 (1H, m), 2.14-1.89 (4H, m).
MS (ESI) m / z: 354 [(M + H) ⁺ ].

(Step 3) 4-amino-1-methyl-2-phenyl-5-{[(2R) -1- (2,2,2-trifluoroacetyl) pyrrolidin-2-yl] methyl} pyrazol-3-one Instead of 5- {3- [tert-butyl (dimethyl) silyl] oxy-3-methylcyclobutyl} -1-methylphenylpyrazol-3-one in Step 3 of Example 7, 1-synthesized in Step 2 Methyl-2-phenyl-5-{[(2R) -1- (2,2,2-trifluoroacetyl) pyrrolidin-2-yl] methyl} pyrazol-3-one is reacted in the same manner, The title compound was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.51-7.40 (4H, m), 7.29-7.23 (1H, m), 4.47-4.40 (1H, m), 3.79-3.68 (2H, m), 3.17-3.02 ( 2H, m), 2.91 (3H, s), 2.76-2.67 (1H, m), 2.15-1.87 (4H, m).
MS (ESI) m / z: 369 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 5 of Example 1 and Steps 6 to 7 of Example 26, and the following Examples 74 to 75 were synthesized.

Example 76 5-Chloro-N- [2,2-dimethyl-4-({1-methyl-5-[((5S) -1-methylpyrrolidin-2-yl) methyl] -3-oxo- 2-Phenylpyrazol-4-yl} amino-4-oxobutyl) -2-ethoxybenzamide

(Step 1) 4-amino-1-methyl-2-phenyl-5-{[(2S) -1- (2,2,2-trifluoroacetyl) pyrrolidin-2-yl] methyl} pyrazol-3-one 2-[(2S) -1-tert-butoxycarbonylpyrrolidin-2-yl] acetic acid instead of 2-[(2R) -1-tert-butoxycarbonylpyrrolidin-2-yl] acetic acid in Step 1 of Example 74 Was used in the same manner as in Step 74 of Example 74 to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.49-7.42 (4H, m), 7.30-7.23 (1H, m), 4.46-4.40 (1H, m), 3.78-3.68 (2H, m), 3.19-3.01 ( 2H, m), 2.91 (3H, s), 2.76-2.68 (1H, m), 2.14-1.85 (4H, m).
Thereafter, the reaction was carried out in the same manner as in Step 5 of Example 26 and Step 3 to Step 4 of Example 1, and the following Examples 76 to 78 were synthesized.

Example 79 5-Chloro-N- (2,2-dimethyl-4-{[1-methyl-3-oxo-2-phenyl-5- (2-piperidylmethyl) pyrazol-4-yl] amino} -4-Oxobutyl) -2-ethoxybenzamide hydrochloride

(Step 1) tert-Butyl 2-[(4-amino-2-methyl-5-oxo-1-phenylpyrazol-3-yl) methyl] piperidine-1-carboxylate 3- [of Step 1 of Example 7 Instead of tert-butyl- (dimethyl) silyl] oxy-3-methylcyclobutane carboxylic acid, 2- (1-tert-butoxycarbonyl-2-piperidyl) acetic acid was used. The reaction was carried out in the same manner to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.50-7.40 (4H, m), 7.29-7.21 (1H, m), 4.58-4.48 (1H, br m), 4.10-3.95 (1H, br m), 3.08 ( 2H, br s), 2.96-2.85 (5H, m), 2.64 (1H, dd, J = 14.6, 5.5 Hz), 1.75-1.57 (6H, m), 1.45 (9H, s).
MS (ESI) m / z: 387 [(M + H) ⁺ ].

(Step 2) {[4-({4-[(5-Chloro-2-ethoxybenzoyl) amino] -3,3-dimethylbutanoyl} amino) -2-methyl-5-oxo-1-phenylpyrazole- 3-yl] methyl} piperidine-1-carboxylate tert-butyl tert-butyl 2-[(4-amino-2-methyl-5-oxo-1-phenylpyrazol-3-yl) methyl] synthesized in Step 1 Piperidine-1-carboxylate 0.655 g (1.62 mmol), intermediate 1a 0.575 g (1.83 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′- To a solution of tetramethylronium hexafluorophosphate (HATU) 0.808 g (2.13 mmol) in N, N-dimethylformamide 12 mL was added N, N-dii. Propylethylamine 0.515mL (0.382g, 2.96mmol) was added was stirred for 15 hours at room temperature. To the reaction mixture was added 10 mL of saturated aqueous sodium bicarbonate / 20 mL of water and extracted with ethyl acetate. The organic layer was extracted once with saturated aqueous sodium bicarbonate / water (1: 2), once with water, and 1 with saturated brine. Washed twice and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (Biotage, hexane / ethyl acetate → ethyl acetate / methanol = 50/50 to 0/100 → 100/0 to 93/7). 1.09 g (yield 89.8%) of the compound was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.91 (1H, br s), 8.37 (1H, br t, J = 6.4 Hz), 8.18 (1H, d, J = 2.4 Hz), 7.47-7.36 (5H, m ), 7.29-7.23 (1H, m), 6.91 (1H, d, J = 8.5 Hz), 4.63-4.51 (1H, br m), 4.20 (2H, q, J = 6.9 Hz), 4.07-3.91 (1H , br m), 3.67-3.49 (2H, br m), 3.27-3.13 (4H, br m), 2.88-2.74 (2H, m), 2.29 (1H, s), 2.28 (1H, s), 1.77- 1.57 (6H, m), 1.52 (3H, t, J = 6.7 Hz), 1.45 (9H, s), 1.15 (3H, s), 1.14 (3H, s).

(Step 3) 5-chloro-N- (2,2-dimethyl-4-{[1-methyl-3-oxo-2-phenyl-5- (2-piperidylmethyl) pyrazol-4-yl] amino}- 4-Oxobutyl) -2-ethoxybenzamide hydrochloride {[4-({4-[(5-chloro-2-ethoxybenzoyl) amino] -3,3-dimethylbutanoyl} amino) -2 synthesized in Step 2 -Methyl-5-oxo-1-phenylpyrazol-3-yl] methyl} piperidine-1-carboxylate 1.09 g (1.45 mmol) was dissolved in 4.0 mL of 1,4-dioxane, and 4N hydrochloric acid was dissolved. -1,4-Dioxane 4.0mL was added and it stirred at room temperature for 3.5 hours. To this, 80 mL of 1,4-dioxane was added, and the mixture was further stirred at room temperature for 15 hours. The mixture was stirred at 60 ° C. for 0.5 hour, cooled to 0 ° C., added with 16 mL of 1N aqueous sodium hydroxide solution, neutralized, and extracted with methylene chloride / isopropanol (3: 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was subjected to amino silica gel column chromatography (Biotage, elution solvent; methylene chloride / methanol = 100/0 to 90/10). And purified. The obtained residue was dissolved in ethyl acetate, 4N hydrochloric acid-ethyl acetate (2.0 mL) was added, and the precipitated solid was collected by filtration and dried to give the title compound (0.821 g, yield 97.7%) as a solid. .
¹ H-NMR (DMSO-D ₆ ) δ: 9.23 (1H, s), 9.18 (1H, br d, J = 9.8 Hz), 9.03-8.89 (1H, br m), 8.33 (1H, br t, J = 6.4 Hz), 7.70 (1H, d, J = 2.4 Hz), 7.56-7.47 (3H, m), 7.45-7.39 (2H, m), 7.37-7.30 (1H, m), 7.19 (1H, d, J = 9.2 Hz), 4.17 (2H, q, J = 6.9 Hz), 3.42-3.24 (4H, br m), 3.12 (3H, s), 3.08-3.00 (1H, m), 2.98-2.80 (2H, m), 2.26 (2H, br s), 1.90-1.42 (6H, m), 1.38 (3H, t, J = 7.0 Hz), 1.05 (3H, s), 1.04 (3H, s).
MS (ESI) m / z: 582 [(M + H) ⁺ ].
Thereafter, the following Examples 80 to 82 were synthesized in the same manner as in Step 4 of Example 1 and the present Example.

Example 83 5-Chloro-N- (2,2-dimethyl-4-{[1-methyl-3-oxo-2-phenyl-5- (tetrahydropyran-4-ylmethyl) pyrazol-4-yl] Amino} -4-oxobutyl) -2-ethoxybenzamide

(Step 1) 4-Amino-1-methyl-2-phenyl-5- (tetrahydropyran-4-ylmethyl) pyrazol-3-one Instead of tetrahydrofuran-2-carboxylic acid in Step 1 of Example 39, tetrahydropyran- Using 4-ylacetic acid, the reaction was carried out in the same manner as in Step 39 of Example 39 to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.42-7.48 (4H, m), 7.23-7.26 (1H, m), 4.00 (2H, dd, J = 11.0, 3.7 Hz), 3.37-3.44 (2H, m) , 3.01 (2H, br s), 2.84 (3H, s), 2.48 (2H, d, J = 7.3 Hz), 1.85-1.96 (1H, m), 1.70-1.74 (2H, m), 1.37-1.48 ( 2H, m).
MS (APCI) m / z: 288 [(M + H) ⁺ ]
Thereafter, the reaction was carried out in the same manner as in Step 2 of Example 1, and the following Examples 83 to 84 were synthesized.

Example 85 5-Chloro-N- [4-({5-[((2S) -1,4-dioxan-2-yl) methyl] -1-methyl-3-oxo-2-phenylpyrazole- 4-yl} amino) -2,2-dimethyl-4-oxobutyl] -2-ethoxybenzamide

(Step 1) 2-[(2S) -1,4-dioxan-2-yl] acetonitrile [(2R) -1,4-dioxan-2-yl] methylmethanesulfonate 10.0 g (51.0 mmol) N , N-dimethylformamide (100 ml) and water (10 ml) were added with sodium cyanide (5.15 g, 102 mmol) and stirred at 100 ° C. for 4 hours. Thereafter, the mixture was stirred at 80 ° C. for 6 hours, returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (Biotage, hexane / ethyl acetate = 100 / 0-50 / 50) to give 1.76 g of the title compound ( Yield 27.0%) was obtained as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 3.90-3.70 (5H, m), 3.68-3.59 (1H, m), 3.45-3.37 (1H, m), 2.51 (2H, d, J = 5.5 Hz).
MS (ESI) m / z: 128 [(M + H) ⁺ ].

(Step 2) Ethyl 4-[(2S) -1,4-dioxane-2-yl] -3-oxobutanoate 1.54 g (23.6 mmol) of zinc dust and 0.440 g of 1,2-dibromoethane (2. 36 mmol) was added to 10 ml of tetrahydrofuran, and the mixture was stirred at 60 ° C. for 3 hours. To the reaction mixture, 1.00 g (7.87 mmol) of 2-[(2S) -1,4-dioxane-2-yl] acetonitrile synthesized in Step 1 at room temperature and 0.300 ml (2.36 mmol) of trimethylsilyl chloride were added. A 3 ml solution was added dropwise over 15 minutes. After stirring for 30 minutes at room temperature, a solution of 2.17 ml (19.7 mmol) of ethylbromoacetic acid in 2 ml of tetrahydrofuran was added dropwise to the reaction mixture over 5 minutes. The reaction mixture was refluxed for 2 hours and then filtered through celite. To the filtrate was added 9 ml (9 mmol) of 1N aqueous hydrochloric acid solution, and the mixture was stirred overnight at room temperature. Ethyl acetate was added for extraction, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (Biotage, hexane / ethyl acetate = 100 / 0-60 / 40) to give 1.41 g of the title compound ( Yield 83.0%) was obtained as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 4.20 (2H, q, J = 7.3 Hz), 4.09-4.02 (1H, m), 3.81-3.68 (4H, m), 3.66-3.54 (1H, m), 3.49 (2H, s), 3.35-3.26 (1H, m), 2.74-2.67 (1H, m), 2.56-2.49 (1H, m), 1.28 (3H, t, J = 7.3 Hz).
MS (ESI) m / z: 217 [(M + H) ⁺ ].

(Step 3) 5-[((2S) -1,4-dioxan-2-yl) methyl] -2-phenyl-4H-pyrazol-3-one 4-[(2S) -1, synthesized in Step 2 0.690 g (6.36 mmol) of phenylhydrazine was added to a 6.25 ml toluene solution of 1.25 g (5.78 mmol) of ethyl 4-dioxan-2-yl] -3-oxobutanoate, and the mixture was stirred at 100 ° C. for 6 hours. did. The reaction composition was purified by silica gel column chromatography (Biotage, hexane / ethyl acetate = 100/0 to 0/100), and 1.32 g (yield 87.0%) of the title compound was obtained. Obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.86 (2H, d, J = 7.9 Hz), 7.39 (2H, t, J = 7.9 Hz), 7.18 (1H, t, J = 7.9 Hz), 3.92-3.70 ( 5H, m), 3.66-3.58 (1H, m), 3.54 (2H, d, J = 4.3 Hz), 3.38 (1H, t, J = 10.7 Hz), 2.59 (2H, d, J = 6.1 Hz).
MS (ESI) m / z: 261 [(M + H) ⁺ ].

(Step 4) 5-[((2S) -1,4-dioxan-2-yl) methyl] -1-methyl-2-phenylpyrazol-3-one 5- {3- [of Step 2 of Example 7 tert-Butyl (dimethyl) silyl] oxy-3-methylcyclobutyl} -2-phenyl-4H-pyrazol-3-one instead of 5-[((2S) -1,4-dioxane synthesized in Step 3 2-yl) methyl] -2-phenyl-4H-pyrazol-3-one was used in a similar manner to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.49-7.44 (2H, m), 7.39-7.36 (2H, m), 7.32-7.27 (1H, m), 5.50 (1H, s), 3.93-3.60 (7H, m), 3.09 (3H, s), 2.72-2.56 (2H, m).
MS (ESI) m / z: 275 [(M + H) ⁺ ].

(Step 5) 4-amino-5-[((2S) -1,4-dioxan-2-yl) methyl] -1-methyl-2-phenylpyrazol-3-one 1- of Example 55, Step 3 5-) ([(2S) -1,4-dioxan-2-yl) methyl] -1-methyl-2-phenyl synthesized in Step 4 instead of methyl-2,5-diphenylpyrazol-3-one Thereafter, the reaction was carried out in the same manner as in Step 55 of Example 55 using pyrazol-3-one to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.50-7.41 (4H, m), 7.26-7.22 (1H, m), 3.93-3.39 (7H, m), 2.83 (3H, s), 2.72-2.64 (1H, m), 2.61-2.53 (1H, m).
MS (ESI) m / z: 290 [(M + H) ⁺ ].
Thereafter, the reaction was performed in the same manner as in Step 2 of Example 1, and Example 85 below was synthesized.

Example 86 N- (4-{[5- (azetidin-1-ylmethyl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino} -2,2-dimethyl-4- Oxobutyl) -5-chloro-2-methoxybenzamide

(Step 1) 4-Nitroantipyrine 10 mL of 70% nitric acid was added to 2.00 g (10.6 mmol) of antipyrine, followed by stirring at 70 ° C. for 1.5 hours. After allowing to cool to room temperature, ice water was added to the reaction solution, the precipitated solid was collected by filtration, the solid was washed with a small amount of chloroform, and dried to obtain 1.63 g (65.8%) of the title compound as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 7.60-7.51 (3H, m), 7.42-7.39 (2H, m), 3.69 (3H, s), 2.70 (3H, s).
MS (API) m / z: 234 [(M + H) ⁺ ].

(Step 2) 5- (Bromomethyl) -1-methyl-4-nitro-2-phenylpyrazol-3-one Suspension of 1.11 g (4.76 mmol) of 4-nitroantipyrine synthesized in Step 1 in 25 mL of methylene chloride To the mixture, 0.0174 g (0.0714 mmol) of 1,1′-azobis (cyclohexane-1-carbonitrile) was added, and 0.850 mg (4.76 mmol) of N-bromosuccinimide was added over 1 hour. After stirring at room temperature for 16 hours, 25 mL of methylene chloride was added to make the reaction system uniform, and the mixture was stirred at room temperature for 24 hours. N-bromosuccinimide (0.420 g, 2.38 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution is purified using silica gel column chromatography (Yamazensha, elution solvent; methanol / ethyl acetate = 1/99 to 5/95) to give 1.20 g (yield 80.8%) of the title compound as a solid. Obtained.
¹ H-NMR (DMSO-D ₆ ) δ: 7.63-7.56 (3H, m), 7.48-7.45 (2H, m), 5.08 (2H, s), 3.48 (3H, s).
MS (API) m / z: 312 [(M + H) ⁺ ].

(Step 3) 5- (Azetidin-1-ylmethyl) -1-methyl-4-nitro-2-phenylpyrazol-3-one 5- (Bromomethyl) -1-methyl-4-nitro-2 synthesized in Step 2 -To a solution of 0.624 g (2.00 mmol) of phenylpyrazol-3-one in 10 mL of dichloroethane was added 0.162 mL (0.137 g, 2.40 mmol) of azetidine and 0.419 mL (0.304 g, 3.00 mmol) of triethylamine. And stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (Yamazensha, elution solvent; methanol / ethyl acetate = 1/99 to 25/75) to give 0.221 g (yield) of the title compound. (Rate 38.3%) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.56-7.47 (3H, m), 7.33-7.30 (2H, m), 4.15 (2H, s), 3.55 (3H, s), 3.41 (4H, t, J = 7.1 Hz), 2.16-2.09 (2H, m).

(Step 4) 4-Amino-5- (azetidin-1-ylmethyl) -1-methyl-2-phenylpyrazol-3-one 5- (azetidin-1-ylmethyl) -1-methyl-4 synthesized in Step 3 -To a solution of 0.215 g (0.746 mmol) of nitro-2-phenylpyrazol-3-one in 10 mL of methanol was added 0.100 g of 5% platinum sulfide carbon, and the mixture was stirred at room temperature for 4 and a half hours in a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (Yamazensha, elution solvent; methanol / chloroform = 1/99 to 15/85) to give 0.125 g of the title compound ( Yield 64.9%) was obtained as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.50-7.41 (4H, m), 7.22-7.20 (1H, m), 3.60 (2H, br s), 3.50 (2H, s), 3.28 (4H, t, J = 7.2 Hz), 2.81 (3H, s), 2.14-2.09 (2H, m).
MS (API) m / z: 259 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 2 of Example 1, and Example 86 below was synthesized.

Example 87 5-Chloro-N- [4-({5-[(3-hydroxyazetidin-1-yl) methyl] -1-methyl-3-oxo-2-phenylpyrazol-4-yl} Amino) -2,2-dimethyl-4-oxobutyl] -2-methoxybenzamide

(Step 1) 4-amino-5-({3- [tert-butyl (dimethyl) silyl] oxyazetidin-1-yl} methyl) -1-methyl-2-phenylpyrazol-3-one of Example 86 Using azetidin-3-yloxy-tert-butyldimethylsilane synthesized with reference to US2008 / 214520 A1 instead of azetidine in Step 3, the reaction is carried out in the same manner as in Step 86 of Example 86, and the title compound is converted. Obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 7.50-7.47 (2H, m), 7.44-7.41 (2H, m), 7.25-7.21 (1H, m), 4.46-4.39 (1H, m), 3.73-3.69 ( 2H, m), 3.56-3.54 (4H, m), 2.94-2.88 (2H, m), 2.80 (3H, s), 0.89 (9H, s), 0.05 (6H, s).
MS (API) m / z: 389 [(M + H) ⁺ ].

(Step 2) N- [4-({5-[(3- [tert-butyl (dimethyl) silyl] oxyazetidin-1-yl} methyl) -1-methyl-3-oxo-2-phenylpyrazole- 4-yl] amino) -2,2-dimethyl-4-oxobutyl] -5-chloro-2-methoxybenzamide tert-butyl 3- (4-amino-2-methyl-5-oxo of Example 2, Step 2 4-amino-5-({3- [tert-butyl (dimethyl) silyl] oxyazetidin-1-yl synthesized in Step 1 instead of -1-phenylpyrazol-3-yl) azetidine-1-carboxylate } Methyl) -1-methyl-2-phenylpyrazol-3-one was reacted in the same manner using Intermediate 1b instead of Intermediate 1i to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.63 (1H, s), 8.31 (1H, t, J = 6.9 Hz), 8.18 (1H, d, J = 2.9 Hz), 7.47-7.38 (5H, m), 7.28-7.27 (1H, m), 6.91 (1H, d, J = 9.2 Hz), 4.45-4.40 (1H, m), 3.97 (3H, s), 3.70-3.67 (4H, m), 3.56 (2H, d, J = 6.9 Hz), 3.20 (3H, s), 2.94 (2H, td, J = 6.2, 1.9 Hz), 2.29 (2H, s), 1.13 (6H, s), 0.87 (9H, s), 0.04 (6H, s).
MS (API) m / z: 670 [(M + H) ⁺ ].

(Step 3) 5-Chloro-N- [4-({5-[(3-hydroxyazetidin-1-yl) methyl] -1-methyl-3-oxo-2-phenylpyrazol-4-yl} amino ) -2,2-Dimethyl-4-oxobutyl] -2-methoxybenzamide N- [4-({5-[(3- [tert-butyl (dimethyl) silyl] oxyazetidine-1- synthesized in Step 2) Yl} methyl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino) -2,2-dimethyl-4-oxobutyl] -5-chloro-2-methoxybenzamide 0.190 g (0. To a solution of 283 mmol) in ethanol (10 mL) was added concentrated hydrochloric acid (2.0 mL), and the mixture was stirred at room temperature for 4 hours and a half. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted 3 times with chloroform. The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was purified using silica gel column chromatography (Yamazensha, elution solvent; methanol / chloroform = 1/99 to 5/95) to give 0.051 g of the title compound (yield 32). .4%) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.55 (1H, s), 8.22 (1H, t, J = 6.6 Hz), 8.12 (1H, d, J = 2.3 Hz), 7.46-7.39 (5H, m), 7.30-7.26 (1H, m), 6.93 (1H, d, J = 8.6 Hz), 4.44-4.39 (1H, m), 3.98 (3H, s), 3.75-3.69 (4H, m), 3.59 (2H, d, J = 6.6 Hz), 3.32-3.28 (1H, m), 3.21 (3H, s), 3.11-3.07 (2H, m), 2.31 (2H, s), 1.14 (6H, s).
MS (API) m / z: 556 [(M + H) ⁺ ].
The following Example 88 was synthesized in the same manner.

Example 89 5-Chloro-N- [2,2-dimethyl-4-[[1-methyl-3-oxo-2-phenyl-5- (pyrrolidin-1-ylmethyl) pyrazol-4-yl] amino ] -4-Oxobutyl] -2-methoxybenzamide

(Step 1) 4-Amino-1-methyl-2-phenyl-5- (pyrrolidin-1-ylmethyl) pyrazol-3-one Instead of azetidine in Step 3 of Example 86, pyrrolidine was used, and the following Examples The reaction was conducted in the same manner as in Step 4 to 86 to give the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.51-7.41 (4H, m), 7.25-7.21 (1H, m), 3.56 (4H, s), 2.83 (3H, s), 2.61-2.59 (4H, m) , 1.84-1.82 (4H, m).
MS (API) m / z: 273 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 2 of Example 1, and the following Example 89 was synthesized.

Example 90 5-Chloro-N- [4-({5-[(3-hydroxypyrrolidin-1-yl) methyl] -1-methyl-3-oxo-2-phenylpyrazol-4-yl} amino ) -2,2-Dimethyl-4-oxobutyl] -2-methoxybenzamide (Step 1) 4-Amino-5-({3- [tert-butyl (dimethyl) silyl] oxypyrrolidin-1-yl} methyl)- 1-methyl-2-phenylpyrazol-3-one

Using tert-butyldimethylpyrrolidin-3-yloxysilane synthesized with reference to US2008 / 146565 A1 instead of azetidine in Step 3 of Example 86, the reaction is performed in the same manner as in Step 4 of Example 86. The title compound was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.51-7.49 (2H, m), 7.44-7.41 (2H, m), 7.25-7.21 (1H, m), 4.42-4.38 (1H, m), 3.67-3.49 ( 4H, m), 2.82-2.80 (5H, m), 2.63-2.54 (2H, m), 2.17-2.10 (1H, m), 1.79-1.73 (1H, m), 0.89 (9H, s), 0.05 ( 3H, s), 0.06 (3H, s).
MS (API) m / z: 403 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 2 to Step 3 of Example 87 to synthesize Example 89 below.

Example 91 5-Chloro-N- [4-({5-[(4-hydroxy-1-piperidyl) methyl] -1-methyl-3-oxo-2-phenylpyrazol-4-yl} amino) -2,2-Dimethyl-4-oxobutyl] -2-methoxybenzamide

(Step 1) 4-amino-5-({4- [tert-butyl (dimethyl) silyl] oxy-1-piperidyl} methyl) -1-methyl-2-phenylpyrazol-3-one Step 3 of Example 86 Using tert-butyldimethyl- (4-piperidyloxy) silane synthesized with reference to WO2003 / 103661 A1 in place of azetidine, the reaction was carried out in the same manner as in Step 4 of Example 86, and the title compound was solidified. Got as.
¹ H-NMR (CDCl ₃ ) δ: 7.49-7.48 (2H, m), 7.44-7.41 (2H, m), 7.23 (1H, t, J = 7.4 Hz), 3.76 (1H, s), 3.63 (2H , s), 3.42 (2H, s), 2.81-2.73 (5H, m), 2.31 (2H, s), 1.82-1.78 (2H, m), 1.65-1.58 (2H, m), 0.90 (9H, s ), 0.06 (6H, s).
MS (API) m / z: 417 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 2 to Step 3 of Example 87, and the following Example 91 was synthesized.

Example 92 5-Chloro-N- [2,2-dimethyl-4-[[1-methyl-5- (morpholinomethyl) -3-oxo-2-phenylpyrazol-4-yl] amino] -4 -Oxobutyl] -2-methoxybenzamide

(Step 1) 4-Amino-1-methyl-5- (morpholinomethyl) -2-phenylpyrazol-3-one Instead of azetidine in Step 3 of Example 86, morpholine was used, and Step 4 of Example 86. The reaction was carried out in the same manner as before to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.50-7.42 (4H, m), 7.26-7.23 (1H, m), 3.75 (4H, t, J = 4.6 Hz), 3.59 (2H, s), 3.45 (2H , s), 2.83 (3H, s), 2.55 (4H, s).
MS (API) m / z: 289 [(M + H) ⁺ ].
Thereafter, the following Examples 92 to 94 were synthesized in the same manner as in Step 2 of Example 1.

Example 95 5-Chloro-N- (2,2-dimethyl-4-{[1-methyl-5- (2-morpholinoethyl) -3-oxo-2-phenylpyrazol-4-yl] amino} -4-oxobutyl) -2-methoxybenzamide

(Step 1) 9.90 g (58.1 mmol) of ethyl ethyl malonate 5- (tert-butoxycarbonylamino) -3-oxopentanoate was suspended in 200 mL of acetonitrile, and 5.54 g (58.1 mmol) of magnesium chloride. ) And 8.10 mL (5.88 g, 58.1 mmol) of triethylamine were added and stirred at room temperature for 2 hours. To this, 10.0 g (52.9 mmol) of 3- (tert-butoxycarbonylamino) propionic acid is dissolved in 200 mL of acetonitrile, 9.43 g (58.1 mmol) of carbonyldiimidazole is added, and the mixture is stirred at room temperature for 3 hours. The active ester solution prepared above was added, and the mixture was heated to reflux for 4 hours after the addition. After cooling to room temperature, the reaction mixture was neutralized by adding 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (Shoko Scientific, elution solvent; hexane / ethyl acetate = 95 / 5-50 / 50) to give 13.7 g (yield 99.0%) of the title compound. Was obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 4.99 (1H, br s), 4.20 (2H, q, J = 7.0 Hz), 3.38 (2H, q, J = 5.6 Hz), 2.78 (2H, t, J = 5.6 Hz), 1.43 (9H, s), 1.29 (3H, t, J = 7.0 Hz).
MS (APCI) m / z: 160 [(M-Boc + H) ⁺ ].

(Step 2) tert-Butyl N- [2- (3-oxo-2-phenyl-1H-pyrazol-5-yl) ethyl] carbamate 5- (tert-Butoxycarbonylamino) -3-oxo synthesized in Step 1 13.7 g (52.9 mmol) of ethyl pentanoate was dissolved in 200 mL of toluene, and 5.91 mL (6.49 g, 58.2 mmol) of phenylhydrazine was added. The reaction mixture was heated to reflux for 7.2 hours and then cooled to room temperature. After standing overnight, the mixture was heated to reflux again for 5.8 hours and then cooled to room temperature. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (Shoko Scientific Co., elution solvent; hexane / ethyl acetate = 95 / 5-25 / 75). The product was obtained. This was suspended in diethyl ether, collected by filtration, and further dried under reduced pressure to obtain 14.1 g (yield 87.7%) of the title compound as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 11.51 (1H, br s), 7.72-7.70 (2H, m), 7.43-7.40 (2H, m), 7.23-7.20 (1H, m), 6.88 (1H , t, J = 5.4 Hz), 5.41 (1H, s), 3.19-3.15 (2H, m), 2.57 (2H, t, J = 7.6 Hz), 1.38 (9H, s).
MS (APCI) m / z: 304 [(M + H) ⁺ ].

(Step 3) benzyl 5- [2- (tert-butoxycarbonylamino) ethyl] -3-oxo-2-phenyl-1H-pyrazole-4-carboxylate tert-butyl N- [2- (synthesized in Step 2) 3-oxo-2-phenyl-1H-pyrazol-5-yl) ethyl] carbamate 10.6 g (35.1 mmol) was dissolved in 360 mL of 1,4-dioxane, and 5.72 g (77.2 mmol) of calcium hydroxide was dissolved. added. After the reaction mixture was stirred at 50 ° C. for 0.8 hour, 5.26 mL (6.28 g, 36.8 mmol) of benzyl chloroformate was added under ice cooling. The reaction mixture was stirred at 90 ° C. for 3 hours and then cooled to room temperature. The reaction mixture was acidified by adding water and 5N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (Yamazensha, elution solvent; hexane / ethyl acetate = 57 / 43-0 / 100) to give the title compound 14. 5 g (yield 94.6%) was obtained as an oily substance.
¹ H-NMR (DMSO-D ₆ ) δ: 7.75-7.70 (2H, m), 7.47-7.44 (4H, m), 7.40-7.36 (2H, m), 7.34-7.28 (3H, m), 6.81 ( 1H, t, J = 5.2 Hz), 5.28 (2H, s), 3.27-3.22 (4H, m), 2.84 (2H, t, J = 7.0 Hz), 1.35 (9H, s).
MS (APCI) m / z: 438 [(M + H) ⁺ ].

(Step 4) benzyl 5- [2- (tert-butoxycarbonylamino) ethyl] -1-methyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxylate tert-butyl N- synthesized in Step 3 5.00 g (11.4 mmol) of [2- (3-oxo-2-phenyl-1H-pyrazol-5-yl) ethyl] carbamate is dissolved in 60 mL of methylene chloride, and 1.68 g (14.7 mmol) of potassium acetate and 1.68 mL (2.44 g, 14.9 mmol) of methyl trifluoromethanesulfonate was added and stirred at room temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the layers were separated. The aqueous layer was extracted with methylene chloride, and the combined organic layers were dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (Yamazensha, elution solvent; hexane / ethyl acetate = 57 / 43-0 / 100) to give the title compound 2. 95 g (57.2% yield) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.52-7.47 (4H, m), 7.42-7.38 (1H, m), 7.35-7.25 (5H, br m), 5.34 (2H, s), 4.98 (1H, t , J = 6.5 Hz), 3.46 (2H, q, J = 6.5 Hz), 3.39 (3H, s), 3.26 (2H, t, J = 6.5 Hz), 1.41 (9H, s).
MS (APCI) m / z: 452 [(M + H) ⁺ ].

(Step 5) 5- [2- (tert-Butoxycarbonylamino) ethyl] -1-methyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxylic acid 5- [2- ( tert-butoxycarbonylamino) ethyl] -1-methyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxylate 3.21 g (7.11 mmol) was dissolved in 70 mL of ethanol, and 10% palladium on carbon catalyst. (M type) 2.0 g was suspended. After replacing the inside of the reaction system with hydrogen, the mixture was stirred at room temperature for 1 hour. The reaction system was replaced with nitrogen and filtered, and then the filtrate was concentrated under reduced pressure to obtain 2.48 g (yield 96.5%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.58-7.50 (3H, m), 7.37-7.35 (2H, m), 5.09 (1H, br s), 3.55-3.50 (2H, m), 3.47 (3H, br s), 3.33 (2H, t, J = 5.8 Hz), 1.40 (9H, s).
MS (APCI) m / z: 362 [(M + H) ⁺ ].

(Step 6) tert-Butyl N- [2- (4-amino-2-methyl-5-oxo-1-phenylpyrazol-3-yl) ethyl] carbamate 5- [2- (tert- Butoxycarbonylamino) ethyl] -1-methyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxylic acid 2.48 g (6.86 mmol) was dissolved in 50 mL of N, N-dimethylformamide. 24 mL (0.90 g, 8.92 mmol) and 1.63 mL (2.08 g, 7.55 mmol) of diphenylphosphoric acid azide were added, and the mixture was stirred at room temperature for 1.8 hours. The reaction mixture was added to a mixed solvent of N, N-dimethylformamide / water (35 mL / 35 mL) heated to 100 ° C. over 1.5 hours, and the mixture was further stirred at the same temperature for 1 hour. After cooling to room temperature, sodium bicarbonate was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel chromatography (Yamazensha, elution solvent; hexane / ethyl acetate → ethyl acetate / methanol = 85/15 to 0/100 → 100/0 to 90 / By purification in 10), 1.17 g (yield 51.3%) of the title compound was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.48-7.42 (4H, m), 7.26-7.23 (1H, m), 5.15 (1H, br s), 3.42-3.38 (2H, m), 3.09 (2H, br s), 2.85 (3H, s), 2.77 (2H, t, J = 6.8 Hz), 1.45 (9H, s).
MS (APCI) m / z: 333 [(M + H) ⁺ ].

(Step 7) tert-butyl N- {2- [4-({4-[(5-chloro-2-methoxybenzoyl) amino] 3,3-dimethylbutanoyl} amino) 2-methyl-5-oxo- 1-phenylpyrazol-3-yl] ethyl carbamate tert-butyl N- [2- (4-amino-2-methyl-5-oxo-1-phenylpyrazol-3-yl) ethyl] carbamate 0 synthesized in Step 6 .417 g (1.15 mmol) and 0.31 g (1.27 mmol) of intermediate 1b were dissolved in 5.0 mL of N, N-dimethylformamide and 0.301 mL (0.224 g, 1.73 mmol) of N, N-diisopropylamine was dissolved. And O- (7-azabenzotriazol-1-yl) -N, N, N ′, N ′,-tetramethyluronium hexafluorophosphate 0.570 g (1.50 mmol) of HATU was added and stirred at room temperature for 1.5 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue obtained was subjected to aminosilica-silica gel column chromatography (Biotage, elution solvent; methylene chloride / methanol = 99/1 to 90 / 10). After collecting and concentrating the fraction containing the desired product, the resulting residue was suspended by adding diethyl ether, and the solid was collected by filtration and dried to obtain 0.507 g (yield 71.8%) of the title compound as a solid. Got as.
¹ H-NMR (CDCl ₃ ) δ: 8.95 (1H, s), 8.26 (1H, t, J = 6.3 Hz), 8.19 (1H, d, J = 2.4 Hz), 7.44-7.43 (4H, m), 7.41 (1H, dd, J = 8.8, 2.4 Hz), 7.29-7.26 (1H, m), 6.94 (1H, d, J = 8.8 Hz), 5.72 (1H, t, J = 6.3 Hz), 3.98 (3H , s), 3.60 (2H, d, J = 6.3 Hz), 3.51 (2H, q, J = 6.3 Hz), 3.13 (3H, s), 2.90 (2H, t, J = 6.3 Hz), 2.27 (2H , s), 1.43 (9H, s), 1.11 (6H, s).
MS (ESI + APCI) m / z: 614 [(M + H) ⁺ ].

(Step 8) N- (4-{[5- (2-aminoethyl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino} -2,2-dimethyl-4-oxobutyl) -5-Chloro-2-methoxybenzamide hydrochloric acid tert-butyl N- {2- [4-({4-[(5-chloro-2-methoxybenzoyl) amino] 3,3-dimethylbutanoyl synthesized in Step 7 } Amino) 0.507 g (0.830 mmol) of 2-methyl-5-oxo-1-phenylpyrazol-3-yl] ethylcarbamate was dissolved in 5.0 mL of 1,4-dioxane, and 4N hydrochloric acid-1,4- Dioxane 10.0mL was added and it stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the resulting residue was suspended by adding diethyl ether, and the solid was collected by filtration and dried to obtain 0.460 g of the title compound as a solid quantitatively.
¹ H-NMR (DMSO-D ₆ ) δ: 9.33 (1H, br s), 8.43 (1H, t, J = 6.3 Hz), 8.18-8.15 (3H, br m), 7.69 (1H, d, J = 2.9 Hz), 7.53-7.50 (3H, m), 7.43-7.41 (2H, m), 7.35-7.32 (1H, m), 7.19 (1H, d, J = 8.8 Hz), 3.88 (3H, s), 3.30 (2H, d, J = 6.3 Hz), 3.14-3.10 (5H, m), 2.92 (2H, t, J = 7.8 Hz), 2.26 (2H, s), 1.03 (6H, s).
MS (ESI + APCI) m / z: 514 [(M + H) ⁺ ].

(Step 9) 5-chloro-N- (2,2-dimethyl-4-{[1-methyl-5- (2-morpholinoethyl) -3-oxo-2-phenylpyrazol-4-yl] amino}- 4-oxobutyl) -2-methoxybenzamide N- (4-{[5- (2-aminoethyl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino}-synthesized in Step 8 2,2-dimethyl-4-oxobutyl) -5-chloro-2-methoxybenzamide hydrochloride (0.200 g, 0.363 mmol) was dissolved in 2.0 mL of N, N-dimethylformamide, and 0.0770 g (0. 726 mmol) and 1-chloro-2- (2-chloroethoxy) ethane 0.0511 mL (0.436 mmol), and added at 60 ° C. for 3 hours and 90 ° C. for 2.5 hours. Stir. After standing at room temperature over the weekend, 0.0770 g (0.726 mmol) sodium carbonate sodium and 0.0511 mL (0.0624 g, 0.436 mmol) 1-chloro-2- (2-chloroethoxy) ethane and tetrabutyl iodide 0.0270 g (0.0730 mmol) of ammonium was added, and the mixture was stirred at 70 ° C. for 9 hours and at 90 ° C. for 9 hours. After returning to room temperature, ethyl acetate was added, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the residue obtained by concentrating the filtrate under reduced pressure was purified by amino silica-silica gel column chromatography (Biotage, elution solvent; methylene chloride / methanol = 99/1 to 90/10). The fraction containing the desired product was concentrated under reduced pressure to suspend the residue obtained by adding diethyl ether, and the solid was collected by filtration and dried to give 0.0270 g (yield 12.0%) of the title compound. ) Was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 9.03 (1H, br s), 8.27 (1H, br s), 8.18 (1H, d, J = 2.9 Hz), 7.46-7.40 (4H, m), 7.28-7.26 (2H, m), 6.93 (1H, d, J = 8.8 Hz), 3.98 (3H, s), 3.74 (4H, br s), 3.59 (2H, d, J = 6.8 Hz), 3.12 (3H, br s), 2.88 (2H, br s), 2.74 (2H, br s), 2.55 (4H, s), 2.27 (2H, s).
MS (ESI + APCI) m / z: 584 [(M + H) ⁺ ].

(Example 96 / Example 97) 5-Chloro-N- {4-[(5-{[1- (dimethylamino) cyclopropyl] methyl} -1-methyl-3-oxo-2-phenylpyrazole-4 -Yl) amino] -2,2-dimethyl-4-oxobutyl} -2-ethoxy-4-fluorobenzamide and 5-chloro-N- {4-[(5-{[1- (dimethylamino) cyclopropyl] Methyl} -1-methyl-3-oxo-2-phenylpyrazol-4-yl) amino] -2,2-dimethyl-4-oxobutyl} -2-ethoxy-4-methoxybenzamide

(Step 1) N- (1-benzylcyclopropyl) -2,2,2-trifluoroacetamide 5.73 g (38.9 mmol) of 1-benzylcyclopropanamine synthesized by the method described in WO2006 / 40179 was converted into methylene chloride. Dissolved in 100 mL, 20.3 mL (15.1 g, 116 mmol) of N, N-diisopropylethylamine was added. Under ice-cooling, 6.50 mL (9.81 g, 46.7 mmol) of trifluoroacetic anhydride was added over 15 minutes, and the mixture was further stirred at the same temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was partitioned. The aqueous layer was extracted with methylene chloride. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by filtering and distilling off the filtrate under reduced pressure was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 95 / 5-80 / 20). The title compound (4.61 g, yield 48.7%) was obtained as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.34-7.25 (3H, m), 7.17-7.15 (2H, m), 6.37 (1H, br s), 2.92 (2H, s), 0.97-0.94 (2H, m ), 0.91-0.88 (2H, m).
MS (APCI) m / z: 244 [(M + H) ⁺ ].

(Step 2) 2- {1-[(2,2,2-trifluoroacetyl) amino] cyclopropyl} acetic acid N- (1-benzylcyclopropyl) -2,2,2-trifluoro synthesized in Step 1 Acetamide (4.61 g, 20.0 mmol) was dissolved in a mixed solvent of carbon tetrachloride / acetonitrile / water (30 mL / 30 mL / 45 mL), and this was dissolved in ice with cooling by ruthenium trichloride hydrate (0.390 g, 1.90 mmol). And 20.3 g (94.8 mmol) of sodium periodate were added, and the mixture was stirred at room temperature for 30 minutes. The temperature was raised to 40 ° C., and the mixture was further stirred for 6.5 hours. The mixture was cooled to room temperature, allowed to stand overnight, and stirred again at 40 ° C. for 8 hours. The mixture was cooled to room temperature, allowed to stand for 3 days, and stirred again at 40 ° C. for 10 hours. After cooling to room temperature and filtration through celite, the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by filtering and distilling off the filtrate under reduced pressure was dissolved again in a mixed solvent of carbon tetrachloride / acetonitrile / water (30 mL / 30 mL / 45 mL), and this was dissolved in an aqueous ruthenium trichloride solution under ice cooling. After adding 0.390 g (1.90 mmol) of the Japanese product and 20.3 g (94.8 mmol) of sodium periodate, the mixture was stirred at room temperature for 30 minutes, and further stirred at 40 ° C. for 17 hours. After cooling to room temperature and filtration through celite, the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was distilled off under reduced pressure to obtain 3.14 g (yield 78.5%) of the title compound as a solid.
¹ H-NMR (CD ₃ OD) δ: 9.56 (1H, br s), 4.91 (1H, br s), 2.60 (2H, s), 0.88 (4H, br s).
MS (APCI) m / z: 212 [(M + H) ⁺ ].

(Step 3) N- {1-[(4-Amino-2-methyl-5-oxo-1-phenylpyrazol-3-yl) methyl] cyclopropyl} -2,2,2-trifluoroacetamide Example 39 Instead of the tetrahydrofuran-2-carboxylic acid in Step 1, the 2- {1-[(2,2,2-trifluoroacetyl) amino] cyclopropyl} acetic acid synthesized in Step 2 was used. The reaction was conducted in the same manner up to Step 5 to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.21 (1H, br s), 7.47-7.41 (4H, m), 7.29-7.26 (1H, m), 3.05 (2H, br s), 2.87 (2H, s) , 2.79 (3H, s), 1.05-1.00 (2H, m), 0.98-0.93 (2H, m).
MS (APCI) m / z: 355 [(M + H) ⁺ ].

(Step 4) 5-chloro-N- (2,2-dimethyl-4-{[1-methyl-3-oxo-2-phenyl-5-({1-[(2,2,2-trifluoroacetyl ) Amino] cyclopropyl} methyl) pyrazol-4-yl] amino} -4-oxobutyl) -2-ethoxy-4-fluorobenzamide N- {1-[(4-amino-2-methyl-) synthesized in Step 3 5-oxo-1-phenylpyrazol-3-yl) methyl] cyclopropyl} -2,2,2-trifluoro-acetamide 0.350 g (0.99 mmol) and intermediate 1c 0.360 g (1.09 mmol) , N-dimethylformamide dissolved in 5.0 mL, where O- (7-azabenzotriazol-1-yl) -N, N, N ′, N ′,-tetramethyluronium hexafluorophor 0.563 g (1.48 mmol) of sulfate (HATU) and 0.516 mL (383 mg, 2.96 mmol) of N, N-diisopropylethylamine were added and stirred at room temperature for 19 hours. A saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the residue obtained by distilling off the filtrate under reduced pressure was purified by silica gel column chromatography (Biotage, elution solvent; hexane / 10% methanol-ethyl acetate = 70/30 to 20/80). As a result, 0.601 g (yield 91.1%) of the title compound was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 9.47 (1H, s), 8.63 (1H, s), 8.28-8.22 (2H, m), 7.47-7.43 (2H, m), 7.40-7.38 (2H, m) , 7.31-7.27 (1H, m), 6.81 (1H, d, J = 10.3 Hz), 4.20 (2H, q, J = 6.9 Hz), 3.64 (2H, d, J = 6.7 Hz), 3.12 (3H, s), 3.09 (2H, s), 2.26 (2H, s), 1.55 (3H, t, J = 6.9 Hz), 1.13 (6H, s), 1.07-1.01 (2H, m), 1.00-0.94 (2H , m).
MS (APCI) m / z: 668 [(M + H) ⁺ ].

(Step 5) N- [4-({5-[(1-aminocyclopropyl) methyl] -1-methyl-3-oxo-2-phenylpyrazol-4-yl} amino) -2,2-dimethyl- 4-oxobutyl] -5-chloro-2-ethoxy-4-fluorobenzamide and N- [4-({5-[(1-aminocyclopropyl) methyl] -1-methyl-3-oxo-2-phenylpyrazole -4-yl} amino) -2,2-dimethyl-4-oxobutyl] -5-chloro-2-ethoxy-4-methoxybenzamide 5-chloro-N- (2,2-dimethyl-4 synthesized in Step 4 -{[1-Methyl-3-oxo-2-phenyl-5-({1-[(2,2,2-trifluoroacetyl) amino] cyclopropyl} methyl) pyrazol-4-yl] amino} -4 -Oxo (Butyl) -2-ethoxy-4-fluorobenzamide (0.596 g, 0.89 mmol) is dissolved in methanol (5.0 mL) and tetrahydrofuran (5.0 mL), 1N aqueous sodium hydroxide solution (5.0 mL) is added, and the mixture is stirred at room temperature for 17 hours. Then, it stirred at 50 degreeC for 3 hours. After standing at room temperature overnight, the mixture was further stirred at 50 ° C. for 8.5 hours. The organic solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was distilled off under reduced pressure to obtain 0.460 g of a 1: 1 mixture of the two title compounds as a solid.
MS (APCI) m / z: 572 [(M + H) ⁺ ], 584 [(M + H) ⁺ ].

(Step 6) 5-chloro-N- {4-[(5-{[1- (dimethylamino) cyclopropyl] methyl} -1-methyl-3-oxo-2-phenylpyrazol-4-yl) amino] -2,2-dimethyl-4-oxobutyl} -2-ethoxy-4-fluorobenzamide and 5-chloro-N- {4-[(5-{[1- (dimethylamino) cyclopropyl] methyl} -1- Methyl-3-oxo-2-phenylpyrazol-4-yl) amino] -2,2-dimethyl-4-oxobutyl} -2-ethoxy-4-methoxybenzamide N- [4-({5 -[(1-aminocyclopropyl) methyl] -1-methyl-3-oxo-2-phenylpyrazol-4-yl} amino) -2,2-dimethyl-4-oxobutyl] -5-chloro-2- Toxi-4-fluorobenzamide and N- [4-({5-[(1-aminocyclopropyl) methyl] -1-methyl-3-oxo-2-phenylpyrazol-4-yl} amino) -2,2 -Dimethyl-4-oxobutyl] -5-chloro-2-ethoxy-4-methoxybenzamide (0.455 g) was dissolved in 10 mL of methylene chloride, and 0.887 g (95%, 3.98 mmol) of sodium triacetoxyborohydride was dissolved. And 0.227 mL (3.98 mmol) of acetic acid was added and stirred. To this, 0.316 mL (3.98 mmol) of 37% aqueous formaldehyde solution was added and stirred at room temperature for 2.6 hours. A saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the residue obtained by distilling off the filtrate under reduced pressure was purified by silica gel column chromatography (Biotage, elution solvent; methylene chloride / methanol = 95/5 to 92/8). 5-chloro-N- {4-[(5-{[1- (dimethylamino) cyclopropyl] methyl} -1-methyl-3-oxo-2-phenylpyrazol-4-yl) amino] -2,2 -Dimethyl-4-oxobutyl} -2-ethoxy-4-fluorobenzamide (Example 96) 0.099 g (20.8% yield, 2 steps) and 5-chloro-N- {4-[(5- { [1- (Dimethylamino) cyclopropyl] methyl} -1-methyl-3-oxo-2-phenylpyrazol-4-yl) amino] -2,2-dimethyl-4-oxobutyl} -2-ethoxy 4-methoxybenzamide (Example 97) 0.069 g (yield: 14.2%, 2 steps) of, respectively, as a solid.

Example 96
¹ H-NMR (CDCl ₃ ) δ: 8.80 (1H, br s), 8.30 (1H, d, J = 9.1 Hz), 8.23 (1H, t, J = 6.7 Hz), 7.47-7.43 (2H, m) , 7.38-7.37 (2H, m), 7.30-7.27 (1H, m), 6.78 (1H, d, J = 10.3 Hz), 4.18 (2H, q, J = 7.1 Hz), 3.56 (2H, d, J = 6.7 Hz), 3.10 (5H, s), 2.44 (6H, s), 2.27 (2H, s), 1.54 (3H, t, J = 7.1 Hz), 1.14 (6H, s), 0.66 (2H, br s), 0.65 (2H, br s).
MS (APCI) m / z: 600 [(M + H) ⁺ ].

Example 97
¹ H-NMR (CDCl ₃ ) δ: 9.12 (1H, br s), 7.46-7.42 (2H, m), 7.39-7.37 (2H, m), 7.28-7.25 (1H, m), 6.49 (1H, s ), 4.23 (2H, q, J = 7.1 Hz), 3.94 (3H, s), 3.55 (2H, d, J = 6.7 Hz), 3.10 (5H, s), 2.45 (6H, s), 2.27 (2H , s), 1.55 (3H, t, J = 7.1 Hz), 1.14 (6H, s), 0.72-0.69 (2H, br m), 0.67-0.64 (2H, br m).
MS (APCI) m / z: 612 [(M + H) ⁺ ].
The following Examples 98 to 99 were synthesized in the same manner.

Example 100 N- [4-({5- [2- (azetidin-1-yl) ethyl] -1-methyl-3-oxo-2-phenylpyrazol-4-yl} amino) -2,2 -Dimethyl-4-oxobutyl] -5-chloro-2-ethoxybenzamide

(Step 1) Methyl 2- (5-oxo-1-phenyl-4H-pyrazol-3-yl) acetate Into a solution of 14.8 g (84.7 mmol) of dimethyl 1,3-acetonedicarboxylate in 340 mL of toluene, 8. 33 mL (9.16 g, 84.7 mmol) was added, and the mixture was stirred for 2 and a half hours under heating and reflux using a Dean-Stark apparatus. After allowing to cool to room temperature, the reaction solution is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (Yamazensha, elution solvent; hexane / ethyl acetate = 57 / 43-0 / 100) to give the title compound 18 .1 g (92.2% yield) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.85-7.83 (2H, m), 7.42-7.38 (2H, m), 7.22-7.18 (1H, m), 3.78 (3H, s), 3.64 (2H, s) , 3.61 (2H, s).
MS (ESI) m / z: 233 [(M + H) ⁺ ].

(Step 2) Methyl 2- (2-methyl-5-oxo-1-phenylpyrazol-3-yl) acetate 2- (5-Oxo-1-phenyl-4H-pyrazol-3-yl) synthesized in Step 1 To a solution of 18.1 g (77.9 mmol) of methyl acetate in 25 mL of N, N-dimethylformamide was added 24.3 mL (55.3 g, 390 mmol) of methane iodide, and the mixture was stirred at 100 ° C. for 7 hours in a sealed tube. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate and saturated brine were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate and 3 times with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (Yamazensha, elution solvent; ethyl acetate / methanol = 100/0 to 85/15) to give 14.8 g of the title compound (yield 76. 9%) was obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 7.49-7.29 (5H, m), 5.59 (1H, s), 3.79 (3H, s), 3.62 (2H, s), 3.11 (3H, s).
MS (APCI) m / z: 247 [(M + H) ⁺ ].

(Step 3) Methyl 2- (2-methyl-4-nitro-5-oxo-1-phenylpyrazol-3-yl) acetate 2- (2-Methyl-5-oxo-1-phenylpyrazole synthesized in Step 2 To a solution of 14.8 g (59.9 mmol) of methyl-3-yl acetate in 150 mL of trifluoroacetic acid, 11.6 mL (16.2 g, 180 mmol) of 70% nitric acid was added dropwise at room temperature over 10 minutes, and then 30 mL at room temperature. Stir for minutes. The reaction mixture was poured into ice water and extracted three times with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained solid was suspended in a mixed solution of ethyl acetate and diethyl ether, collected by filtration and dried to obtain 13.1 g (yield 75.1%) of the title compound as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 7.63-7.55 (3H, m), 7.45-7.43 (2H, m), 4.37 (2H, s), 3.71 (3H, s), 3.48 (3H, s) .
MS (APCI) m / z: 292 [(M + H) ⁺ ].

(Step 4) Methyl 2- (4-amino-2-methyl-5-oxo-1-phenylpyrazol-3-yl) acetate 2- (2-methyl-4-nitro-5-oxo- synthesized in Step 3 1-Phenylpyrazol-3-yl) methyl acetate (5.00 g, 17.2 mmol) was added with methanol (120 mL) and N, N-dimethylformamide (40 mL), 10% palladium carbon (containing water) (2.50 g) was added, and hydrogen atmosphere was added. The mixture was stirred at room temperature for 3 hours. After the reaction solution was filtered and concentrated under reduced pressure, the resulting residue was subjected to amino silica gel column chromatography (Yamazensha, elution solvent; hexane / ethyl acetate = 25 / 75-0 / 100 → ethyl acetate / methanol = 100 / 0-90 / 10). After concentration under reduced pressure, the obtained solid was suspended in diethyl ether, collected by filtration, and dried to obtain 3.28 g (yield 73.1%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.49-7.42 (4H, m), 7.28-7.23 (1H, m), 3.78 (3H, s), 3.56 (2H, s), 3.29 (2H, s), 2.85 (3H, s).
MS (APCI) m / z: 262 [(M + H) ⁺ ].

(Step 5) methyl 2- [4- (benzyloxycarbonylamino) -2-methyl-5-oxo-1-phenylpyrazol-3-yl] acetate 2- (4-amino-2-methyl) synthesized in Step 4 To a solution of 2.54 g (9.72 mmol) of methyl 5-oxo-1-phenylpyrazol-3-yl) acetate in 45 mL of methylene chloride was added 2.48 mL (1.88 g, 14.6 mmol) of N, N-diisopropylethylamine. After cooling with ice, 1.67 mL (1.99 g, 11.7 mmol) of benzyl chloroformate was added, and the mixture was stirred at room temperature for 1.5 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted 3 times with methylene chloride. 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 (Yamazensha, elution solvent; methylene chloride / ethyl acetate = 53 / 47-0 / 100). After concentration under reduced pressure, the obtained solid was suspended in diethyl ether, collected by filtration and dried to obtain 2.79 g (yield 72.6%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.49-7.30 (10H, m), 6.40 (1H, s), 5.16 (2H, s), 3.87 (2H, s), 3.75 (3H, s), 3.07 (3H , s).
MS (APCI) m / z: 396 [(M + H) ⁺ ].

(Step 6) 2- [4- (Benzyloxycarbonylamino) -2-methyl-5-oxo-1-phenylpyrazol-3-yl] acetic acid 2- [4- (benzyloxycarbonylamino) synthesized in Step 5 2-methyl-5-oxo-1-phenylpyrazol-3-yl] acetic acid methyl (1.00 g, 2.53 mmol), tetrahydrofuran (15.2 mL), methanol (7.6 mL), 1N aqueous sodium hydroxide (7.59 mL) (7. 59 mmol) was added and stirred at room temperature for 17 hours. After distilling off the organic solvent from the reaction solution under reduced pressure, 1N hydrochloric acid was added to the residue, and the precipitated solid was collected by filtration and dried to obtain 0.846 g (yield 87.7%) of the title compound as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 12.84 (1H, s), 8.64 (1H, s), 7.52 (2H, t, J = 7.9 Hz), 7.38-7.32 (8H, m), 5.08 (2H , s), 3.72 (2H, s), 3.09 (3H, s).
MS (APCI) m / z: 382 [(M + H) ⁺ ].

(Step 7) Benzyl N- (5- {2- [methoxy (methyl) amino] -2-oxoethyl} -1-methyl-3-oxo-2-phenylpyrazol-4-yl) carbamate 2 synthesized in Step 6 -To a solution of 0.381 g (1.00 mmol) of [4- (benzyloxycarbonylamino) -2-methyl-5-oxo-1-phenylpyrazol-3-yl] acetic acid in 10 mL of N, N-dimethylformamide, O-dimethylhydroxyamine hydrochloride 0.195 g (2.00 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU) ) 0.570 g (1.50 mmol), N, N-diisopropylethylamine 0.680 mL (0.517 g, 4.00 mmol) And stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue obtained was purified by silica gel column chromatography (Yamazensha, elution solvent; ethyl acetate / methanol = 100/0 to 85/15) to give 0.465 g of the title compound (yield> 100 %) As a solid. It was used in the next step without further purification.
¹ H-NMR (CDCl ₃ ) δ: 7.47-7.26 (10H, m), 6.40 (1H, s), 5.15 (2H, s), 3.97 (2H, s), 3.64 (3H, s), 3.21 (3H , s), 3.11 (3H, s).
MS (APCI) m / z: 425 [(M + H) ⁺ ].

(Step 8) Benzyl N- {5- [2- (azetidin-1-yl) ethyl] -1-methyl-3-oxo-2-phenylpyrazol-4-yl} carbamate Benzyl N- (synthesized in Step 7 A solution of 0.424 g (1.00 mmol) of 5- {2- [methoxy (methyl) amino] -2-oxoethyl} -1-methyl-3-oxo-2-phenylpyrazol-4-yl) carbamate in 10 mL of tetrahydrofuran was added to ice. After cooling, 5.94 mL (6.00 mmol) of 1.01 mol / L diisobutylaluminum hydride and n-hexane solution was added, stirred for 30 minutes under ice-cooling, and then stirred at room temperature for 30 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted 3 times with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained residue was dissolved in 10 mL of methylene chloride, 0.135 mL (0.114 g, 2.00 mmol) of azetidine was added, and the mixture was stirred for 15 minutes, and then 0.424 g (2 of sodium triacetoxyborohydride) .00 mmol) and 0.114 mL (0.120 g, 2.00 mmol) of acetic acid were added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted 3 times with methylene chloride. The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by amino silica gel column chromatography (Yamazensha, elution solvent; ethyl acetate / methanol = 100/0 to 85/15). After concentration under reduced pressure, the residue was solidified with diethyl ether, and the solid was collected by filtration and dried to obtain 0.146 g (yield 35.9%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.47-7.26 (10H, m), 6.52 (1H, s), 5.17 (2H, s), 3.20 (4H, t, J = 7.0 Hz), 3.05 (3H, s ), 2.68 (4H, s), 2.11-2.04 (2H, m).
MS (APCI) m / z: 407 [(M + H) ⁺ ].

(Step 9) 4-amino-5- [2- (azetidin-1-yl) ethyl] -1-methyl-2-phenylpyrazol-3-one benzyl N- {5- [2- (synthesized in Step 8) Azetidin-1-yl) ethyl] -1-methyl-3-oxo-2-phenylpyrazol-4-yl} carbamate 0.146 g (0.359 mmol) in 10 mL of ethanol was 10% palladium on carbon (containing water). 05 g was added, and the mixture was stirred at room temperature for 2 and a half hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure to obtain 115 mg (yield> 100%) of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.50-7.41 (4H, m), 7.25-7.21 (1H, m), 3.26 (4H, t, J = 7.0 Hz), 2.80 (3H, s), 2.72 (2H , t, J = 6.7 Hz), 2.52 (2H, t, J = 6.7 Hz), 2.14-2.07 (2H, m).
MS (APCI) m / z: 273 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 5 of Example 26 to synthesize Example 100 below.

Example 101 5-Chloro-N- [4-({5-[(3R) -1,3-dimethylpyrrolidin-3-yl] -1-methyl-3-oxo-2-phenylpyrazole-4- Yl} amino) -2,2-dimethyl-4-oxobutyl] -2-ethoxybenzamide

(Step 1) tert-butyl (3R) -3-methyl-1-[(1R) -1-phenylethyl] pyrrolidine-3-carboxylate (3R) -3-methyl synthesized by the method described in WO2006 / 123767 25.8 g (85.1 mmol) of tert-butyl-2-oxo-1-[(1R) -1-phenylethyl] pyrrolidine-3-carboxylate was dissolved in 200 mL of tetrahydrofuran, and a borane-tetrahydrofuran complex (0.95 M tetrahydrofuran). Solution) 200 mL (190 mmol) was added at 0 ° C. over 1.5 hours. Thereafter, the mixture was further stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in 300 mL of methanol, 30 mL of water and 41.3 mL (30.1 g, 298 mmol) of water were added thereto, and the mixture was heated to reflux for 7.5 hours. Water was added to the residue obtained by distilling off the solvent under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the residue obtained by concentrating the filtrate under reduced pressure is purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 95/5 to 75/25) to give the title compound. 21.0 g (yield 85.3%) was obtained as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.33-7.26 (4H, m), 7.23-7.19 (1H, m), 3.19 (1H, q, J = 6.7 Hz), 2.88 (1H, d, J = 9.7 Hz ), 2.68 (1H, td, J = 8.4, 6.5 Hz), 2.46-2.34 (2H, m), 2.31 (1H, d, J = 9.7 Hz), 1.59-1.49 (1H, m), 1.43 (9H, s), 1.32 (3H, d, J = 6.7 Hz), 1.27 (3H, s).
MS (APCI) m / z: 290 [(M + H) ⁺ ].

(Step 2) tert-Butyl (3R) -3-methylpyrrolidine-3-carboxylate (3R) -3-methyl-1-[(1R) -1-phenylethyl] pyrrolidine-3-carboxyl synthesized in Step 1 21.0 g (72.6 mmol) of tert-butyl acid was dissolved in 720 mL of methanol, and 7.73 g of 10% palladium carbon catalyst (M type) was suspended. The reaction system was replaced with hydrogen and stirred at 60 ° C. for 8.5 hours. After cooling to room temperature, the reaction system was purged with nitrogen and filtered. The filtrate was concentrated under reduced pressure to obtain 12.3 g (yield 91.6%) of the title compound as an oily substance.
¹ H-NMR (CD ₃ OD) δ: 3.20 (1H, d, J = 11.5 Hz), 2.93 (2H, t, J = 7.0 Hz), 2.58 (1H, d, J = 11.5 Hz), 2.24-2.17 (1H, m), 1.62-1.56 (1H, m), 1.45 (9H, s), 1.25 (3H, s).
MS (APCI) m / z: 186 [(M + H) +].

(Step 3) tert-Butyl (3R) -3-methyl-1- (2,2,2-trifluoroacetyl) pyrrolidine-3-carboxylate (3R) -3-methylpyrrolidine-3- synthesized in Step 2 12.3 g (66.5 mmol) of tert-butyl carboxylate was dissolved in 500 mL of methylene chloride, and 57.9 mL (42.9 g, 332 mmol) of N, N-diisopropylethylamine was added. To this was added 30 mL of a methylene chloride solution of 13.9 mL (28.2 g, 100 mmol) of trifluoroacetic anhydride at 0 ° C. over 30 minutes, and the mixture was further stirred at 0 ° C. for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture and the layers were separated. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the residue obtained by concentrating the filtrate under reduced pressure is purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 95 / 5-20 / 80) to give the title compound. 17.2 g (92.0% yield) was obtained as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 4.12 (0.6H, d, J = 10.9 Hz), 4.02 (0.4H, d, J = 12.8 Hz), 3.77-3.56 (2H, br m), 3.35 (1H, d, J = 11.5 Hz), 2.48-2.35 (1H, m), 1.92-1.85 (0.4H, m), 1.82-1.75 (0.6H, m), 1.45 (9H, s), 1.35 (3H, 2s) .

(Step 4) (3R) -3-Methyl-1- (2,2,2-trifluoroacetyl) pyrrolidine-3-carboxylic acid (3R) -3-Methyl-1- (2,2) synthesized in Step 3 , 2-trifluoroacetyl) pyrrolidine-3-carboxylic acid tert-butyl (17.2 g, 61.2 mmol) was added with 4M hydrochloric acid-dioxane solution (50 mL, 200 mmol) and stirred at room temperature for 36 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 95/5 to 0/100) to give 12.3 g of the title compound. (Yield 89.5%) Obtained as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 8.28 (1H, br s), 4.18 (0.5H, d, J = 10.9 Hz), 4.12 (0.5H, d, J = 12.8 Hz), 3.83-3.62 (2H, m), 3.46-3.41 (1H, m), 2.57-2.43 (1H, m), 2.02-1.95 (0.5H, m), 1.92-1.85 (0.5H, m), 1.45 (3H, 2 s).
MS (APCI) m / z: 226 [(M + H) +].

(Step 5) 4-amino-1-methyl-5-[(3R) -3-methyl-1- (2,2,2-trifluoroacetyl) pyrrolidin-3-yl] -2-phenylpyrazole-3- On (3R) -3-methyl-1- (2,2) synthesized in Step 4 instead of 1- (2,2,2-trifluoroacetyl) pyrrolidine-3-carboxylic acid in Step 2 of Example 26 , 2-trifluoroacetyl) pyrrolidine-3-carboxylic acid was used to carry out the reaction in the same manner as in Step 26 of Example 26 to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.52-7.50 (2H, m), 7.47-7.43 (2H, m), 7.28-7.24 (1H, m), 4.10-4.08 (0.4, m), 4.03-3.89 ( 2H, m), 3.84-3.72 (1.6H, m), 3.14 (2H, 2br s), 2.85 (3H, 2s), 2.67-2.49 (0.4H, m), 2.42-2.37 (1H, m), 2.28 -2.22 (0.6H, m), 1.47 (3H, s).
MS (APCI) m / z: 369 [(M + H) +].
Thereafter, the reaction was carried out in the same manner as in Step 5 of Example 1 and Steps 6 to 7 of Example 26, and the following Examples 101 to 102 were synthesized.

Example 103 5-Chloro-N- [4-({5- [1- (2-hydroxyethyl) pyrrolidin-3-yl] -1-methyl-3-oxo-2-phenylpyrazol-4-yl } Amino) -2,2-dimethyl-4-oxobutyl] -2-methylbenzofuran-7-carboxamide

(Step 1) N- (4-{[5- (1- {2- [tert-butyl (dimethyl) silyl] oxyethyl} pyrrolidin-3-yl) -1-methyl-3-oxo-2-phenylpyrazole- 4-yl] amino} -2,2-dimethyl-4-oxobutyl) -5-chloro-2-methylbenzofuran-7-carboxamide 5-chloro-N- {2,2-dimethyl-synthesized in Example 23 4-[(1-Methyl-3-oxo-2-phenyl-5-pyrrolidin-3-yl-pyrazol-4-yl) amino] -4-oxobutyl} -2-methylbenzofuran-7-carboxamide 0.390 g (0.691 mmol) is dissolved in 6 mL of methanol and 6 mL of methylene chloride, and 0.618 mL (0 of tert-butyl (dimethyl) silyloxy) acetaldehyde is added. .566 g, 3.46 mmol) was added and stirred at room temperature. To this, 0.733 g (3.46 mmol) of sodium triacetoxyborohydride was added and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by concentrating the filtrate was subjected to amino silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate → ethyl acetate / methanol = 30 / 70-0 / 100 → 100/0 80/20) to obtain 0.469 g (yield 93.9%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.68 (1H, s), 7.94-7.92 (2H, m), 7.55 (1H, d, J = 2.0 Hz), 7.44-7.43 (4H, m), 7.26-7.25 (1H, m), 6.43 (1H, d, J = 1.0 Hz), 3.74 (2H, t, J = 6.1 Hz), 3.69 (2H, t, J = 6.8 Hz), 3.52-3.46 (1H, m) , 3.23 (3H, s), 3.06-3.04 (1H, m), 2.96-2.94 (1H, m), 2.82 (1H, t, J = 9.3 Hz), 2.71-2.66 (1H, m), 2.64-2.59 (1H, m), 2.57-2.55 (1H, m), 2.51 (3H, d, J = 1.0 Hz), 2.33-2.29 (3H, m), 2.15-2.12 (1H, m), 1.19 (6H, s ), 0.87 (9H, s), 0.04 (6H, s).

(Step 2) 5-Chloro-N- [4-({5- [1- (2-hydroxyethyl) pyrrolidin-3-yl] -1-methyl-3-oxo-2-phenylpyrazol-4-yl} Amino) -2,2-dimethyl-4-oxobutyl] -2-methylbenzofuran-7-carboxamide N- (4-{[5- (1- {2- [tert-butyl (dimethyl)) synthesized in Step 1 Silyl] oxyethyl} pyrrolidin-3-yl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino} -2,2-dimethyl-4-oxobutyl) -5-chloro-2-methylbenzofuran -7-Carboxamide 0.467 g (0.646 mmol) was dissolved in methanol 4.0 mL, 4N hydrochloric acid-dioxane 1.0 mL was added, and the mixture was stirred at room temperature for 0.5 hr. The solvent was distilled off under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain 0.352 g (yield 89.5%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.92 (1H, s), 7.94 (1H, d, J = 2.0 Hz), 7.86 (1H, t, J = 6.6 Hz), 7.56 (1H, d, J = 2.0 Hz), 7.46-7.43 (4H, m), 7.29-7.24 (1H, m), 6.43 (1H, s), 3.74-3.66 (3H, m), 3.52-3.45 (1H, m), 3.33 (1H, br s), 3.17 (3H, s), 3.11-3.09 (1H, m), 2.97-2.95 (1H, m), 2.89-2.87 (1H, m), 2.73-2.72 (2H, m), 2.63-2.60 (2H, m), 2.51 (3H, s), 2.36-2.29 (3H, m), 2.25-2.20 (1H, m), 1.21 (3H, s), 1.20 (3H, s).
MS (ESI + APCI) m / z: 608 [(M + H) ⁺ ].

Example 104 N- (5-chloro-2-methoxyphenyl) -N '-(5-cyclopropyl-1-methyl-3-oxo-2-phenylpyrazol-4-yl) -3,3-dimethyl Pentanediamide

(Step 1) 4-Amino-5-cyclopropyl-1-methyl-2-phenylpyrazol-3-one Instead of ethyl 3-oxo-3-phenylpropionate in Step 1 of Example 55, 3-cyclopropyl The reaction was performed in the same manner as in Step 4 of Example 55 using methyl 3-oxopropionate to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.49-7.40 (4H, m), 7.25-7.20 (1H, m), 3.10 (2H, s), 2.93 (3H, s), 1.62-1.55 (1H, m) , 1.02-0.97 (2H, m), 0.89-0.85 (2H, m).
MS (API) m / z: 230 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 2 of Example 1, and Example 104 below was synthesized.

Example 105 5-Chloro-2-ethoxy-N- (4-{[5- (4-fluorophenyl) -1-methyl-2- (6-methyl-2-pyridyl) -3-oxopyrazole- 4-yl] amino} -2,2-dimethyl-4-oxobutyl) benzamide

(Step 1) Methyl 2- (6-chloro-2-pyridyl) -5- (4-fluorophenyl) -1H-pyrazol-3-one 3- (4-fluorophenyl) -3-oxopropanoate 2.00 g (10.2 mmol) was dissolved in 40 mL of ethanol, 1.48 g (10.3 mmol) of (6-chloro-2-pyridyl) hydrazine was added, and the mixture was stirred at room temperature for 19.5 hours. The reaction mixture was concentrated to dryness, then suspended again in 40 mL of ethanol, 1.26 g (11.2 mmol) of potassium tert-butoxide was added at 0 ° C., and the mixture was stirred at 0 ° C. for 15 minutes and at room temperature for 4 hours. did. The reaction mixture was concentrated under reduced pressure, 50 mL of water was added to the residue, 1.0 mL of concentrated hydrochloric acid was added, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure. 2.63 g (yield 89.0%) of the title compound was obtained as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 8.04 (1H, d, J = 7.9 Hz), 7.96 (1H, t, J = 7.9 Hz), 7.85 (2H, dd, J = 8.5, 5.5 Hz), 7.37 (1H, d, J = 7.9 Hz), 7.25 (2H, t, J = 8.9 Hz), 5.81 (1H, br s).
MS (APCI) m / z: 290 [(M + H) ⁺ ]

(Step 2) 2- (6-Chloro-2-pyridyl) -5- (4-fluorophenyl) -1-methylpyrazol-3-one 2- (6-Chloro-2-pyridyl)-synthesized in Step 1 2.63 g (9.08 mmol) of 5- (4-fluorophenyl) -1H-pyrazol-3-one was dissolved in 30 mL of N, N-dimethylformamide, and 5.65 mL (12.9 g, 90.8 mmol) of methyl iodide. ) And stirred at 100 ° C. for 3 hours. After bringing to room temperature, 5.65 mL (12.9 g, 90.8 mmol) of methyl iodide was added, and the mixture was again stirred at 100 ° C. for 6.5 hours. After reaching room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the filtrate was concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 80 / 20-0). / 100) to give 1.37 g (yield 49.7%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.11 (1H, d, J = 8.2 Hz), 7.78 (1H, t, J = 8.2 Hz), 7.65-7.62 (2H, m), 7.24-7.18 (3H, m ), 5.71 (1H, s), 3.31 (3H, s).
MS (APCI) m / z: 304 [(M + H) ⁺ ]

(Step 3) 5- (4-Fluorophenyl) -1-methyl-2- (6-methyl-2-pyridyl) pyrazol-3-one 2- (6-Chloro-2-pyridyl)-synthesized in Step 2 1.37 g (4.51 mmol) of 5- (4-fluorophenyl) -1-methylpyrazol-3-one was dissolved in a mixed solvent of 28 mL of 1,4-dioxane and 2.8 mL of water. Add 87 g (13.5 mmol), 3.90 mL (14.0 mmol) of 3.5 M trimethylboroxine-tetrahydrofuran solution and 0.521 g (0.451 mmol) of tetrakistriphenylphosphine palladium, and add 2 at 100 ° C. under a nitrogen atmosphere. Stir for 5 hours. Water was added to the reaction mixture, the organic solvent was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solid obtained by concentrating the filtrate was suspended in ethyl acetate and collected by filtration to obtain 1.04 g (yield 81.4%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.88 (1H, d, J = 7.9 Hz), 7.72 (1H, t, J = 7.6 Hz), 7.65-7.62 (2H, m), 7.21 (2H, t, J = 8.2 Hz), 7.04 (1H, d, J = 7.3 Hz), 5.72 (1H, s), 3.27 (3H, s), 2.60 (3H, s).
MS (APCI) m / z: 284 [(M + H) ⁺ ]

(Step 4) 4-Amino-5- (4-fluorophenyl) -1-methyl-2- (6-methyl-2-pyridyl) pyrazol-3-one 5- (2-chloro) of Step 2 of Example 62 5- (4-Fluorophenyl) -1-methyl-2- (6-methyl-2-pyridyl) pyrazole synthesized in Step 3 instead of -4-pyridyl) -methyl-2-phenylpyrazol-3-one Thereafter, the reaction was carried out in the same manner as in Step 62 of Example 62 using -3-one to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.96 (1H, d, J = 7.9 Hz), 7.73-7.67 (3H, m), 7.22 (2H, t, J = 8.5 Hz), 7.02 (1H, d, J = 7.9 Hz), 3.43 (2H, br s), 2.98 (3H, s), 2.60 (3H, s).
MS (APCI) m / z: 299 [(M + H) ⁺ ].
Thereafter, the reaction was performed in the same manner as in Step 2 of Example 1, and Example 105 below was synthesized.

[Test Example 1]
ATPase assay of TIP48 / TIP49 complex ATPase assay of TIP48 / TIP49 complex was performed using rTIP48 and rTIP49. Human TIP48 and TIP49 DNA were purchased from Open biosystems. Using the purchased DNA, human TIP48 and TIP49 cDNA cloned by the PCR method were incorporated into an E. coli expression plasmid and expressed in Escherichia coli, thereby obtaining rTIP48 and rTIP49.
The test compound was dissolved to 10 mM using DMSO. The dissolved solution was diluted with DMSO to 10 concentrations from 10 mM to 4-fold dilution.
2x assay buffer (100 mM Tris-HCl, pH 7.5, 100 mM NaCl, 40 mM MgCl2, 2 mM DTT, 20 μM ATP, 0.2 mg / mL BSA) was dispensed in 24.5 μL to each well of a 384 well assay plate.
1 μL of the test compound solution was dispensed into each well, and then the solution in each well was mixed using a plate mixer.
rTIP48 and rTIP49 were diluted to a concentration of 50 μg / mL with sterile water. 24.5 μL of the diluted solution was dispensed into each well of a 384-well assay plate, and then the solution in each well was mixed using a plate mixer (final concentration 24.5 μg / mL) (for each test compound solution). Concentration: 200 μM, 50 μM, 12.5 μM, 3.12 μM, 0.78 μM, 0.20 μM, 0.049 μM, 0.012 μM, 0.003 μM, 0.0007 μM, DMSO concentration 2%).
After mixing using a plate mixer, the assay plate was allowed to stand at room temperature for 1.5 hours.
5 μL of the solution in each well was transferred to a white assay plate, and 5 μL of ADP-Glo Reagent was dispensed into each well from ADP-Glo Kinase Assay (PROMEGA, catalog number V9101) to stop the reaction. Let stand for a minute. Further, 5 μL of Kinase Detection Reagent was dispensed into each well and allowed to stand at room temperature for 30 minutes, and then the amount of luminescence was measured with a plate reader.
ATPase inhibitory activity was calculated by the following formula.
The luminescence level of the well to which the test compound and TIP48 / TIP49 complex were added was A, the luminescence level of the well to which only the TIP48 / TIP49 complex was added was B, and both the test compound and TIP48 / TIP49 complex were added. The issuance amount of the wells that were not present was C, and the ratio (T / C value) between the test compound added group and the test compound non-added group was determined by the following calculation formula.
T / C = 100 × [(AC) / (BC)]
Using each concentration of serially diluted test compound and ATPase inhibitory activity (%) at that concentration, an optimal curve was calculated with GraphPad Prism 4, and the concentration at which ATPase activity was inhibited by 50% (IC50 value) was calculated. The results are shown in Table 50.

[Test Example 2]
Cell growth inhibition test using RAMOS cells A cell growth inhibition test was performed by treating a human lymphoma cell line RAMOS cells (American Type Culture Collection (ATCC) CRL-1596) with a test compound for a certain period of time, followed by MTT assay or CellTiter-Glo Luminescent. This was carried out by measuring the number of viable cells by Cell Viability Assay (Promega, hereinafter referred to as ATP assay).

MTT assay RAMOS cells were suspended in medium (RPMI 1640 medium containing 10% fetal calf serum) and seeded in a 96-well multi-well plate at 5000 cells / 150 μL / well. A test compound was dissolved in DMSO and diluted with a medium to prepare a sample solution (DMSO concentration of 1% or less). Next, 50 μL of a medium or specimen solution to which no test compound was added was added to each well. The MTT assay was performed on the day the sample solution or DMSO dilution was added to the cells and after the sample solution or medium was added to the cells and incubated at 37 ° C., 5% CO ₂ for 3 days. The MTT assay was performed as follows.
5 mg / mL MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide, Sigma, M-2128 using phosphate buffer (Dulbecco's Phosphate-buffered Salines) ) A solution was prepared, and 20 μL of this MTT solution was added to each well. The plates were then incubated for 4 hours at 37 ° C., 5% CO ₂ . After centrifuging the plate at 1200 rpm for 5 minutes, the culture supernatant was removed by suction with a dispenser. DMSO was added in an amount of 150 μL to each well to dissolve the generated formazan. The color of each well was made uniform by stirring the plate using a plate mixer. The absorbance of each well was measured using a plate reader under the conditions of OD 540 nm and reference 660 nm.
Since it was confirmed that the number of living cells and absorbance (hereinafter referred to as OD value) correlated, the cell proliferation rate was calculated by the following formula. Cell proliferation rate of test compound-added well (T / C%) = 100 × [(BC) / (AC)] A: OD value of well not containing test compound (culture last day) B: test compound OD value of wells containing cell (culture last day) C: OD value of wells at the start of cell contact with test compound (on day of cell seeding)
Obtain T / C% at each concentration of the test compound, calculate the concentration of the test compound giving a growth rate of 50% from the growth rate and the concentration at two points across 50% as a 50% growth inhibitory concentration (GI50) value, It is shown in Table 50.
ATP assay RAMOS cells were seeded at 4000 cells / 40 μL / well per well of a 384-well plate in a 384-well plate containing a compound prepared at a predetermined concentration. After cell seeding, the cells were cultured at 37 ° C. and 5% CO 2 for 3 days. On the day of cell seeding and the last day of culture, CellTiter-Glo reagent corresponding to ¼ volume of the culture solution was added and stirred for 2 minutes at room temperature, and the amount of luminescence was measured with a plate reader. Cell viability was calculated by the following formula.
Since it was confirmed that the number of living cells and the amount of luminescence were correlated, the cell proliferation rate was calculated by the following formula. Cell proliferation rate of test compound added well (T / C%) = 100 × [(BC) / (AC)] A: Light emission amount of well not containing test compound (culture last day) B: Test compound Luminescence level of wells containing cells (culture last day) C: Luminescence level of wells at the start of cell contact with test compound (on day of cell seeding)
The T / C% at each concentration of the test compound was determined, and the concentration of the test compound giving a growth rate of 50% was calculated as the GI50 value from the growth rate and concentration at two points across 50%.

[Test Example 3]
Cell growth inhibition test The cell growth inhibition test was carried out by treating a cultured cancer cell line with a test compound for a certain period, and then measuring the number of viable cells with CellTiter-Glo Luminescent Cell Viability Assay (manufactured by Promega).
The following cells were seeded in a 384 well plate containing a compound prepared in advance at a predetermined concentration.
Human bladder cancer cell line T24 (ATCC HTB-96), human breast cancer cell lines MDA-MB-468 (ATCC HTB-132), MCF7 (ATCC HTB-22), HCC1954 (ATCC CRL-2338), MDA-MB-231 (ATCC HTB-26), CAL-51 (DSMZ ACC 302), SK-BR-3 (ATCC HTB-30), BT-20 (ATCC HTB-19) and BT-474 (ATCC HTB-20), human brain tumor Cell lines D283 Med (ATCC HTB-185), A-172 (ATCC CRL-1620), U251 (NCI) and U-138 MG (ATCC HTB-16), human colon cancer cell line HCT 116 (ATCC CCL-247) , RKO (ATCC CRL-2577), COLO 05 (ATCC CCL-222), SW620 (ATCC CCL-227), HT-29 (ATCC HTB-38), HCT-15 (ATCC CCL-225) and SW948 (ATCC CCL-237), human ovarian cancer cell line OVCAR -5 (NCI), RL95-2 (ATCC CRL-1671), ES-2 (ATCC CRL-1978), SK-OV-3 (ATCC HTB-77) and AN3 CA (ATCC HTB-111), human gastric cancer cells Strains SNU-1 (ATCC CRL-5971), NCI-N87 (ATCC CRL-5822) and MKN45 (JCRB0254), human head and neck cancer cell line FaDu (ATCC HTB-43), human kidney cancer cell line 786-O (ATCC) CRL-2932), A-498 (ATCC H TB-44) and ACHN (ATCC CRL-1611), human leukemia cell lines MOLT-3 (ATCC CRL-1611), Kasumi-1 (ATCC CRL-2724), MOLT-4 (ATCC CRL-1582), NALM-6 (DSMZ ACC 128), MV-4-11 (ATCC CRL-9591), CCRF-CEM (ATCC CCL-119) and K-562 (ATCC CCL-243), human multiple myeloma cell line RPMI 8226 (ATCC CCL) -155) and U266B1 (ATCC TIB-196), human lymphoma cell lines RAMOS (ATCC CRL-1596), OCI-LY7 (DSMZ ACC 688), KARPAS 422 (ECACC 06101702) and DOHH-2 (DSMZ) CC 47), human liver cancer cell lines Hep G2 (ATCC HB-8065) and HuH-7 (JCRB0403), human lung cancer cell lines COR-L23 (ECACC 92031919), NCI-H460 (ATCC HTB-177), Calu-6 (ATCC HTB-56), NCI-H1975 (ATCC CRL-5908), DMS 273 (ECACC 9506830), A549 (ATCC CCL-185) and NCI-H146 (ATCCHTB-173), human pancreatic cancer cell line BxPC-3 ( ATCC CRL-1687), CAPAN-2 (ATCC HTB-80) and PANC-1 (ATCC CRL-1469), human prostate cancer cell lines DU 145 (ATCC HTB-81) and PC-3 (ATCC CRL-143) ), Human skin cancer cell lines A-431 (ATCC CRL-1555), COLO 829 (ATCC CRL-1974), A375 (ATCC CRL-1619) and SK-MEL-28 (ATCC HTB-72), human bone soft tissue tumor Cell lines HT-1080 (ATCC CCL-121), U-2 OS (ATCC HTB-96) and SJSA-1 (CRL-2098) were seeded at 200 to 4000 cells per well of a 384 well plate. .
After cell seeding, the cells were cultured at 37 ° C. and 5% CO 2 for 3 days. On the day of cell seeding and the last day of culture, CellTiter-Glo reagent corresponding to ¼ volume of the culture solution was added and stirred for 2 minutes at room temperature, and the amount of luminescence was measured with a plate reader.
Cell viability was calculated by the following formula.
Since it was confirmed that the number of living cells and the amount of luminescence were correlated, the cell proliferation rate was calculated by the following formula. Cell proliferation rate of test compound-added well (T / C%) = 100 × [(BC) / (AC)] A: Luminescence amount of well not containing test compound (culture last day) B: Test compound Luminescence level of wells containing cells (culture final day) C: Luminescence level of wells at the start of cell contact with the test compound (cell seeding day)
Further, T / C% at each concentration of the serially diluted test compound was obtained, and the concentration of the test compound giving a growth rate of 50% from the growth rate and the concentration at two points sandwiching 50% was calculated as a GI50 value. 51.

[Test Example 4]
In vivo test of test compound: Antitumor test using mouse subcutaneous transplantation model Lymphoma strain RAMOS cells were suspended in a culture flask, centrifuged, and the supernatant was removed. The cells were washed twice with PBS (Phosphate Buffered Saline, Life Technologies), suspended in PBS, and 6-week-old SCID mice (FOX CHASE SCID CB17 / Icr-scid / scidJcl, Claire Japan, Inc.). Or CB17 / Icr-Prkdcscid / CrlCrlj, Charles River Japan Co., Ltd.) was transplanted subcutaneously at the right axilla at 1 × 10 ⁷ cells / mouse. Using tumor-bearing mice having an estimated tumor volume (major axis × minor axis × minor axis / 2) of 200-350 mm ³ , distribute the tumor-bearing mice so that there is no significant difference from the negative control group in the average value of the estimated tumor volume And tested. The compound of the Example shown in Table 57 was suspended in 0.5% methylcellulose aqueous solution, and the tumor diameter was measured the next day after oral administration twice a day (BID) at 150 or 100 mg / kg for 4 days.
Also in the above test, the tumor growth inhibition rate was calculated by the following formula and shown in Table 57.
Table 52 shows the results of tumor growth inhibition rate (%) (= 100− (mean value of tumor volume in test compound administration group) / (mean value of tumor volume in solvent administration group) × 100).

  The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is useful as a therapeutic agent for tumors because it has an excellent inhibitory effect on the ATPase activity of the TIP48 / TIP49 complex.

Claims (14)

Formula (I)

[Where:
R ¹ is a hydrogen atom, a C ₁ -C ₆ alkyl group that may have 1 to 3 substituents independently selected from the following group A, and a substituent 1 independently selected from the following group A. A C _{2 to} C ₆ alkenyl group which may have 1 to 3 or a C _{2 to} C ₆ alkynyl group which may have 1 to 3 substituents independently selected from the following group A;
Z is a single bond, or _C 1 -C ₃ represents an alkylene group,
R ² may have 1 to 3 heteroatoms in the ring independently selected from the group consisting of a C _{3 to} C ₆ cycloalkyl group, a phenyl group, a nitrogen atom, an oxygen atom, and a sulfur atom. 5-membered ring which may have 1 to 3 heteroatoms independently selected from the group consisting of 3-membered to 7-membered aliphatic heterocyclic groups or nitrogen, oxygen and sulfur atoms Or a 6-membered aromatic heterocyclic group,
The C _{3 to} C ₆ cycloalkyl group and the phenyl group may have 1 to 5 substituents independently selected from the following group B, and the 3- to 7-membered aliphatic heterocyclic ring And the 5-membered or 6-membered aromatic heterocyclic group may have 1 to 3 substituents independently selected from the following group B,
R ³ represents a hydrogen atom, a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkoxy group,
R ⁴ and R ⁵ are each independently a hydrogen atom, a hydroxyl group, a halogen atom, a C ₁ -C ₆ alkyl group optionally having 1 to 3 halogen atoms, a C ₁ -C ₆ alkoxy group, or C Represents a _{1 to} C ₆ alkylcarbonyloxy group, or
R ⁴ and R ⁵ are a combination of R ⁴ and R ⁵ together with a 3- to 6-membered cycloalkyl ring, or
A 5-membered or 6-membered aliphatic heterocyclic ring which may have 1 to 3 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom may be formed ,
W is the following W ^{1 to} W ³

Indicates one of
R ⁶ may have a phenyl group optionally having 1 to 5 substituents independently selected from the following group E, and may have 1 to 3 substituents independently selected from the following group E 5 to 6 member which may have 1 to 3 hetero atoms independently selected from the group consisting of a good C _{3 to} C ₇ cycloalkyl group or a nitrogen atom, an oxygen atom and a sulfur atom An aromatic heterocyclic group of
The 5-membered or 6-membered aromatic heterocyclic ring may have 1 to 4 substituents independently selected from the following group E,
R ⁷ represents a hetero atom independently selected from the group consisting of a phenyl group, a nitrogen atom, an oxygen atom, and a sulfur atom, which may have 1 to 5 substituents independently selected from the following group F: 1 to 3 heteroatoms independently selected from the group consisting of a 5- or 6-membered aromatic heterocyclic group, nitrogen atom, oxygen atom and sulfur atom which may have 1 to 3 in the ring Or an 8- to 10-membered bicyclic aromatic heterocyclic group optionally having 3 or 3 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in the ring An aliphatic heterocyclic group in which a part of the 8- to 10-membered bicyclic ring optionally having 1 to 3 is unsaturated,
The 5-membered or 6-membered aromatic heterocyclic group, the 8-membered to 10-membered bicyclic aromatic heterocyclic group, and an aliphatic heterocyclic group in which a part of the bicyclic ring is unsaturated May have 1 to 4 substituents independently selected from Group F below. ]
Or a pharmacologically acceptable salt thereof.

Group A: _hydroxyl, C 1 -C ₆ alkoxy group, amino _group, C 1 -C ₆ alkylamino group, di _C 1 -C ₆ alkylamino group, a nitrogen atom, an oxygen atom, and more independently the group consisting of sulfur atoms 5-membered or 6-membered aliphatic heterocyclic group B which may have 1 to 3 heteroatoms in the ring: halogen atom, hydroxyl group, —NR ^2a R ^2b , —CONR ^2c R ^2d , 1 to 3 C ₁ -C ₆ alkyl groups optionally having 1 to 3 substituents independently selected from the following group C, ₁ to 3 substituents independently selected from the following group D C ₁ -C ₆ alkoxy group, optionally having 1 to 3 substituents independently selected from group D below C ₁ -C ₆ alkoxycarbonyl group, independently selected from group C below C _1- which may have 1 to 3 substituents C ₆ alkylcarbonyl groups R ^2a and R ^2b each independently have a hydrogen atom, a C ₁ -C ₆ alkyl group optionally having 1 to 3 substituents independently selected from the following group C, C ₁ -C ₆ alkylcarbonyl group optionally having 1 to 3 substituents independently selected from Group C, or 1 to 3 substituents independently selected from Group D below It shows good _C 1 -C ₆ alkoxycarbonyl group optionally,
R ^2c and R ^2d each independently represent a hydrogen atom or a C ₁ -C ₆ alkyl group.
Group C: halogen atom, hydroxyl group, phenyl group Group D: may have 1 to 3 heteroatoms in the ring independently selected from the group consisting of halogen atom, phenyl group, oxygen atom and sulfur atom 5 Membered or 6-membered aromatic heterocyclic group E group: halogen atom, C ₁ -C ₆ alkyl group optionally substituted by 1 to 3 halogen atoms, C ₁ -C ₆ alkoxy group F group: halogen atom , _hydroxyl, C 1 -C ₆ alkyl group, 1 to 3 of which may be substituted with a halogen atom _C 1 -C ₆ alkoxy _group, C 1 -C ₆ alkoxy _C 1 -C ₆ alkyl _{group, C} 3 ~ C ₆ cycloalkoxy group, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy group In the formula (I),
The compound or pharmacologically acceptable salt thereof according to claim ₁ , wherein R ¹ represents a C _{1 to} C ₆ alkyl group. In the formula (I),
Z represents a single bond or a methylene group;
R ² may have 1 or 2 heteroatoms independently selected from the group consisting of a C _{3 to} C ₆ cycloalkyl group, a phenyl group, a nitrogen atom and an oxygen atom in the ring. Member aliphatic heterocyclic group, or pyridyl group,
The C ₃ -C ₆ cycloalkyl group, the 4-membered to 6-membered aliphatic heterocyclic group, and the pyridyl group may have one substituent independently selected from Group G below. Item 3. The compound according to Item 1 or 2, or a pharmacologically acceptable salt thereof.
Group G: halogen atom, a hydroxyl group, one _C 1 may be substituted with a hydroxyl -C ₆ alkyl _group, C 1 -C ₆ alkoxy group, amino _group, C 1 -C ₆ group, di _C 1 ~ C ₆ amino group In the formula (I),
W is W ¹ or W ² below

The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein In the formula (I),
R ⁶ represents a phenyl group or a pyridyl group optionally substituted with a methyl group,
The compound according to any one of claims 1 to 4, or a pharmacologically acceptable salt thereof. In the formula (I),
R ⁷ represents the following formula (II) or (III)

(Where
R ⁷¹ represents a halogen atom,
R ⁷² represents a hydrogen atom, a halogen atom, or a C ₁ -C ₆ alkoxy group,
R ⁷³ represents a C ₁ -C ₆ alkoxy group, or a C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy group,
R ⁷⁴ represents a C ₁ -C ₆ alkyl group,
V represents a nitrogen atom or CH)
The compound according to any one of claims 1 to 5, or a pharmacologically acceptable salt thereof. Formula (IV)

[Where:
R ⁸ represents a phenyl group, a pyridyl group, a cyclopropyl group, a cyclopentyl group, a cyclobutyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a tetrahydrofuryl group, a tetrahydropyryl group, a dioxanyl group, or a morpholinyl group,
The phenyl group may be substituted with one substituent selected from the group consisting of an amino group and a dimethylamino group,
The pyridyl group may be substituted with one methyl group,
The cyclopropyl group, the cyclopentyl group, and the cyclobutyl group may have one or two substituents independently selected from the group consisting of a hydroxyl group, a methyl group, a methoxy group, and a dimethylamino group,
The azetidinyl group, the pyrrolidinyl group, the piperidinyl group, the tetrahydrofuryl group, the tetrahydropyryl group, the dioxanyl group, and the morpholinyl group may be substituted with one C ₁ -C ₃ alkyl group ,
R ⁹ represents a halogen atom,
R ¹⁰ represents a hydrogen atom or a halogen atom,
R ¹¹ represents an ethoxy group or a methoxymethoxy group,
T represents a single bond or a methylene group;
U represents a nitrogen atom or CH. ]
Or a pharmacologically acceptable salt thereof. Any one compound chosen from the following group, or its pharmacologically acceptable salt.
5-chloro-N- (2,2-dimethyl-4-{[1-methyl-5- (1-methylazetidin-3-yl) -3-oxo-2-phenylpyrazol-4-yl] amino} -4-oxobutyl) -2-ethoxybenzamide,
5-chloro-2-ethoxy-4-fluoro-N- (4-{[5- (3-hydroxycyclobutyl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino} -2 , 2-dimethyl-4-oxobutyl) benzamide,
5-chloro-2-ethoxy-N- (4-{[5- (3-methoxycyclobutyl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino} -2,2-dimethyl -4-oxobutyl) benzamide,
5-chloro-N- (2,2-dimethyl-4-{[1-methyl-5- (1-methylpyrrolidin-3-yl) -3-oxo-2-phenylpyrazol-4-yl] amino}- 4-oxobutyl) -2-ethoxypyridine-3-carboxamide,
5-Chloro-N- (2,2-dimethyl-4-{[1-methyl-5-((3S) -1-methylpyrrolidin-3-yl) -3-oxo-2-phenylpyrazol-4-yl Amino} -4-oxobutyl) -2-ethoxybenzamide,
5-Chloro-N- (2,2-dimethyl-4-{[1-methyl-5-((3R) -1-methylpyrrolidin-3-yl) -3-oxo-2-phenylpyrazol-4-yl] Amino} -4-oxobutyl) -2-ethoxybenzamide,
5-chloro-N- (2,2-dimethyl-4-{[1-methyl-5- (1-methyl-3-piperidyl) -3-oxo-2-phenylpyrazol-4-yl] amino} -4 -Oxobutyl) -2-ethoxybenzamide,
5-chloro-N- (2,2-dimethyl-4-{[1-methyl-5- (4-methylmorpholin-2-yl) -3-oxo-2-phenylpyrazol-4-yl] amino}- 4-oxobutyl) -2-ethoxybenzamide,
5-chloro-N- {2,2-dimethyl-4-[(1-methyl-3-oxo-2-phenyl-5-tetrahydrofuran-3-yl-pyrazol-4-yl) amino] -4-oxobutyl} 2-ethoxybenzamide,
5-chloro-N- {2,2-dimethyl-4-[(1-methyl-3-oxo-2-phenyl-5-tetrahydrofuran-3-ylpyrazol-4-yl) amino] -4-oxobutyl}- 2- (methoxymethoxy) benzamide,
5-Chloro-N- {2,2-dimethyl-4-[(1-methyl-3-oxo-2-phenyl-5-tetrahydropyran-3-yl-pyrazol-4-yl) amino] -4-oxobutyl } -2-Ethoxybenzamide,
5-Chloro-N- {2,2-dimethyl-4-[(1-methyl-3-oxo-2-phenyl-5-tetrahydropyran-4-yl-pyrazol-4-yl) amino] -4-oxobutyl } -2-Ethoxybenzamide,
5-chloro-N- (4-{[5- (1,4-dioxan-2-yl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino} -2,2-dimethyl -4-oxobutyl) -2-ethoxybenzamide,
N- (4-{[5- (4-aminophenyl) -1-methyl-3-oxo-2-phenylpyrazol-4-yl] amino} -2,2-dimethyl-4-oxobutyl) -5-chloro 2-ethoxybenzamide,
5-chloro-N- (2,2-dimethyl-4-{[1-methyl-3-oxo-2-phenyl-5- (3-pyridyl) pyrazol-4-yl] amino} -4-oxobutyl)- 2- (methoxymethoxy) benzamide,
5-chloro-N- {4-[(5-{[1- (dimethylamino) cyclopropyl] methyl} -1-methyl-3-oxo-2-phenylpyrazol-4-yl) amino] -2,2 -Dimethyl-4-oxobutyl} -2-ethoxy-4-fluorobenzamide,
5-chloro-N- {4-[(5-{[1- (dimethylamino) cyclopropyl] methyl} -1-methyl-3-oxo-2-phenylpyrazol-4-yl) amino] -2,2 -Dimethyl-4-oxobutyl} -2-ethoxybenzamide,
5-chloro-N- {4-[(5-{[1- (dimethylamino) cyclopropyl] methyl} -1-methyl-3-oxo-2-phenylpyrazol-4-yl) amino] -2,2 -Dimethyl-4-oxobutyl} -2-ethoxypyridine-3-carboxamide A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof as an active ingredient. An ATPase activity inhibitor of a TIP48 / TIP49 complex comprising the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof as an active ingredient. The antitumor agent which uses the compound of any one of Claims 1 thru | or 8, or its pharmacologically acceptable salt as an active ingredient. Tumor is bladder cancer, breast cancer, brain tumor, colon cancer, ovarian cancer, stomach cancer, head and neck cancer, kidney cancer, leukemia, multiple myeloma, lymphoma, liver cancer, lung cancer, pancreatic cancer, prostate cancer, skin cancer, or bone The antitumor agent of Claim 11 which is a soft tissue tumor. A therapeutic agent for a tumor in which the expression level of TIP48 / TIP49 complex is increased, comprising the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof as an active ingredient. The therapeutic agent of the tumor which can be treated by inhibiting the ATPase activity of TIP48 / TIP49 complex which uses the compound of any one of Claims 1 thru | or 8, or its pharmacologically acceptable salt as an active ingredient. .